There is a huge need to search for new treatment options and potential biomarkers of therapeutic response to antidepressant treatment. Depression and metabolic syndrome often coexist while pathophysiological overlap, including microbiota changes, may play a role. The aim of the study is to assess the effect of probiotic supplementation on symptoms of depression, anxiety and stress, metabolic parameters, inflammation and oxidative stress markers, and faecal microbiota in adult patients with depressive disorders depending on the co-occurance of MetS. The trial will be a four-arm, parallel group, prospective, randomized, double-blind, controlled design that will include 200 participants and will last 20 weeks. The probiotic preparation will contain Lactobacillus helveticus Rosell®-52, Bifidobacterium longum Rosell®-175. We will assess the level of depression, anxiety and stress, quality of life, blood pressure, body mass index and waist circumference, white blood cells count, serum levels of C-reactive protein, HDL cholesterol, triglicerides, fasting glucose, faecal microbiota composition and the level of some faecal microbiota metabolites, as well as inflammation markers and oxidative stress parameters in serum. The trial may establish a safe and easy-to-use treatment option as an adjunct in a subpopulation of depressive patients only partially responsive to pharmacologic treatment. (ClinicalTrials.gov identifier: ).

Two new zoanthamine alkaloids, namely 3-acetoxynorzoanthamine (1) and 3-acetoxyzoanthamine (2), have been isolated from the zoantharian Zoanthus cf. pulchellus collected off the coast of the Peninsula of Santa Elena – Ecuador, together with three known alkaloids zoanthamine, norzoanthamine and 3-hydroxynorzoanthamine. The chemical structures of 1 and 2 were determined by interpretation of their 1D and 2D NMR data and comparison with literature data. This is the first report of zoanthamine-type alkaloids from Zoanthus cf. pulchellus collected in the Tropical Eastern Pacific. The neuroinflammatory activity of all the isolated compounds were evaluated in microglia BV-2 cells and high inhibitory effects were observed in ROS and NO generation.

In the modern world, the problem of antibiotic therapy is acute. Despite the diversity of existing antibiotic drugs, their efficacy decreases as new, resistant forms of pathogenic microorganisms emerge. It is extremely difficult to control such processes and even more difficult to treat severe bacterial infections. In such situations, an individual approach to each patient is required and physicians need parameters to estimate the efficacy of antibiotic therapy. This review discusses the significance of monitoring the content of antibiotics in the blood for this purpose, in combination with the content of inflammatory markers, such as C-reactive protein and procalcitonin. The basic principles of antibiotic therapy, and factors in the resistance of microorganisms to antibiotics, are examined. Approaches to assess the efficacy of antibiotic therapy, as well as methods to detect antibiotics and inflammatory markers in the blood of patients, and comparative assessment of their capabilities and limitations, are described.

Coronavirus disease of 2019 (COVID-19) is the clinical manifestation of the respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While primarily recognized as a respiratory disease, it is clear that COVID-19 is systemic illness impacting multiple organ systems. One defining clinical feature of COVID-19 has been the high incidence of thrombotic events. The underlying processes and risk factors for the occurrence of thrombotic events in COVID-19 remain inadequately understood. While severe bacterial, viral or fungal infections are well recognized to activate the coagulation system, COVID-19 associated coagulopathy is likely to have unique mechanistic features. Inflammatory-driven processes are likely primary drivers of coagulopathy in COVID-19, but the exact mechanisms linking inflammation to dysregulated hemostasis and thrombosis are yet to be delineated. Cumulative findings of microvascular thrombosis has raised question if the endothelium and microvasculature should be a point of investigative focus. Von Willebrand Factor (VWF) and its protease, ADAMTS13 play important role in the maintenance of microvascular hemostasis. In inflammatory conditions, imbalanced VWF-ADAMTS13 characterized by elevated VWF levels and inhibited and/or reduced activity of ADAMTS13 has been reported. Also, an imbalance between ADAMTS13 activity and VWF antigen is associated with organ dysfunction and death in patients with systemic inflammation. A thorough understanding of VWF-ADAMTS13 interactions during early and advanced phases of COVID-19 could help better define the pathophysiology, guide thromboprophylaxis and treatment and improve clinical prognosis.

Background and objectives: Diabetes mellitus is a disease of insulin deficiency or its inability of usage by the target tissues leading to impairment of carbohydrate, lipid, and protein metabolisms. Resveratrol, having robust anti-inflammatory and anti-oxidant properties, has a high potential to treat or prevent the pathogenesis of diseases. This study was conducted to reveal the relationship between diabetes-induced oxidative stress and tissue inflammation with changes in main enzymatic antioxidants (cat, sod, gpx, and gst) and the components of the insulin signaling pathway (insulin Rβ, irs-1, pi3k, akt, mtor) in kidney tissues. Additionally, the effects of resveratrol on these parameters were evaluated. Materials and Methods: Male Wistar rats were randomly divided into four groups; (1) control/vehicle; (2) control/20 mg/kg resveratrol; (3) diabetic/vehicle; (4) diabetic/20 mg/kg resveratrol. Gene and protein expressions of antioxidant enzymes and insulin signaling elements were evaluated in renal tissues. Results: Downregulation of antioxidant enzymes’ gene expression in the kidney tissues of diabetic rats was demonstrated and this situation was devoted partially to the reduced gene expression of nfκb. Moreover, the components of renal insulin signaling elements were upregulated at both gene and protein expression levels in diabetic rats, and resveratrol treatment decreased this sensitization towards the control state. Conclusion: Resveratrol partially improved diabetes-induced renal oxidative stress and inflammation due to healing action on renal antioxidant enzymes and insulin signaling pathway components.

Background: The UK dairy sheep industry is relatively small but growing, particularly for cheese and yogurt products. Anecdotally, sheep milk (SM) is better tolerated by humans than cows’ milk and could have environmental as well as health benefits. All milk contains sub-micron particles called extracellular vesicles (EV) which are mainly derived from the mammary epithelium. Physiologically, milk derived EV are thought to aid development of infant immunity and the microbiome but may also have health benefits to adult humans. Methods: Using sequential ultracentrifugation vesicles of <1µm (LEV) followed by <200nm (sEV) were isolated from six individual sheep during mid lactation. RNA was extracted and microRNA analysed by RTqPCR for sequences previously identified in cows’ milk. Human THP-1 monocytes were differentiated into macrophages and incubated with SM-derived LEV and sEV in the presence of pro-inflammatory LPS to measure effects on secretion of the chemokine CCL-2 or in the presence of DMNQ and fluorescent dihydrorhodamine-1,2,3 to measure reactive oxygen species. Results: LEV induced an increase in ROS in both monocytes and macrophages, whilst sEV decreased DMNQ-mediated ROS in macrophages but not monocytes. Interestingly, the LEV did not induce CCL2 release, however they increased LPS-induced CCL2 secretion in monocytes but not macrophages. miR26a, miR92a, miR125b, miR155, miR223, were identified in both sEV and LEV by RT-qPCR and could be responsible for modulation of ROS and CCL2 expression. Conclusions: These findings suggest that sheep milk can influence human monocyte/macrophage responses and so is worthy of further investigation for its potential human and non-human animal health benefits.

Doxorubicin (DOX) is an incessantly used chemotherapeutic drug that can cause detrimental dose-dependent effects such as cardiotoxicity and congestive heart failure. Hence, there is a need to discover innovative therapeutic approaches to counteract DOX-induced cardiotoxicity (DIC). MSC-Exos have shown to reduce apoptosis and cardiac fibrosis and promote cardiomyocyte proliferation in myocardial infracted mice. However, the effect of MSC-Exos on ameliorating DOX-induced pyroptosis has not been investigated. In this current study H9c2 were first exposed to DOX to stimulate pyroptosis, followed by subsequent treatment with MSC-Exos, with further analysis performed through immunocytochemistry, western blotting, and RT-PCR. Our data depicted that post-treatment with MSC-Exos significantly (p<0.05) reduced the HMGB1/TLR4 axis, inflammasome formation (NLRP3), pyroptotic markers (caspase-1, IL-1β, and IL-18), and the pyroptotic executioner (GSDMD) in DOX-treated H9c2 cells. In conclusion, our data shows that MSC-Exos attenuates inflammation-induced pyroptosis in our in vitro DIC model. Our findings indicate that MSC-Exos may serve as a promising therapeutic intervention for mitigating DIC, as they maintain the therapeutic capabilities of MSCs while circumventing the drawbacks associated with traditional stem cell therapy.

Mangoes have a unique nutrient profile (carotenoids, polyphenols, sugars, vitamins) that we hypothesized would mitigate post-exercise inflammation. This study examined the effects of mango ingestion in moderating exercise-induced inflammation in a randomized crossover trial with 22 cyclists. In random order with trials separated by a 2-week washout period, the cyclists ingested 330 g/day mangoes with 0.5 liters water or 0.5 liters water alone for 2 weeks, followed by a 2.25-h cycling bout challenge. Blood and urine samples were collected pre- and post-2 weeks supplementation, with additional blood samples collected immediately post-exercise, and then 1.5-h, 3-h, and 24-h post-exercise. Urine samples were analyzed for targeted mango-related metabolites. The blood samples were analyzed for 67 oxylipins that are upstream regulators of inflammation and other physiological processes. After 2-weeks mango ingestion, three targeted urine mango-related phenolic metabolites were significantly elevated compared to water alone (interaction effects, p≤0.003). Significant post-exercise increases were measured for 49 oxylipins, but various subgroup analyses showed no differences in the pattern of change between trials (all interaction effects, p>0.150). The 2.25-h cycling bouts induced significant inflammation but no countermeasure effect was found after 2-weeks mango ingestion despite the elevation of mango gut-derived phenolic metabolites.

Increased insulin levels may support the development of neural circuits involved in cognition, while chronic mild inflammation may also result in cognitive impairment. This study aimed to gain more insight into whether cognition is impacted already during adolescence in a genetic rat model for obesity and type 2 diabetes. Cognitive functioning throughout adolescence and early adulthood was investigated in Zucker Diabetic Fatty (ZDF), ZDF lean and healthy outbred Long Evans rats using operant touchscreens. Blood glucose, insulin and lipids were longitudinally analyzed. Histological analyses were performed in the liver, white adipose tissues and the prefrontal cortex. Adolescent ZDF obese rats outperformed lean rats on visual discrimination performance. During the longitudinal cognitive testing period, insulin levels sharply increased over weeks in ZDF obese rats and were significantly enhanced from 6 weeks of age onwards. Early signs of liver steatosis and enlarged adipocytes in white adipose tissue were observed in ZDF early adult obese rats. Histological analyses at early adulthood showed no group differences in the number of prefrontal cortex neurons and microglia, nor PSD95 and SIRT1 mRNA expression levels. Together, our data show that adolescent obese ZDF rats even display enhanced cognition despite their early diabetic profile.

Interleukin (IL)-23 is a central proinflammatory cytokine with a broad range of effects on immune responses. The pathological consequences of excessive IL-23 signaling have been linked to its ability to promote the production of inflammatory mediators such as IL-17, IL-22 by stimulating the differentiation and proliferation of T helper type 17 (Th17 cells). Emerging evidence suggests a potential pro-fibrotic role for IL-23 in the development of chronic inflammatory autoimmune diseases characterized by intense fibrosis. In this review, we summarized the biological features of IL-23 and gathered recent research on the role of IL-23 in fibrotic autoimmune conditions, which could provide a theoretical basis for clinical targeting and drug development.

Anastomotic leakage (AL) after the creation of a gastrointestinal (GI) anastomosis remains an important complication in GI surgery. From its introduction more than 60 years ago, Cyanoacrylate (CA) has gained popularity in colorectal surgery to provide “prophylaxis” against AL. However although in surgical practice it is increasingly used, evidences on humans are still lacking. The aim of this study is to evaluate in humans the safety of CA to seal colorectal anastomosis. All consecutive patients from Jannuary 2022 through December 2022 who underwent minimally invasive colorectal surgery were retrospectively analysed from a prospectively maintained database. Inclusion criteria were histological diagnosis of cancer, totally minimally invasive procedure and absence of intraoperative complications. 103 patients were included in the study, N-butyl cyanoacrylate with metacryloxisulfolane (Glubran 2 ®) was used to seal colorectal anastomosis, no adverse reactions to CA or postoperative complications related to inflammation and adhesions occurred, only one case of AL (0.9%) was recorded. We can consider this study an important proof of concept on safety of CA to seal colorectal anastomosis. It opens the possibility to start performing prospective and comparative studies in humans to evaluate effectiveness of CA in preventing colorectal AL.

The lethal combination involving TB and HIV, known as 'syndemic’ diseases synergistically act upon one another to magnify the disease burden. Individuals on ART are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). The underlying inflammatory complication includes the rapid restoration of immune responses following ART eventually leading to exaggerated inflammatory responses to MTB antigens. TB-IRIS continues to be a cause of morbidity and mortality among HIV/TB coinfected patients initiating ART, and although significant quantum of knowledge has been acquired on the pathogenesis of IRIS, the underlying pathomechanisms and identification of a sensitive and specific diagnostic markers still remain a grey area of investigation. Here, we reviewed the latest research developments in IRIS immunopathogenesis, and outlined the modalities to prevent and manage strategies for better clinical and diagnostic outcomes for IRIS.

Ranolazine (Rn) is a drug used to treat persistent chronic coronary ischemia. It has also been shown to have therapeutic benefits on the central nervous system and an anti-diabetic effect by lowering blood glucose levels and however, no effects of Rn on cellular sensitivity to insulin (Ins) have been demonstrated yet. The present study aimed to investigate the permissive effects of Rn on the actions of Ins in astrocytes in primary culture. Ins at 10-8 M, Rn (10-6 M) and Ins+Rn (10-8 M and 10−6 M respectively) were added to astrocytes during 24 h. In comparison to control cells, Rn and/or Ins caused modifications in cell viability and proliferation. p-AKT, p-ERK, p-eNOS, Mn-SOD, COX-2, and the anti-inflammatory protein COX-2 were all upregulated by ins. On the contrary, no significant changes were found in the protein expression of Cu/Zn-SOD, NF-κB and IκB. The presence of Rn produced an increase in p-ERK protein and a significant decrease in COX-2 protein expression. Furthermore, Rn significantly increased the effects of Ins on the expression of p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ. On the other hand, Rn+Ins produced a significant decrease in COX-2 expression. In conclusion, Rn facilitated the effects of insulin on the p-AKT, p-eNOS, p-ERK, Mn-SOD and PPAR-γ, signaling pathways, as well as on the anti-inflammatory and antioxidant effects of the hormone.

HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in brain specimens of HAND donors. Immunoblot revealed CB1 and CB2 were differentially expressed in frontal cortices from HAND brains compared to neurocognitively unimpaired (NUI) brains from PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution on neuronal processes of NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.

Ulcerative colitis (UC) is a relatively frequent, chronic disease that impacts significantly the patient’s quality of life. Although many therapeutic options are available, additional approaches are needed because many patients either do not respond to current therapies or show significant side effects. Cardiotrophin-1 (CT-1) is a cytokine with potent cytoprotective, anti-inflammatory, and antiapoptotic properties. The purpose of this study was to assess if the administration of CT-1 could reduce colon damage in mice with experimental UC. UC was induced with 5% dextran sulfate sodium (DSS) in the drinking water. Some mice received i.v. dose of CT-1 (200 µg/kg) 2 hours before and 2 and 4 days after DSS administration. Animals were followed during 7 days after DSS. The severity of UC was measured by standard scores. Colon damage was assessed by histology and immunohistochemistry. Inflammatory mediators were measured by Western blot and PCR. CT-1 administration to DSS-treated mice ameliorated both the clinical course (disease activity index), histological damage, inflammation (colon expression of TNF-α, IL-17, IL-10, INF-γ, and iNOS), and apoptosis. Our results suggest that CT-1 administration before UC induction improves the clinical course, tissue damage and inflammation degree in DSS-induced UC in mice.

Atherosclerosis is a chronic inflammatory disease which results in thickening of the vessel wall and narrowing of the lumen. It is a leading cause of death worldwide. Preventive treatment is taken into prioritized consideration since currently no effective approaches to cure atherosclerosis are available. These treatments mainly focus on lowering blood cholesterol levels, especially LDL-C, by statins. Even so, lowering lipid levels is not sufficient to reduce the risk of cardiovascular events in all patients. Recently, atherosclerosis has increasingly been recognized as a chronic inflammatory disease involving the immune system, initiating new therapeutic approaches which could alleviate or prevent atherosclerosis by modulating inflammation. Mesenchymal stem cells (MSCs) have emerged as a promising option to relieve inflammation and balance immune responses in inflammatory diseases. Several studies including our group also reported that MSCs may be a new therapeutic option for atherosclerosis. This review summarizes the updated state of our knowledge in the administration of MSCs to alleviate atherosclerosis and discusses some of the key unresolved challenges that need to be solved in future studies.

Rationale: Major depressive disorder (MDD) is characterized by signaling aberrations in interleukin (IL)-6, IL-10, beta-endorphins as well as mu (MOR) and kappa (KOR) opioid receptors. Here we examined whether these biomarkers may aid in the classification of unknown subjects into the target class MDD.Methods: The aforementioned biomarkers were assayed in 60 first-episode, drug-naïve depressed patients and 30 controls. We analyzed the data using joint principal component analysis (PCA) performed on all subjects to check whether subjects cluster by classes; support vector machine (SVM) with 10-fold validation; and linear discriminant analysis (LDA) and SIMCA performed on calibration and validation sets and we computed the figures of merit and learnt from the data. Results: PCA shows that both groups were well separated using the first three PCs, while correlation loadings show that all 5 biomarkers have discriminatory value. SVM and LDA yielded an accuracy of 100% in validation samples. Using SIMCA there was a highly significant discrimination of both groups (model-to-model distance=87.5); all biomarkers showed a significant discrimination and modeling power, while 10% of the patients were identified as outsiders and no aliens could be identified.Discussion: We have delineated that MDD is a distinct class with respect to neuro-immune and opioid biomarkers and that future unknown subjects can be authenticated as having MDD using this SIMCA fingerprint. Precision psychiatry should employ SIMCA a) to authenticate patients as belonging to the claimed target class and identify other subjects as outsiders, members of another class or aliens; and b) to acquire knowledge through learning from the data by constructing a biomarker fingerprint of the target class.

Acute inflammation is a physiological response to injury or infection, with a cascade of steps that ultimately leads to recruitment of immune cells to clear invading pathogens and heal wounds. However, chronic inflammation arising from continued presence of the initial trigger, or dysfunction of signalling and/or effector pathways, is harmful to health. While successful ageing in older adults including centenarians is associated with low levels of inflammation, elevated inflammation increases the risk of poor health and death [1–3]. Hence inflammation has been described as one of seven pillars of ageing. Age-associated sterile, chronic, and low-grade inflammation is commonly termed inflammageing - it is not simply a consequence of increasing chronological age, but is also a marker of biological ageing, multimorbidity and mortality risk. While inflammageing was initially thought to be caused by “continuous antigenic load and stress”, reports from the last two decades describe a much more complex phenomenon also involving cellular senescence and ageing of the immune system. In this review, we explore the sources and consequences of inflammageing and highlight potential interventions. In particular, we assess the contribution of cellular senescence to age-associated inflammation, identify patterns of pro- and anti-inflammatory markers characteristic of inflammageing, describe alterations in the ageing immune system that lead to elevated inflammation, and finally assess the ways that diet, exercise and pharmacological interventions can reduce inflammageing and thus improve later life health.

Chronic kidney disease (CKD) affects worldwide 8-16% of the population. In developed countries, the most important risk factors for CKD are diabetes, hypertension and obesity, calling into question the importance of educating and acting on lifestyles and nutrition. A balanced nutrition and supplementation can indeed support the maintenance of a general health status, including preservation of renal function, and help to manage and curb the main risk factors for renal damage. While the concepts of protein and salt restriction in nephrology are historically acknowledged, the role of some nutrients on renal health and the importance of nutrition as a preventative measure for renal care are less known. In this review, we provide an overview of the demonstrated and potential actions of some selected nutrients, nutraceuticals and xenobiotics on renal health and function. The effects on kidney of fibres, proteins, fatty acids, curcumin, steviol glycosides, green tea, coffee, nitrates, nitrites, and alcohol, both direct and indirect, in CKD and non-CKD condition, are reviewed here. In a view of a functional and personalized nutrition, understanding the renal and systemic effects of dietary components is essential since many chronic conditions and CKD are related to systemic dysfunctions such as chronic low-grade inflammation.

: Cytokine storm is usually described as one of the main reasons behind COVID-associated mor-tality. Cytokines are essential protein molecules engaged in immune responses; they play a critical role in protection against infections. However, they also contribute to inflammatory reactions and tissue damage, becoming a double-edged sword in the context of COVID-19. Recent studies have suggested various cytokines and chemokines that play a crucial role in the immune response to SARS-CoV-2 infection. One such cytokine is Interleukin 27 (IL-27), which has been found to be elevated in the blood plasma of patients with COVID-19. Within this study, we will explore the role of IL-27 in immune responses and address our own findings concerning this cytokine in COVID-19. It affects a wide variety of immune cells; regardless of the pathological process it is involved in, IL-27 is critical for upholding the necessary balance between tissue damage and cytotoxicity against in-fectious agents and/or tumors. In COVID-19, it is involved in multiple processes, including antiviral cytotoxicity via CD8+ cells, IgG subclass switching, and even the activation of Tregs.

Male infertility (MI) involves various endogenous and exogenous facts. These include oxidative stress (OS), which is known to alter several physiological pathways and it is estimated to be present at high levels in up to 80 % of infertile men. That is why since the late 20th Century, the relationship between OS and MI has been widely studied. New terms have emerged, such as Male Oxidative Stress Infertility (MOSI), which is proposed as a new category to define infertile men with high OS levels. Another important term is MOXI: Male, Antioxidants, and Infertility. Such term refers to the hypothesis that antioxidants could improve male fertility without the use of assisted reproductive technology. However, there is no evidence-based antioxidant treatments that directly improve seminal parameters or birth ratio. In this regard, there is controversy about their use. While certain scientists argue against their use due to the lack of results, others support this use because of their safety profile and low price. Some uncertainties related to the use of antioxidants for treating MI are their questionable efficacy or the difficulties to know their correct dosage. In addition, the lack of quality methods for OS detection can lead to an excessive antioxidant supplementation, resulting in “reductive stress”. Another important problem is that, although the inflammatory process is interdependent and closely linked to OS, it is usually ignored. To solve these uncertainties, new trends have recently emerged. These include the use of molecules with anti-inflammatory and antioxidant potential, and which are also able to specifically target the reproductive tissue; as well as the use of new methods that allow for reliable quantification of OS and a quality diagnosis. This review aims to elucidate the main uncertainties about MOXI and to outline the latest trends in research to achieve effective therapies with clinically relevant outcomes.

Colistin is used in treatment against gram-negative bacteria. It causes toxic effects due to oxidative stress in a dose-dependent manner. Naringin is a flavonoid with strong antioxidant properties found naturally in many plants, especially citrus fruits. This study aimed to determine the protective effects of NRG in CLS-induced sciatic nerve injury. Thirty-five male Spraque rats were randomly divided into five groups: control, NRG, CLS, CLS+NRG50, and CLS+NRG100. CLS was administered orally at a 15mg/kg for seven days. NRG was administered orally at 50 or 100 mg/kg for seven days. CLS caused toxic damage in sciatic nerve tissue by increasing MDA and decreasing antioxidant capacity (SOD, CAT, GPx, and GSH); increasing NF-κB, TNF-α, nNOS release; increasing apoptotic factor (Caspase-3); decreasing HO-1 and nCAM; and inducing 8-OHdG, MAPK and GFAP. NRG, on the other hand, reversed all these changes in sciatic nerve tissue and reduced CLS-induced oxidative stress damage, inflammatory damage and apoptotic damage. These effects were more effective at the 100mg/kg dose of NRG than at the 50mg/kg dose. In sciatic nerve tissue, CLS-induced sciatic nerve toxicity with increased oxidative stress, inflammation, and apoptotic damage. NRG showed a protective effect against CLS-induced sciatic nerve toxicity.

This randomized trial compared pea protein, whey protein, and water-only supplementation on muscle damage, inflammation, delayed onset of muscle soreness (DOMS), and physical fitness test performance during a 5-day period after a 90-minute eccentric exercise bout in non-athletic, non-obese males (n=92, ages 18-55 years). The two protein sources (0.9 g protein/kg divided into three doses/day) were administered under double blind procedures. The eccentric exercise protocol induced significant muscle damage and soreness, and reduced bench press and 30-second Wingate performance. Whey protein supplementation significantly attenuated post-exercise blood levels for biomarkers of muscle damage compared to water-only, with large effect sizes for creatine kinase and myoglobin during the 4th and 5th days of recovery (Cohen's d >0.80); pea protein versus water supplementation had an intermediate, non-significant effect (Cohen's d <0.50); and no significant differences between whey and pea protein were found. Whey and pea protein compared to water supplementation had no significant effects on post-exercise DOMS and the fitness tests. In conclusion, high intake of whey protein for 5 days after intensive eccentric exercise mitigated efflux of muscle damage biomarkers, with intake of pea protein having an intermediate effect in part due to the 24% lower leucine amino acid content.

(1) Background: This study aimed to evaluate the implications of IL-31 in the pathogenesis of chronic spontaneous urticaria (CSU) and to assess the differences that occur between its serum values compared to controls. Additionally, the serum IL-31 levels were measured alongside other clinical and paraclinical parameters identified in the patients to understand its immunological importance in this skin disease and to determine if it could potentially serve as a therapeutic target in CSU in the future. (2) Methods: The serum levels of IL-31 were estimated in 50 patients diagnosed with CSU according to the international guidelines. Additionally, 38 controls who had not experienced any episodes of urticaria during their lifetime were included. (3) Results: Our data have shown higher serum levels of IL-31 in CSU patients compared to controls. A correlation between the serum level of IL-31 and other inflammatory markers, such as ERS, CRP, or serum eosinophils and total IgE was not identified. On the other hand, statistically significant differences were found in IL-31 serum values in UCS patients depending on the severity of the disease, its impact on the patients' quality of life, the severity of itching, and the response to H1 antihistamines. (4) Conclusions: In the present study, IL-31 did not change directly with non-specific inflammation, nor with eosinophilic inflammation or atopy. However, its expression was modified in CSU depending on major characteristics of the disease: severity, pruritus, and response to H1 antihistamines. The focus on the pathogenesis of CSU is of indisputable significance since any additional information in understanding the mechanisms of this disease can open doors to new therapeutic targets. This is particularly important considering that the available therapies are deficient, incomplete, and the remaining symptoms are uncontrolled in many cases.

Background: Physiosomatic symptoms are an important part of schizophrenia phenomenology. The aim of this study is to examine the biomarker, neurocognitive and symptomatic correlates of physiosomatic symptoms in schizophrenia. Methods: We recruited 115 schizophrenia patients and 43 healthy controls and measured the Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) scale, schizophrenia symptom dimensions, and the Brief Assessment of Cognition in Schizophrenia. We measured neuro-immune markers including plasma CCL11 (eotaxin), interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box 1 protein (HMGB1) and endogenous opioid system (EOS) markers including κ-opioid receptor (KOR), µ-opioid receptor (MOR), endomorphin-2 (EM2) and β-endorphin. Results: Patients with an increased FF score display increased ratings of psychosis, hostility, excitement, formal though disorders, psychomotor retardation and negative symptoms as compared with patients with lower FF scores. A large part of the variance in the FF score (55.1%) is explained by the regression on digit sequencing task, token motor task, list learning, IL-10, age (all inversely) and IL-6 (positively). Neural network analysis shows that the top-6 predictors of the FF score are (in descending order): IL-6, HMGB1, education, MOR, KOR and IL-10. We found that 45.1% of the variance in a latent vector extracted from cognitive test scores, schizophrenia symptoms and the FF score was explained by HMGB-1, MOR, EM2, DKK1, and CCL11. Conclusions: FF symptoms are an integral part of the phenome of schizophrenia. Neurotoxic immune and neurodegenerative pathways and to a lesser extent the EOS appear to drive FF symptoms in schizophrenia.

Inotodiol, a lanostane-type triterpenoid, and many phytochemicals from Chaga mushroom have been investigated for various allergic diseases. However, antiaging and anti-inflammatory activities of inotodiol under different types of oxidative stress and impact of inotodiol on collagen and hyaluronan synthesis are not sufficiently studied. Lanostane triterpenoids-rich concentrate, which contained 10% inotodiol as major (the inotodiol concentrate), was prepared from Chaga and compared with pure inotodiol in terms of anti-inflammatory activities on a human keratinocyte cell line, HaCaT cells, under various stimulation such as stimulation with ultraviolet (UV) B or tumor necrosis factor (TNF)-α. In stimulation with TNF-α, interleukin (IL)-1β, IL-6, and IL-8 genes were significantly repressed by 0.44~4.0 μg/mL of pure inotodiol. UVB irradiation induced overexpressions of pro-inflammatory cytokines, but those genes were significantly suppressed by pure inotodiol or inotodiol concentrate. Moreover, pure inotodiol/inotodiol concentrate could also modulate synthesis of collagen and hyaluronic acid by controlling COL1A2 and HAS2/3 expression, which implies a crucial role of pure inotodiol/inotodiol concentrate in prevention of skin aging. These results enlighten anti-inflammatory and anti-aging effect of pure inotodiol/inotodiol concentrate, and it is highly conceivable that pure inotodiol and inotodiol concentrate could be promising natural bioactive substances to be incorporated in therapeutic and beautifying applications.

Objective: About a third of schizophrenia patients are treatment-resistant to antipsychotic therapy. No studies established the fingerprints or pathway-phenotypes of treatment-resistant schizophrenia. The present study aimed to delineate the pathway-phenotypes of non-responders (NRTT) and partial responders (PRTT) to treatment using machine learning. Methods: We recruited 115 schizophrenia patients and 43 healthy controls and measured schizophrenia symptom dimensions, neurocognitive tests, plasma CCL11, interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box-1 protein (HMGB1), κ- and µ-opioid receptors (KOR and MOR, respectively), endomorphin-2 (EM-2), and β-endorphin. Results: Machine learning showed that the NRTT group is a qualitatively distinct class and is significantly discriminated from PRTT with an accuracy of 100% using a neuro-immune-opioid-cognitive (NIOC) pathway-phenotype with as main determinants list learning, controlled word association, and Tower of London test scores, CCL11, IL-6, and EM2. The top-5 symptom domains separating NRTT from PRTT were in descending order: psychomotor retardation, negative symptoms, psychosis, depression, and mannerism. Moreover, a NIOC pathway also discriminated PRTT from healthy controls with an accuracy of 100% while all PRTT and controls were authenticated as belonging to their respective classes. Conclusion: A non-response to treatment with antipsychotics is determined by increased severity of specific symptom profiles coupled with deficits in executive functions, and episodic and semantic memory, and aberrations in neuro-immune and opioid pathways. No patients showed complete remission after treatment indicating that non-remitting in PRTT is attributable to increased HMGB1 and residual deficits in attention, executive functions, and semantic memory.

Hesperidin is a major flavonoid isolated from citrus fruits that exhibits several biological activities. This study aims to evaluate the effect of hesperidin on cardiovascular remodeling induced by N-nitro L-arginine methyl ester (L-NAME) in rats. Male Sprague-Dawley rats were treated with L-NAME (40 mg/kg); L-NAME plus hesperidin (15 mg/kg), or hesperidin (30 mg/kg), or captopril (2.5 mg/kg) for five weeks (n = 8/group). Hesperidin or captopril significantly prevented the development of hypertension in L-NAME rats. Moreover, hesperidin or captopril alleviated L-NAME-induced cardiac remodeling; increases in wall thickness, cross sectional area (CSA) and fibrosis of left ventricular (LV), and vascular remodeling; increases in wall thickness, CSA, vascular smooth muscle cells and collagen deposition in the aorta. These were associated with reduced oxidative stress markers, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1) and enhancing plasma nitric oxide metabolite (NOx) in L-NAME treated groups. Furthermore, up-regulation of tumor necrosis factor receptor type 1 (TNF-R1) and TGF-β1 protein expression and the over-expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) were suppressed in L-NAME rats treated with hesperidin or captopril. These data suggested that hesperidin had cardioprotective effects in L-NAME hypertensive rats. The possible mechanism may involve its antioxidant and anti-inflammatory effects.

In this review paper, the latest literature on the functional properties of phospholipids in relation to inflammation and inflammation-related disorders has been critically appraised and evaluated. The paper is divided into three sections: Section one addresses the relationship between the anti-inflammatory bioactivities of different phospholipids in relation to their structures and compositions. Sections two and three are dedicated to the structures, functions and anti-inflammatory properties of dietary phospholipids from animal and marine sources. Most of the dietary phospholipids of animal origin come from meat, egg and dairy products. To date, there is very limited work published on meat phospholipids, undoubtedly due to the negative perception that meat consumption is an unhealthy option due to its putative associations with several chronic diseases. These assumptions are addressed with respect to the phospholipid composition of meat products. Recent research trends indicate that dairy phospholipids possess anti-inflammatory properties, which has led to an increased interest into their molecular structures and reputed health benefits. Finally, the structural composition of phospholipids of marine origin is discussed. Extensive research has been published in relation to ω-3 polyunsaturated fatty acids (PUFAs) and inflammation, however this research has recently come under scrutiny and has proved to be unreliable and controversial in terms of the therapeutic effects of ω-3 PUFA, which are generally in the form of triglycerides and esters. Therefore, this review focuses on recent publications concerning marine phospholipids and their structural composition and related health benefits. Finally, the strong nutritional value of dietary phospholipids are highlighted with respect to marine and animal origin and avenues for future research are discussed.

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spirals down to immune cell activation and chronic state of low‐level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback-loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.

Cadaver bone is possibly the most common transplant material used today. Common types of cadaver bone transplants are freeze dried bone allografts and xenografts. In the case of freeze dried bone allograft transplants, it was theorized that these materials mineralize by way of osteoinduction and stimulating osteogenesis. However, these theories have been proven false. It has been proposed that these materials mineralize via osteoconduction however, there are no studies to support this hypothesis. This study was undertaken to determine how these transplants mineralize and what type of bone they produce. Materials and Methods: This study is a histological analysis of human cadaver bone graft healing from the incipient stages of mineralization through completed mineralization. All cadaver bone grafts used for evaluation in this study were particulate bone graft materials in the maxilla or mandible. No block grafts were evaluated. Results: The mineralization of cadaver bone transplants was produced by an inflammatory response to the transplanted tissue. The histologic findings of the mineralized bone produced by this process was sclerotic bone. No resorption of cadaver bone graft particles was found. When loaded the sclerotic bone was found to fail through an accumulation of microfractures.Conclusions: Particulate freeze-dried bone allografts and xenografts do not heal via the normal processes of mineralization. Cadaver bone grafts produce significant inflammation and are hypothesized to mineralize by a process termed antigenic ossification. The process of antigenic ossification produces sclerotic bone that is not capable of self-repair which can ultimately lead to bone failure.

Anxiety disorders manifest in women more than in men by almost twofold. This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing on the interactions of sex and tryptophan/serotonin with anxiety.A literature search was conducted using Google Scholar, PubMed/MEDLINE, Scopus, and EMBASE databases from inception until December 31, 2017. This review shows that sex may interact with many serotonin functions thereby modulating anxiety, including 5-HT1A and 5-HT2C receptors, 5-HT transporter and central 5-HT concentrations and metabolism. Sex-steroids modulate the expression of serotonin transporter genes, creating a difference in serotonin availability. Sex and estrous cycle phases lead to varying anxiety responses to tryptophan depletion. Testosterone, progesterone and estrogen are important factors in mediating sex differences in serotonin responses to anxiety-generating behavioral tests. At prenatal levels, there are sex-related differences in the reciprocal relationships between serotonin and the HPA-axis, which modulate anxiety-like behaviors. Activated immune-inflammatory pathways induce indoleamine-2,3-dioxynease (IDO) and the tryptophan catabolite (TRYCAT) pathway thereby increasing tryptophan degradation and increasing the production of TRYCATs including kynurenine and quinolinic acid, which may create an overall anxiogenic effect. The effects of immune activation on IDO are significantly more pronounced in women than men and therefore females may show increased levels of anxiogenic TRYCAT following immune challenge. Aberrations in the IDO-activated TRYCAT pathway are found in pregnant females and parturients and are associated with increased anxiety levels in the postnatal period. The results of this review underscore the necessity of studying the associations between serotonin and anxiety in both sexes taking into account the effects of immune activation on IDO and production of anxiogenic TRYCATs. Future anxiety research should focus on the interactions between serotonin/tryptophan and sex, sex hormones, the menstrual cycle, pregnancy, the HPA axis and the immune system through production of anxiogenic TRYCATs.

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR). Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity. The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors. We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity.Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia (“OSOS”); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in the OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated). Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM.

Background and Objectives: Zonulin is a molecule that has been identified as an intestinal permeability marker in recent years. Zonulin previously linked to Diabetes Mellitus, Obesity and Cardiovascular Disease but but its role in chronic kidney disease (CKD) was unclear. This study aims to investigate the relationship between Zonulin and systemic inflammation (SI), endothelial dysfunction (ED), especially renal functions, in patients with CKD. Materials and Methods: One hundred sixty-three participants were enrolled in this study. All participants were divided into two groups, patient and control groups, according to the presence of CKD (eGFR <60 mL/min/1.73m²). Results: A total of 104 patients with CKD (mean age 58.9 ±1.4) and 59 control subjects (mean age 59.0 ±1.1 ) were included, and age (p =0.934) and gender (p =0.196) were similar between the groups. In the comparison analysis, plasma zonulin levels in the CKD group (166.16 ± 53.54) were significantly higher than the controls group (143.30 ± 60.92) (p <0.001). In the correlation analysis, serum zonulin level showed positive correlation with claudin-3 (r =0.612, p <0.001), IL-6 (r =0.307,p <0.001), creatinine (r =0.313, p <0.001) and negative correlation with eGFR (r =-0.320, p <0.001) and TC (r =-0.074, p =0.047). Additionally, in linear regression analysis, zonulin level was significantly associated to eGFR, after adjustment for age and SBP (β value =-0.918, p =0.012). Conclusion: High serum zonulin levels in patients with CKD reflect increased intestinal permeability and were associated with impaired renal function. Moreover, it was thought that zonulin level could be associated with SI, but novel clinical studies were needed to elucidate its relationship with ED.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system caused by myelin-specific autoreactive T cells. We previously demonstrated intestinal barrier disruption and signs of inflammation in experimental autoimmune encephalomyelitis (EAE), a model of MS. Fecal calprotectin is a disease activity biomarker in inflammatory bowel diseases, released by neutrophils in response to inflammation. We aimed to further investigate EAE manifestations in the gastrointestinal tract, and to determine whether calprotectin is a useful biomarker of intestinal inflammation in EAE. Calprotectin was analyzed in feces, cecal contents, and plasma of EAE mice. Infiltrating neutrophils and goblet cells were investigated in different parts of the gastrointestinal tract, before onset of neurological symptoms and during established disease. We found increased calprotectin levels in feces, cecal content and plasma, preceding EAE onset that further escalated during disease progression. Increased neutrophil infiltration in the intestinal tissue concomitant with IL-17 expression and myeloperoxidase activity was found correlating well with clinical activity. Increased goblet cells in intestine similar to irritable bowel syndrome (IBS) were also observed. The results suggest calprotectin as a good biomarker of gastrointestinal inflammation in EAE, also the potential of this model as a useful animal model for IBS.

Atherosclerosis is a chronic systemic inflammatory condition of the vasculature and a leading cause of stroke. Luminal stenosis severity is an important factor in determining vascular risk. Conventional imaging modalities, such as angiography or duplex ultrasonography, are used to quantify stenosis severity and inform clinical care but provide limited information on plaque biology. Inflammatory processes are central to atherosclerotic plaque progression and destabilization. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a validated technique for quantifying plaque inflammation. In this review, we discuss the evolution of FDG-PET as an imaging modality to quantify plaque vulnerability, challenges to standardization of image acquisition and analysis, its potential application to routine clinical care after stroke, and the possible role it will play in future drug discovery.

Rosacea is a chronic inflammatory skin disease characterized by recurrent erythema, flushing, telangiectasia, papules, pustules, and phymatous changes in the central area of the face. Patients with this condition often experience a significant negative impact on their quality of life, self-esteem, and overall well-being. Despite its prevalence, the pathogenesis of rosacea is not yet fully understood. Recent research advances are reshaping our understanding of the underlying mechanisms of rosacea, and treatment options based on the pathophysiological perspective hold promise to improve patient outcomes and reduce incidence. In this comprehensive review, we investigate the pathogenesis of rosacea in-depth, with a focus on emerging and novel mechanisms, and provide an up-to-date overview of therapeutic strategies that target the diverse pathogenic mechanisms of rosacea. Lastly, we discuss potential future research directions aimed at enhancing our understanding of the condition and developing effective treatments.

Tea and coffee are the most commonly used beverages throughout the world. Both decoctions are rich in small organic molecules such as phenolics/polyphenolics, purine alkaloids, many methylxanthines, substituted benzoic and cinnamic acids. Many of these molecules are physiologically chemopreventive and chemoprotective agents against many severe conditions such as cancer, Alzheimer, Parkinsonism, inflammation, sleep apnea, cardiovascular disorders, bradycardia, fatigue, muscular relaxation, and oxidative stress. Caffeine, a purine alkaloid, is a common metabolite of both tea and coffee aqueous decoctions and its concentration in tea/coffee depends on the fermentation process, preparation of the water extract and quality of tea leaves/coffee beans. A 250 ml of a coffee cup contains 100-150 mg caffeine while the same volume of strong tea contains 25-40 mg caffeine. The present paper presents the potential of caffeine as a potent chemopreventive agent that can be used for numerous physiological disorders.

Background: First episode psychosis (FEP), schizophrenia and affective disorders are accompanied by activation of the immune inflammatory response system (IRS). The compensatory immune-regulatory reflex system (CIRS) is a regulatory immune response that is induced by the IRS but exerts negative feedback through, for example, increased levels of anti-inflammatory cytokines such as IL-4, IL-13 and IL-10. Different phenotypes of schizophrenia may exhibit distinct IRS and CIRS immune profiles.Aims: This study aims to examine the IRS and CIRS components, including macrophagic M1, T-helper (Th)-1, Th-2, Th-17 and T-regulatory (Treg) phenotypes, in antipsychotic-naïve FEP patients before and after risperidone treatment.Methods: We included 31 antipsychotic-naïve FEP patients who had measurements of IRS and CIRS biomarkers before and after treatment with risperidone for 10 weeks, and 22 healthy controls.Results: Antipsychotic-naive FEP patients showed interrelated increments in M1, Th-1, Th-2, Th-17 and Treg phenotypes and a relatively greater IRS response (especially granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6 and IL-12) as compared with the CIRS response (IL-4, IL-13, IL-5 and IL-10). Inflammatory markers, especially IL-6 and IL-8, were significantly correlated with negative, psychotic, affective and excitation symptom dimensions. Treatment with risperidone significantly suppressed the IRS and CIRS. Baseline levels of CIRS biomarkers, especially higher soluble tumor necrosis factor receptor-1 and IL-10 predicted clinical improvement during treatment.Discussion: Our findings indicate that FEP is characterized by robust IRS (M1 + Th-1 + Th-17) and CIRS responses, suggesting that monocytes, macrophages, Th-1, Th-2, Th-17 and Treg cells are activated. The findings indicate that a) FEP patients are prone to the detrimental effects of M1, Th-1, Th-17 and Th-2 cells, which may contribute to long-lasting abnormalities in brain circuitry; and b) in FEP, the CIRS may contribute to recovery from the acute phase of illness. Enhancing the CIRS is a new drug target to treat FEP.

The role of epigenetic alterations in the pathogenesis of age-related macular degeneration (AMD) has been pending so far. Our study investigated the effect of oxidative stress and inflammation on DNA methyltransferases (DNMTs) and Sirtuin 1 (SIRT1) functions, as well as on long interspersed nuclear element-1 (LINE-1) methylation, in human retinal pigment epithelial (ARPE-19) cells. Therefore, we evaluated whether treatment with resveratrol may restore changes in LINE-1 methylation by modulating DNMTs and SIRT1 functions. Cells were treated with 25 mU/ml glucose oxidase (GOx) or 10 µg/ml lipopolysaccharide (LPS) to mimic oxidative or inflammatory conditions, respectively. Oxidative stress decreased DNMT1, DNMT3a, DNMT3b and SIRT1 expression (p-values <0.05), as well as total DNMTs (-28.5%; p<0.0001) and SIRT1 (-29.0%;p<0.0001) activities. Similarly, inflammatory condition decreased DNMT1 and SIRT1 expression (p-values<0.05), as well as total DNMTs (-14.9%;p=0.007) and SIRT1 (-20.1%;p<0.002) activities. Interestingly, GOx- and LPS-treated cells exhibited lower LINE-1 methylation compared to controls (p-values<0.0001). We also demonstrated that treatment with 10 μM resveratrol for 24 hours counteracted the detrimental effect on LINE-1 methylation via increasing DNMTs and SIRT1 functions in cells upon oxidative and inflammatory conditions. However, further studies should explore the perspectives of resveratrol as a suitable strategy for the prevention and/or treatment of AMD.

Esculetin is a coumarin compound, which belongs to the class of benzopyrone enriched in various plants such as Sonchus grandifolius, Aesculus turbinata, and many others. Glycosides and caffeic acid conjugates are the common forms of esculetin present in medicinal plants. Esculetin acts as an antioxidant, anti-inflammatory, anti-diabetic, anti-hepatic, and anti-cancer agent by inhibiting the production of free radicals, inflammatory mediators, and genes that cause liver diseases and cancer. It also aids in the regulation of blood sugar. Scientists developing pharmaceutical formulations require some rationale and preliminary studies for drug design, but a small number of clinical studies on humans containing esculetin limit its potential for use as a safe alternative drug. Therefore, in this review article, the published studies have been reviewed to identify the pathogenesis of cancer, oxidative stress, inflammation, arthritis, diabetes and fatty liver along with the discussion on potential therapeutic strategies of esculetin. Advancements in our understanding of these diseases will aid in the development of new and innovative medications for treating many ailments. In conclusion, esculetin has immense potential to be used as a safe drug against many diseases but requires further testing and confirmation through clinical trials.

Cardiovascular disease is the most common cause of death. Oxidative stress and inflammation are pathophysiological processes involved in the development of cardiovascular diseases, so anti-inflammatory and antioxidant agents that modulate redox balance have become the targets of research to evaluate their molecular mechanisms and therapeutic properties. Astaxanthin, a carotenoid of the xanthophyll group, has potent antioxidant effects due to its molecular structure and its arrangement in the plasma membrane, factors that favor the neutralization of reactive oxygen and nitrogen species. This carotenoid also stands out for its anti-inflammatory activity, possibly interrelated with its antioxidant effect, as well as for its modulation of lipid and glucose metabolism. Considering the potential positive effects of astaxanthin on cardiovascular health evidenced by preclinical and clinical studies, this paper describes the molecular and cellular mechanisms related to the antioxidant and anti-inflammatory properties of this carotenoid in cardiovascular diseases, especially atherosclerosis.

Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. The rise in airways epithelial barrier permeability alters the tissue homeostasis and allows the allergen and other external agents penetration. Different factors contribute to barrier impairment, such as eosinophilic infiltrate and allergens proteases action: the eosinophilic cationic proteins and the allergens' proteolytic activity have a central role in contributing to epithelial damage. In the airways, the allergens proteases degrade the epithelial junctional proteins allowing the allergen penetration and the uptake by dendritic cells. The increase in allergen-immune system interactions induce the release of the alarmins and the activation of type 2 inflammatory pathways causing, or worsening, the main symptoms at skin, bowel and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic proteases-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance and progression. We further will explore clinical and radiological potential biomarkers of airways remodeling in allergic asthma patients.

Cancer remains a leading cause of death despite advancements in research and treatment, with traditional therapies often causing significant side effects and resistance. Oxyhydrogen gas, a mixture of 66% molecular hydrogen (H₂) and 33% molecular oxygen (O₂) has shown exceptional promise as a novel therapeutic agent due to its ability to modulate oxidative stress, inflammation, and apoptosis. H2, a key component of oxy-hydrogen gas, neutralises reactive oxygen and nitrogen species, enhancing existing treatments and reducing harmful oxidative states in cancer cells. H₂ also lowers pro-inflammatory mediators including chemokines, cytokines and interleukins, inhibiting cancer cell proliferation and boosting the effectiveness of conventional therapies. Additionally, hydrogen can induce apoptosis in cancer cells by modulating pathways such as MAPK and inhibiting the PI3K/Akt phosphorylation cascade. Preclinical and clinical evidence supports oxyhydrogen gas's potential in treating various cancers. In lung cancer models, it inhibits cell proliferation, induces apoptosis, and enhances chemotherapy sensitivity. Similar results have been observed in breast cancer, where patients reported improved quality of life. In colorectal cancer, oxyhydrogen gas suppresses tumour growth, induces apoptosis and improves intestinal microflora dysbiosis. The unique properties of oxyhydrogen gas make it a promising adjunctive or standalone cancer treatment. However, further research is needed to understand H₂'s mechanisms, optimise treatment protocols, and evaluate long-term safety and efficacy in human patients.

The COVID-19 pandemic remains a serious public health problem globally. During winter flu seasons, more aggressive SARS-CoV-2 infections with fatalities have been documented, indicating that influenza co-infections may significantly impact the disease outcome of COVID-19. Both influenza and SARS-CoV-2 viruses share many similarities in their transmission and cellular tropism for their replication in the human respiratory tract. However, it is still unclear how the two pathogens interplay to ensure their survival in the same lung microenvironment. In addition, clinical studies on influenza co-infections in COVID-19 patients do not provide conclusive evidence on how influenza co-infection mechanistically modifies the disease outcome in COVID-19. This mini-review discusses various viral as well as host factors that potentially influence the survival or synergism of these two respiratory pathogens in the infected lung microenvironment.

Background: Although persistent systemic inflammation is considered to be predictive for future cardiovascular events, it remains unclear whether or not C-reactive protein (CrP) plays an active role in coronary-plaque instability. Here, we report a case of a patient with failed and super-infected renal allograft as a source for systemic inflammation presenting with repeat acute coronary syndromes. Case presentation: A 52-years-old male type-2 diabetic with a failed kidney transplant who was hospitalized for acute urinary-tract infection. In the presence of other, classic cardiovascular risk factors, peak values of CrP coincided with episodes of unstable angina treated by percutaneous coronary interventions. Besides pyelonephritis, the histological examination of the kidney transplant revealed signs of chronic rejection and the presence of a renal cell carcinoma in situ. Once the renal allograft has been removed, systemic inflammation was attenuated, the patient was not re-hospitalized for acute-coronary syndrome within the next 12 months. Conclusion: In this case, systemic inflammation was paralleled by instability of coronary plaques as documented by repeat percutaneous coronary interventions.

Background. The aim of this study is to examine whether biomarkers of the immune-inflammatory response (IRS) and endogenous opioid (EOS) systems are associated with affective symptoms in schizophrenia. Methods. We recruited 115 schizophrenia patients and 43 healthy controls and assessed the Hamilton Depression (HDRS) and Anxiety (HAM-A) rating Scale scores as well as serum levels of interleukin (IL)-6, IL-10, eotaxin (CCL11), high mobility group box 1 (HMGB1), Dickkopf-related protein 1 (DKK1), and mu (MOR) and kappa (KOR) opioid receptors.Results. The HDRS and HAM-A scores are significantly and positively correlated with a) psychosis, hostility, excitation, mannerism, negative symptoms, psychomotor retardation, and formal thought disorders; and b) lowered scores on semantic and episodic memory, executive functions, and attention tests as measured with the Brief Assessment of Cognition in Psychiatry. Both HDRS and HAM-A are significantly increased in non-responders to treatment as compared with partial responders. Both affective scores are strongly associated with latent vectors extracted from all symptoms, reflecting overall severity of psychosis (OSOS), and neurocognitive test scores, reflecting a generalized cognitive decline (G-CoDe). The HDRS score was strongly and positively associated with IL-6, HMGB1, KOR, and MOR levels, and the HAM-A score with IL-6, IL-10, CCL11, HMGB1, KOR, and MOR levels. A single latent trait may be extracted from OSOS, G-CoDe, and the HDRS and HAMA scores, and this latent vector score is strongly predicted by HMGB1, MOR, and DKK1.Conclusion. Immune-inflammatory and EOS pathways contribute to the phenome of schizophrenia, which comprises OSOS, affective, and physiosomatic symptoms, and G-CoDe.

Perturbation in the microbial population/colony index has harmful consequences on human health. Both biological and social factors influence the composition of the gut microbiota and promote gastric diseases. Changes in the gut microbiota manifest in disease progression owing to epigenetic modification in host which influences differentiation and function of immune cells adversely. Uncontrolled use of antibiotics; chemotherapeutic drugs and change in the diet pattern usually contribute to the changes in the colony index of sensitive strains known to release microbial content in the tissue micromillieu. Ligands released from dying microbes induce TLR mimicry on interaction with TLR abnormally which skew hypoxia and sterile inflammation contributing to severity of disease like IBD autoimmunity and cancer. Various modalities/interventions practiced across the globe and future strategies for microbiota based therapeutic approaches with special emphasis on tumor and inflammatory diseases are reviewed here. Therefore the major aim and scope of this manuscript is to both discuss various modalities/interventions across the globe and to design future microbiota based therapeutic approaches for mitigating the burden with special emphasis on tumor and Inflammatory diseases.

Psoriasis is a chronic inflammatory disease characterized by skin lesions. Psoriasis development has been associated both with genetic and environmental factors. Though skin and gut microbiota has been implicated in number of pathologies including atopic dermatitis, inflammatory bowel disease, Crohn’s disease, allergy, obesity, its role has been poorly studied in psoriatic disease, which incorporates both psoriasis and psoriatic arthritis. This literature review summarizes the most recent and major findings on microbiota features in psoriatic disease as well as gives immune system role in the given condition. Despite conflicting findings, psoriasis patients were frequently found to have distinct microbial composition in both skin and guts especially in the major bacterial phyla, Firmicutes, Bacteroidetes, and Akkermansia. Furthermore, bacterial DNA has been found in psoriatic patients both locally and systemically, and altogether suggesting role of bacteria in the chronic disease and future studies in this field.

Myeloperoxidase (MPO) belong to the family of heme containing peroxidases, produced mostly from polymorphonuclear neutrophils. The active enzyme (150 kD) is the product of MPO gene located on long arm of chromosome 17. The primary gene product undergoes several modifications like removal of introns and signal peptide and leads to the formation of enzymatically inactive glycosylated apoproMPO which complexes with chaperons, producing active proMPO by the insertion of heme moiety. The active enzyme is a homodimer of heavy and light chain protomers. This enzyme is released into extracellular fluid after oxidative stress and different inflammatory responses. MPO is the only type of peroxidase using H2O2 to oxidize several halides and pseudohalides to form different hypohalous acids. So the antibacterial activities of MPO involve the production of reactive oxygen and reactive nitrogen species. Controlled MPO release at the site of infection is of prime importance for its efficient activities. Any uncontrolled degranulation exaggerates the inflammation that can also lead to tissue damage even in absence of inflammation. Several types of tissue injuries and pathogenesis of several other major chronic diseases like rheumatoid arthritis, cardiovascular diseases, liver diseases, diabetes and cancer have been reported to be linked with myeloperoxidase derived oxidants. So the enhanced level of MPO activity is one of the best diagnostic tool of inflammatory and oxidative stress biomarkers among these commonly occurring diseases.

Introduction: Multiple sclerosis (MS) is a long-term inflammatory disease that affects the central nervous system due to an abnormal immune response. Hormonal and enzyme changes in these patients can influence the progression and prognosis of the disease. In this research, the levels of cortisol, adrenocorticotropic hormone (ACTH), melatonin, and lactate dehydrogenase (LDH) in the blood of MS patients were studied.Methods: This study involved 50 MS patients and 50 healthy individuals. The levels of ACTH, melatonin, and cortisol in the blood were measured using specific ELISA kits. The data obtained were then analyzed statistically using SPSS software.Results: The findings revealed a significant increase in the levels of cortisol and LDH in MS patients (P<0.05), while the levels of melatonin and ACTH showed a significant decrease (P<0.05). The elevated cortisol levels may be attributed to chronic stress and inflammation associated with MS. An increase in LDH levels can indicate tissue damage caused by myelin destruction. On the other hand, decreased melatonin levels may lead to sleep disturbances and increased stress in these patients, while decreased ACTH levels may be linked to disruptions in the hypothalamic-pituitary-adrenal (HPA) axis. Conclusion: The hormonal and enzyme changes observed in MS patients illustrate the wide-ranging impact of the disease on various body systems. The increase in cortisol and LDH as well as the decrease in melatonin and ACTH could serve as useful biomarkers for predicting disease progression and managing the condition. These findings align with previous studies and contribute to a deeper understanding of the pathological mechanisms of MS.

Background: There is now evidence that schizophrenia and deficit schizophrenia are neuro-immune conditions and that oxidative stress toxicity (OSTOX) may play a pathophysiological role. Aims of the study: To compare OSTOX biomarkers and antioxidant (ANTIOX) defenses in deficit versus non-deficit schizophrenia. Methods: We examined lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), sulfhydryl (-SH) groups, paraoxonase 1 (PON1) activity and PON1 Q192R genotypes, total radical-trapping antioxidant parameter (TRAP) as well as immune biomarkers in patients with deficit (n=40) and non-deficit (n=40) schizophrenia and healthy controls (n=40). Results: Deficit schizophrenia is characterized by significantly increased levels of AOPP and lowered -SH, and PON1 activity, while no changes in the OSTOX/ANTIOX biomarkers were found in non-deficit schizophrenia. An increased OSTOX/ANTIOX ratio was significantly associated with deficit versus non-deficit schizophrenia (Odds ratio=3.15, p<0.001). Partial least squares analysis showed that 47.6% of the variance in a latent vector extracted from psychosis, excitation, hostility, mannerism, negative symptoms, psychomotor retardation, formal thought disorders, and neurocognitive test scores was explained by LOOH+AOPP, PON1 genotype + activity, CCL11, tumor necrosis factor (TNF)-α, IgA responses to neurotoxic tryptophan catabolites (TRYCATs), whereas -SH groups and IgM responses to MDA showed indirect effects mediated by OSTOX and neuro-immune biomarkers. Discussion: Our findings indicate that with increasing overall severity of schizophrenia, neuro-immune and neuro-oxidative (especially protein oxidation indicating chlorinative stress) toxicities become more prominent and together with lowered antioxidant defenses and impairments in innate immunity-associated resilience against neurotoxic processes shape a distinct nosological entity, namely deficit schizophrenia.

There is evidence that schizophrenia is characterized by activation of the immune-inflammatory response (IRS) and compensatory immune-regulatory (CIRS) systems and lowered neuroprotection. Studies performed on antipsychotic-naïve first episode psychosis (AF-FEP) and schizophrenia (FES) patients are important as they may disclose the pathogenesis of the disease. However, the interactome of FEP/FES is not well delineated. The aim of the current study was to delineate the characteristics of the protein-protein interaction (PPI) network of AN-FEP and its transition to FES and the biological functions, pathways, and molecular patterns, which are over-represented in FEP/FES. PPI network analysis shows that FEP and FEP/FES are strongly associated with a response to a bacterium, TNF, NFκB, RELA, SP1, JAK-STAT, death receptor and TLR4 signaling, and tyrosine phosphorylation of STAT proteins. Specific molecular complexes of the peripheral immune response are associated with microglial activation, neuroinflammation and gliogenesis. FEP/FES is accompanied by lowered protection against inflammation in part attributable to dysfunctional miRNA maturation, deficits in neurotrophin/Trk, RTK and Wnt/catenin signaling and adherens junction organization. Lowered neuroprotection due to reduced neurotrophin/Trk and Wnt/catenin signaling, and DISC1 expression and multiple interactions between lowered BDNF, CDH1, CTNNB, and DISC1 expression, increase the vulnerability to the neurotoxic effects of immune products including cytokines and complement factors. All pathways or molecular patterns enriched in the interactome of FEP/FES are directly or indirectly affected by LPS. In summary: FEP appears to be triggered by a biotic stimulus (e.g. Gram-negative bacteria) which may induce neuro-immune toxicity cascades especially when anti-inflammatory and neurotrophic protections are deficient.

Background. COVID-19 patients suffer from hypercoagulation and activated immune-inflammatory pathways. This study was performed to assay serum complement C3 and C4, and thromboxane A2 (TxA2) and prostacyclin (PGI2) in association with chest CT scan anomalies (CCTAs) and peripheral oxygen saturation (SpO2) Methods. Serum levels of C3, C4, TxA2, and PGI2 were measured by ELISA and albumin, calcium, and magnesium by spectrophotometric method in 60 COVID-19 patients and 30 controls. Results. C3 and C4 are significantly decreased and TxA2 and PGI2 significantly increased in COVID-19 patients as compared with controls. Neural networks showed that a combination of C3, albumin, and TxA2 yielded a predictive accuracy of 100% in detecting COVID-19 patients. SpO2 was significantly decreased in COVID-19 patients and was inversely associated with TxA2 and PGI2, and positively with C3, C4, albumin, and calcium. CCTAs were accompanied by lower SpO2 and albumin, and increased PGI2 levels. Patients with positive IgG results show significantly higher SpO2, TxA2, PGI2, and C4 levels than IgG negative patients. Conclusion. Hypoalbuminemia, which is strongly associated with lung lesions and lowered peripheral oxygen saturation, is characterized by increased TxA2, suggesting that interactions between immune-inflammatory pathways and platelet hyperactivity participate in the pathophysiology of COVID-19 and consequently may play a role in enhanced risk of hypercoagulability and venous thromboembolism. These mechanisms are aggravated by lowered calcium and magnesium levels.

23-Hydroxy ursolic acid (23-OH UA) is a potent atheroprotective and anti-obesogenic phytochemical, with anti-inflammatory and inflammation resolving properties. In this study, we examined whether dietary 23-OH UA protects mice against the acute onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Female C57BL/6 mice were fed either a defined low-calorie maintenance diet (MD) or an MD supplemented with 0.2 % wgt/wgt 23-OH UA for 5 weeks prior to actively inducing EAE and during the 30 days post-immunization. We observed no difference in the onset of EAE between both groups of mice, but ataxia and EAE disease severity were suppressed by 52% and 48%, respectively, and disease incidence was reduced by over 49% in mice that received 23-OH UA in their diet. Furthermore, disease-associated weight loss was strikingly ameliorated in 23-OH UA-fed mice. ELISPOT analysis showed no significant differences in frequencies of T cells producing IL-17 or IFN- between 23-OH UA fed mice and control mice, suggesting that 23-OH UA does not appear to regulate peripheral T-cell responses. In summary, our findings demonstrate that dietary 23-OH UA may represent an effective oral adjunct therapy for the prevention and treatment of relapsing-remitting MS.

Patients with transfusion-dependent thalassemia (TDT) show disorders in calcium metabolism. The α-klotho protein is predominantly expressed in tissues that are involved in calcium homeostasis, and lowered levels are associated with bone disease. Aim of the study. To study the associations between low α-klotho status and calcium metabolism in relation to iron status in children with TDT. Methods. α-klotho, calcium, parathyroid hormone (PTH), calcyphosin, vitamin D3, phosphorous, fibroblast growth factor receptor 2 (FGFR2), as well as iron and erythron biomarkers were measured in 60 children with TDT and 30 healthy control children. Results. A meaningful part of TDT patients showed lowered α-klotho levels, and those children also showed low serum total and ionized calcium concentrations. TDT patients showed increased PTH, FGFR2, and calcyphosin and lowered vitamin D3 as compared with healthy children. The α-klotho levels were significantly correlated with total and ionized calcium (positively) and with iron overload biomarkers and the number of blood transfusions (inversely). Partial Least Squares path analysis showed that 40.1% of the variance in serum total calcium could be explained by the regression on α-klotho, vitamin D3 (both positively), and calcyphosin (inversely) and that the effects of the latter are mediated by iron overload and the number of blood transfusions. Conclusion. In TDT, iron overload and its consequences may induce lowered levels of α-klotho which in turn may lead to lower calcium thereby explaining at least in part the effects of TDT on bone metabolism including spontaneous pathological fractures, osteoporosis, osteopenia, and skeletal deformities.

Beta-thalassemia major (β-TM) patients are treated with repeated blood transfusions, which may cause iron overload (IO), which in turn may induce immune aberrations. Patients with β-TM have an increased risk of major depressive disorder (MDD). The aims of the present study are to examine whether repeated blood transfusions, IO and immune-inflammatory responses are associated with MDD in children (6-12 years) with β-TM. The Children’s Depression Inventory (CDI), iron status (serum iron, ferritin, transferrin, TS%) and serum levels of CCL11, IL-1β, IL-10, and TNF-α were measured in β-TM with (n=54) and without (n=57) MDD and in healthy children (n=55). The results show that MDD in β-TM is associated with a greater number of blood transfusions, increased IO and IL-1β levels. Partial Least Squares path analysis shows that 68.8% of the variance in the CDI score is explained by the number of blood transfusions, IO, and increased levels of IL-1β and TNF-α. The latter two cytokines partly mediate the effects of IO on the CDI score, while the effects of blood transfusions on the CDI score are partly mediated by IO and the path from IO to immune activation. IO is also associated with increased IL-10 and lower CCL11 levels but these alterations are not significantly associated with MDD. In conclusion, blood transfusions may be causally related to MDD in β-TM children and their effects are in part mediated by increased IO and the consequent immune-inflammatory response. The results suggest that not only IO and its consequences including inflammation and ferroptosis, but also other factors related to the number of transfusions may cause MDD including psychosocial stressors. Current treatment modalities with folic acid and vitamin C are insufficient to attenuate IO and immune-inflammatory responses and to prevent MDD is children with β-TM undergoing blood transfusions.

Excessive extracellular histones can damage cells despite their importance in DNA structure and gene regulation. We previously showed the harmful effect of histone 3.3 (H3.3) and its acetylated form (AcH3.3) in chronic obstructive pulmonary disease (COPD), but further research is needed to understand the in vivo underlying mechanisms. To investigate this, we administered a single dose of recombinant histones via intra-tracheal instillation in C57BL/6 mice and analyzed the outcomes after 48 hours. Both rH3.3 and rAcH3.3 effectively reached the bronchial and alveolar space. Lung histology revealed severe immune cell infiltration, rupture, damage, and thickening of many alveolar walls. Micro-CT scans showed macroscopic structure changes with a decreased tissue volume to total volume ratio. The administration of rH3.3 and rAcH3.3 induced lung apoptotic activity, as indicated by increased levels of cleavage caspase 3 and 9. Moreover, elevated plasma levels of pro-inflammatory cell mediators, including TNF-alpha, IL-6, MCP-3, and CXCL-1, were observed. The pathological changes and pro-inflammatory cytokine response were more pronounced in animals treated with rAcH3.3, which also exhibited leukocytosis and lymphocytosis. These findings emphasize the crucial role of extracellular H3.3 acetylation in inducing cytotoxicity and a robust, acute inflammatory response similar to what occurs in the lungs of COPD patients.

Inflammation is a vital aspect of the body's immune response, appearing either as an acute reaction that swiftly develops (e.g., after injury or during an infection) or as a chronic condition that persists over a prolonged period, often linked with autoimmune disorders or cancer. This study introduces potential TNF-alpha inhibitors investigated by Molecular Docking investigation. They are Dactolisib with a binding energy of -10.1 kcal/mol, Nilotinib with -9.6 kcal/mol, Eltrombopag with -9.7 kcal/mol, Radotinib with -9.6 kcal/mol, and Nilotinib again with -9.7 kcal/mol. Additionally, Hypericin exhibited a notable binding energy of -9.9 kcal/mol, suggesting its potential as a natural TNF-alpha inhibitor. While these computational results are preliminary, they provide a foundation for further biological studies to confirm their efficacy. The significance of these findings extends to the scientific community, offering potential applications in the field of inflammatory diseases.

As symbionts of fungi and algae, lichens produce a variety of secondary products which pharmacological activities. This study aimed to investigate the anti-inflammatory activities of Heterodermia hypoleuca and its main compound, atraric acid. The results confirmed that atraric acid could regulating induced pro-inflammatory cytokine, nitric oxide, induced nitric oxide synthase and cyclooxygenase-2 expression by lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Means while, atraric acid down-regulated expression of phosphorylated IκB, ERK and nuclear factor kappa B (NFκB) signaling pathway to exhibit anti-inflammatory effects in LPS-stimulated RAW264.7 cells. Based on these results, the anti-inflammatory effect of atraric acid during LPS-induced endotoxin shock in a mouse model was confirmed. In the atraric acid treated-group, cytokine production was decreased in the peritoneum and serum, and each organ damaged by LPS-stimulation was recovered. These results show that atraric acid has an anti-inflammatory effect and its molecular mechanism may be involved in the inactivation of the ERK/NFκB signaling pathway, demonstrating its value as a potential therapeutic for inflammatory diseases.

Pregnancy-induced hypertension and preeclampsia are associated with significant maternal and fetal mortality. A better understanding of those diseases, delineation of molecular pathomechanism, and efficient treatment development are some of the most urgent tasks in obstetrics and gynecology. Recent findings indicate a crucial role of inflammation in the development of hypertension and preeclampsia. Although the mechanism is very complex and needs further explanation, it appears that high levels of cholesterol, urate, and glucose activates NLRP3 inflammasome, which produces IL-1β, IL-18 and gasdermin D. Production of these proinflammatory chemokines is a beginning of local and general inflammation, what results in sympathetic outflow, angiotensin II production, proteinuria, hemolysis, liver damage, immunothrombosis, and coagulopathy. NLRP3 inflammasome is a critical complex in the mediation of inflammatory response, which makes it crucial for the development of pregnancy-induced hypertension and preeclampsia, as well as its complications, such as placental abruption and HELLP syndrome. Herein presented the article delineate molecular mechanisms of those processes, indicating directions of future advance.

Rapid urbanization, increasing population and increased industrialization to cater to demands of the growing population has imposed upon us a huge environmental cost. The significantly deteriorated air quality across the globe is associated with a direct and indirect impact on public health. While associated disorders such as chronic obstructive pulmonary diseases, heart failures are well documented, less is known about the biological basis of the process. We hypothesize that the worsening air quality may likely impact common systemic inflammatory processes, thus driving communicable and non-communicable diseases alike.Receptor mediated entry of particulate matter (PM2.5) results in activation of signaling cascades which culminate in production of inflammatory chemokine and cytokine responses, traversing through the blood mediating impacting not only on other organs but also dysbiosis of microflora. For the purpose of the review we choose tuberculosis (TB) as a model for communicable infectious disease and type 2 diabetes mellitus (T2DM) as a marker for non-communicable disorder. The increasing prevalence of these co-morbidities and the burdening of public health systems justifies this example. However the hypothesis may be applicable to other inflammation driven disorders also.

Three new polyketides (penidihydrocitrinins A–C, 1–3) and 14 known compounds (4–17) were isolated from the deep-sea-derived Penicillium citrinum W17. Their structures were elucidated by comprehensive analyses of 1D and 2D NMR, HRESIMS, and ECD calculations. Compounds 1–17 were evaluated for their anti-inflammatory and anti-osteoporotic bioactivities. All isolates exhibited significant inhibitory effects on microglial activation in LPS-stimulated BV-2 cells in a dose-response manner. Notably, compound 14 displayed the strongest effect with the IC50 value of 4.7 µM. Moreover, compounds 6, 7, and 8 not only suppressed osteoclastogenesis, but also promoted osteoblast mineralization.

Schizophrenia is characterized by an interrelated activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS), which downregulates the IRS. Deficit schizophrenia is characterized by a deficit in natural regulatory autoimmune responses to tryptophan catabolites. The presence and correlates of IgM isotype antibodies to oxidative specific epitopes (OSEs), nitroso (NO) and nitro (NO₂) adducts in schizophrenia remain unknown.This study measured IgM antibodies to malondialdehyde (MDA), azelaic acid, phosphatidylinositol, oleic acid, NO-tryptophan, NO-albumin, NO-cysteinyl and NO₂-tyrosine in a sample of 80 schizophrenia patients, divided into those with and those without deficit schizophrenia, and 38 healthy controls.Deficit schizophrenia was characterized by significantly lower IgM antibody levels to all OSEs as compared with non-deficit schizophrenia and controls. Lowered IgM antibodies to MDA coupled with increased IgM levels to NO-cysteinyl and NO₂-tyrosine strongly predict deficit schizophrenia versus non-deficit schizophrenia with an area under the ROC curve of 0.913. A large part of the variance (21.2 – 42.2 %) in the negative symptoms of schizophrenia and excitation is explained by IgM antibody titers to MDA (inversely) and NO-cysteinyl and/or NO₂-tyrosine (both positively). Lower IgM antibodies to MDA are significantly associated with impairments in episodic memory including direct and delayed recall.These findings further indicate that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by lower natural IgM antibody levels to OSEs and relative increments in nitrosylation and nitration of proteins. It is concluded that deficits in lowered IgM responses to MDA and azelaic acid (part of the CIRS) attenuate the negative immune-regulatory feedback on the primary immune response and that this process may drive negative symptoms and impairments in episodic memory and thus deficit schizophrenia.

The Signal Transducer and Activator of Transcription (STAT)3 and 5 are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association to survival in cancer patients. The molecular mechanisms that underpins the oncogenic activity of STAT3/5 signaling includes the regulation of genes that control cell cycle, cell death, inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling including the p19ARF/p53 pathway, tyrosine phosphatases, suppressor of cytokine signaling 1 and 3, the sumo ligase PIAS3, the E3 ubiquitin ligase TMF/ARA160 and the miRNAs miR-124 and miR-1181. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated to STAT3/5 signaling explaining their context dependent association to tumor progression both in human cancers and animal models.

Inflammation is an important biological response to any tissue injury. The immune system responds to any stimulus, such as irritation, damage, or infection, by releasing pro-inflammatory cytokines. Overproduction of pro-inflammatory cytokines, including TNF-α and IL-1b, can lead to several diseases eg.,, cardiovascular diseases, joint disorders, cancer, and allergies. Emerging science suggests that whole grains may lower the markers of inflammation. Whole grains are a significant source of dietary fibres and phenolic acids that have inverse association with the risk of inflammation. The dietary fibres and phenolic acids composition of whole grains is very distinct over different grains. Whole grains (cereals and pseudo-cereals) are rich in both dietary fibres e.g., arabinoxylan, β-glucan and phenolic acids e.g., hydroxycinnamic acids, hydroxybenzoic acids, which are predominantly present in the bran layer. Although the biological mechanisms underlying widely reported association between whole grains consumption and a lower risk diseases are not fully understood. The modulatory effects of whole grains on inflammation also likely to be influenced by several mechanisms, including the effect of dietary fibres and phenolic acids, while some of these effects are direct, others involve gut microbiota, which transform important bioactive substances into more useful metabolites that moderate inflammatory signaling pathway. Thus, the aim of this review is two folded: first is to discuss the types of dietary fibres and phenolic acids commonly found in cereals and pseudo-cereals, and their health benefits observed in animal and human studies. Second, we review existing literature on the linkage between consumption of whole grains and markers of subclinical inflammation, the role of dietary fibres, phenolic acids, and gut microbiota on the anti-inflammatory activity of whole grains intake. Altogether, scientific data on the ant-inflammatory properties of whole grains are encouraging, further researches are needed to cover the gap between the emerging sciences of whole grains dietary fibres, phenolic acids and inflammation.

A subset of patients with schizophrenia experience physio-somatic symptoms reminiscent of chronic fatigue and fibromyalgia. In schizophrenia, these symptoms contribute to impaired quality of life, and are strongly related to neuro-cognitive deficits, and increased IgA responses to tryptophan catabolites. Negative and PHEM (psychosis, hostility, excitation, mannerism) symptoms, psychomotor retardation (PMR) and formal thought disorders, appear to be manifestations of a single trait reflecting overall severity of schizophrenia (OSOS). In this study, 120 patients with deficit schizophrenia (DEFSCZ) and 54 healthy subjects were assessed with the FibroFatigue (FF) rating scale, and the above-mentioned symptom domains as well as neuro-cognitive tests and biomarkers were measured. In DEFSCZ, there were robust associations between the FF score and all above-mentioned symptom domains, and impairments in semantic and episodic memory and executive functions. Furthermore, the FF score loaded highly on an OSOS latent vector (LV), which showed adequate convergent validity, internal consistency reliability and predictive relevance and fitted a reflective model. Soft Independent Modelling of Class Analogy (SIMCA) showed that the FF items discriminated DEFSCZ from controls with an overall accuracy of 100%. Interleukin IL-1β, IL-1 receptor antagonist (sIL-1RA), tumour necrosis factor (TNF)-α and CCL-11 (eotaxin) explained 66.8% of the variance in the FF score and 59.4% of the variance in OSOS. In conclusion, these data show that physio-somatic symptoms are a core component of the phenomenology of DEFSCZ and are largely mediated by neurotoxic effects of activated immune pathways, including aberrations in CCL-11, IL-1β and TNF-α signalling.

Vascular inflammation is recognized as the primary trigger of acute coronary syndrome (ACS). However, current noninvasive methods are not capable of accurately detecting coronary inflammation. Epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT), in addition to their role as an energy reserve system, have been found to contribute to the development and progression of coronary artery calcifica-tion, inflammation, and plaque vulnerability. They also participate in the vascular re-sponse during ischemia, sympathetic stimuli, and arrhythmia. As a result, the evalua-tion of EAT and PCAT using imaging techniques such as computed tomography (CT), cardiac magnetic resonance (CMR), and nuclear imaging has gained significant atten-tion. PCAT-CT attenuation, which measures the average CT attenuation in Hounsfield units (HU) of the adipose tissue, reflects adipocyte differentiation/size and leukocyte infiltration. It is emerging as a marker of tissue inflammation and has shown prognos-tic value in coronary artery disease (CAD), being associated with plaque development, vulnerability, and rupture. In patients with acute myocardial infarction (AMI), an in-flammatory pericoronary microenvironment promoted by dysfunctional EAT/PCAT has been demonstrated, and more recently, it has been associated with plaque rupture in non-ST-segment elevation myocardial infarction (NSTEMI). Endothelial dysfunc-tion, known for its detrimental effects on coronary vessels and its association with plaque progression, is bidirectionally linked to PCAT. PCAT modulates the secretory profile of endothelial cells in response to inflammation and also plays a crucial role in regulating vascular tone in the coronary district. Consequently, dysregulated PCAT has been hypothesized to contribute to type 2 myocardial infarction with non-obstructive coronary arteries (MINOCA) and coronary vasculitis. Recently, quan-titative measures of EAT derived from coronary CT angiography (CCTA) have been included in artificial intelligence (AI) models for cardiovascular risk stratification. These models have shown incremental utility in predicting major adverse cardiovas-cular events (MACE) compared to plaque characteristics alone. Therefore, the analysis of PCAT and EAT, particularly through PCAT-CT attenuation, appears to be a safe, valuable, and sufficiently specific noninvasive method for accurately identifying cor-onary inflammation and subsequent high-risk plaque. These findings have been sup-ported by biopsy and in vivo evidence. Although speculative, these pieces of evidence open the door to a fascinating new strategy in cardiovascular risk stratification. The incorporation of PCAT and EAT analysis, mainly through PCAT-CT attenuation, could potentially lead to improved risk stratification and guide early targeted primary pre-vention and intensive secondary prevention in patients at higher risk of cardiac events.

Inflammation plays a key role in the development and progression of type-2 diabetes (T2D), a disease characterised by peripheral insulin resistance and systemic glucolipotoxicity. Visceral adipose tissue (AT) is the main source of inflammation early in disease course. Macrophages are innate immune cells that populate all peripheral tissues, including AT. Dysregulated AT macrophage (ATM) responses to microenvironmental changes are at the root of aberrant inflammation and development of insulin resistance, locally and systemically. The inflammatory activation of macrophages is regulated at multiple levels: cell surface receptor stimulation, intracellular signalling, transcriptionally and metabolically. This review will cover the main mechanisms involved in AT inflammation and insulin resistance in T2D. First, we will describe the physiological and pathological changes in AT that lead to inflammation and insu- lin resistance. We will next focus on the transcriptional and metabolic mechanisms described that lead to the activation of ATMs. We will discuss more novel metabolic mechanisms that influence macrophage polarisation in other disease or tissues contexts that may be relevant to future work in insulin resistance and T2D.

Aim: Complementary effects of dabigatran etexilate (DE), exercise training (ET) and combination (DE+ET) on the development and composition of the atherosclerotic lesions in diabetic apoE knockout (apoE-/-) mice. Methods: In 48 male apoE-/- diabetic mice, streptozotocin (STZ) was induced for 5 consecutive days. Mice received figh-fat diet (HFD) for 8 weeks and were randomized into 4 groups (1.Control/CG, 2.DEG: HFD with DE, 3.ETG: ET on treadmill, 4.DE+ETG: Combination DE and ET treatment). At the end of 8th week, all mice were euthanatized and morphometry of the aortic lesions at the level of aortic valve was obtained. Collagen, elastin, TNF-a, MCP-1, matrix-metalloproteinases (MMP-2,-3,-9), and TIMP-1 concentration within plaques at aortic valve were determined. Results: All active groups had significantly smaller aorta stenosis (DEG:7.9±2.2%, ETG:17.3±5.3%, DE+ETG:7.1±2.7%) compared to CG (23.3±5.5% p&lt;0.05), reduced the relative intra-plaque concentrations of macrophages, MCP-1, MMP-3 and MMP-9, and considerably increased collagen, elastin and TIMP-1 (p&lt;0.05). Group 4 showed the most pronounced results (p&lt;0.05). Both DEG and DE+ETG significantly reduced MMP-2 and TNF-a concentrations compared to ETG and CG (p&lt;0.010). Conclusion: DE and ET treatment in diabetic apoE-/- mice showed complementary amelioration of atherosclerotic lesions development and stability, mediated by the anti-inflammatory modulation of both DE and ET.

Objective: To examine whether 1) immune and nitro-oxidative stress (IO&NS) biomarkers are associated with premenstrual syndrome (PMS); and 2) changes in IO&NS biomarkers during the menstrual cycle (MC) are associated with PMS symptoms and plasma estradiol and progesterone. Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days and MC Associated Syndrome (MCAS) was diagnosed when the summed DRSP score during the MC is > 0.666 percentile. We assayed plasma levels of complement C3 and C4, highly sensitive C-reactive protein (hsCRP), haptoglobin (Hp), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), sulfhydryl (-SH) groups and the activity of paraoxonase (PON)1 at days 7 (D7), 14 (D14), 21 (D21) and 28 (D28) of the MC. Results: All biomarkers, except hsCRP, showed significant alterations during the MC. Arylesterase (AREase) was lowered at D28, while LOOH increased at D14 and C4 at D21 in women with MCAS. The total DRSP score was predicted by the combined effects of C4 (positively) and AREase and malondialdehyde (MDA) (both inversely associated). Progesterone lowered levels of LOOH, AOPP and C3 and estradiol lowered levels of Hp while both sex hormones increased 4-(chloromethyl)phenyl acetate (CMPA)ase and AREase activities and levels of -SH groups. Conclusion: PMS/MCAS is not accompanied by a peripheral inflammatory response. Lowered MDA and antioxidant defenses and increased C4 may play a role in MC-associated symptoms while sex hormones may have a protective effect against oxidative stress toxicity.

Cardiovascular disease (CVD) is the primary cause of mortality globally with a multifactorial etiology that involves epigenetics. Chromobox 3 (CBX3), the major isoform of heterochromatin protein 1, is involved in intricate epigenetic mechanisms affecting congestive heart failure. In patients with CVD affected by lung cancer risk, CBX3 exerts a sophisticated mechanism of action, suppressing the proliferation, migration, and formation of neointima in vascular smooth muscle cells (VSMCs) by affecting the Notch3 pathway, indicating a potential protective function against vascular remodeling and atherosclerosis. However, the broader impact of CBX3 on endothelial function, as well as its effects on monocyte/macrophage and lymphocyte infiltration and function within the arterial wall, remain poorly understood. Since very little is known so far, more definite research would be needed to reveal the fine mechanisms of CBX3 action, along with its relationship in molecular processes and prospects as a biomarker. Specifically, CBX3 biological features could be examined to gain a greater insight into CVD risks. This review outlines the role of CBX3 in mechanisms associated with CVD and feasibility for optimizing pre-existing therapy and developing new therapeutic strategies based on personalized medi-cine.

Obesity induces inflammation in the hypothalamus and adipose tissue, resulting in metabolic disorders. A novel hypothalamic neuropeptide, neurosecretory protein GM (NPGM), was previously identified in the hypothalamus of vertebrates. While NPGM plays an important role in lipid metabolism in chicks, its metabolic regulatory effects in mammals remain unclear. In this study, a novel Cre driver line, NPGM-Cre, was generated for cell-specific manipulation. Cre-dependent overexpression of Npgm led to fat accumulation without increased food consumption in NPGM-Cre mice. Chemogenetic activation of NPGM neurons acutely promoted feeding behavior and chronically resulted in a transient increase in body mass gain. Furthermore, the ablated NPGM neurons exhibited a tendency to be glucose intolerant, with infiltration of proinflammatory macrophages into the adipose tissue. These results suggest that NPGM neurons may regulate lipid storage and inflammatory responses, thereby maintaining glucose homeostasis.

Rats fed a high-fat diet with a single streptozotocin (STZ) injection developed obesity, prediabetes, cardiac hypertrophy and diastolic dysfunction. Here we aimed to explore the renal consequences of prediabetes in the same groups of rats. Male Long-Evans rats were fed normal chow (CON; n = 9) or high-fat diet containing 40% lard and were administered STZ at 20 mg/kg (i.p.) at week four (prediabetic rats, PRED, n = 9). At week 21 cardiac functions were examined (Koncsos et al., 2016) and blood and urine samples were taken. Kidney samples were collected for histology, immunohistochemistry and for analysis of gene expression. High-fat diet and streptozotocin increased body weight gain and visceral adiposity, and plasma leptin, elevated fasting blood glucose levels, impaired glucose and insulin tolerance, despite hyperleptinemia, plasma C-reactive protein concentration decreased in PRED rats. Immunohistochemistry revealed elevated collagen IV protein expression in the glomeruli, and Lcn2 mRNA expression increased, while Il-1β mRNA expression decreased in both the renal cortex and medulla in PRED vs. CON rats. Kidney histology, urinary protein excretion, plasma creatinine, glomerular Feret diameter, desmin protein expression and cortical and medullary mRNA expression of TGF-β1, Nrf2, PPARγ were similar in CON and PRED rats. Reduced AMPKα phosphorylation of the autophagy regulator Akt was the first sign of liver damage, while serum lipid and liver enzyme levels were similar. In conclusion, glomerular collagen deposition and increased lipocalin-2 expression were the early signs of kidney injury, while most biomarkers of inflammation, oxidative stress and fibrosis were negative in the kidneys of obese, prediabetic rats with mild heart and liver injury.

FDG PET has been widely used in oncology studies as well as for cardiovascular diseases. This technique has recently been applied to detect active cardiovascular inflammation, mainly owing to enhanced glucose utilization by the activation of granulocytes and macrophages. To identify active inflammation by FDG PET, physiological uptake in the normal myocardium should be suppressed by appropriate patient preparation. FDG PET has been used to detect active lesions and assess the response to anti-inflammatory therapy in patients with cardiac sarcoidosis. In addition, other active cardiovascular inflammations, such as endocarditis, aortitis, and unstable atherosclerosis may be identified by FDG PET. After cancer treatment, FDG PET is considered an elegant approach not only for the assessment of tumor response to cancer therapy, but also for early detection of possible cardiovascular involvement. This review summarizes the clinical values of FDG PET for the assessment of active cardiovascular inflammation under suitable patient preparation.

Previous studies have revealed the microbial metabolism of dietary choline in the gut, leading to its conversion into trimethylamine (TMA), a precursor of the cardiovascular inflammatory marker trimethylamine N-oxide (TMAO). Polymethoxyflavones (PMFs), exemplified by tangeretin, demonstrate efficacy in mitigating TMAO-induced cardiovascular inflammation. However, the specific mechanism by which these compounds exert their effects, particularly in modulating the gut microbiota, remains uncertain. This investigation focused on tangeretin, a representative PMFs, exploring its influence on the gut microbiota and the choline-TMA conversion process. Experimental results showed that tangeretin treatment attenuated the population of CutC-active bacteria, specifically Clostridiaceae and Lactobacillus, induced by choline chloride in rat models. This inhibition resulted in reduced efficiency in choline conversion to TMA, thereby ameliorating cardiovascular inflammation resulting from prolonged choline consumption. In conclusion, tangeretin's preventive action against cardiovascular inflammation is intricately linked to its targeted modulation of TMA-producing bacterial activity.

Background: A decline in the prevalence of Helicobacter pylori infection has been claimed to increase the probability of developing atopic diseases. Aims: To evaluate the prevalence of atopic disorders in a pediatric population according to seropositivity against H. pylori. Methods: Children referred to the local Pediatric Hospital were investigated to identify risk factors, especially H. pylori infection, associated with atopic disorders. A questionnaire, including demographics, house size, history of breastfeeding, residence, school or daycare center attendance, exposure to animals, and a diagnosis of atopy, was filled out by a trained pediatrician according to parents’ answers. A blood sample was collected from each participant. Results: Seroprevalence of H. pylori infection was 11.7% among 492 children (240 females); 32 of them had a diagnosis of asthma and 12 of allergy. No one child showed both conditions. Statistically significant differences in H. pylori seropositivity were not detected between children with or without atopy (8.4 vs. 12.6; p=0.233). Although atopic disorders were more frequent in children exposed to traditional risk factors none showed to be significant after adjusting for all covariates. Conclusions: H. pylori infection, serologically assessed, was not significantly associated with a reduced risk of atopic diseases in children.

Immune disorders, characterized by dysregulation at cellular and inflammatory levels, result from a complex interplay of genetics and environmental factors that lead to an abnormal immune response against autoantigens, triggering tissue damage. Recent research highlights reactive antibodies as key players in autoimmune diseases and graft rejection, but the complexity of their determination limits their use in clinic. Hence, we studied the specific binding profile of serological antibodies against a panel of cellular membranes in order to determine whether this antigenic panel could be used to diagnose specific immune disorders in humans. For this purpose, cell membrane microarrays of spleen, liver, and kidney tissues of monkey, rat, and human were developed, and human sera were analyzed, including healthy controls, patients with autoimmune disorders, and kidney transplant patients. A significant increase in antibody reactivity against specific monkey kidney and spleen membranes was observed in the serum of patients with lupus nephritis, while kidney transplant patients showed a significant enhancement against human tissues and Human embryonic kidney 293 cells. These results show the potential importance for clinical and basic research purposes of studying the presence of specific IgG against membrane antigens in the serum of patients as potential biomarkers of immune disorders.

Osteoarthritis (OA) is a debilitating degenerative joint disease that results in chronic pain and inflammation due to progressive mechanical and proteolytic cartilage degradation. Articular chondrocytes, the main cell type present in cartilage, are responsible for the deposition and maintenance of the cartilage extracellular matrix (ECM). However, following damage and inflammation, chondrocytes undergo hypertrophy, apoptosis, and contribute to inflammation and ECM degradation. NF-κB signaling is known to be dysregulated in OA. TRAPPC9, a vesicle trafficking protein, is known to directly activate NF-κB signaling in neuronal and bone cells, however, the biological significance of this protein in chondrocytes has yet to be elucidated. Here, we demonstrate that TRAPPC9 enhances pro-inflammatory gene and protein expression in murine primary articular chondrocytes. Furthermore, we show that TRAPPC9 elicits these responses via phosphorylation of P-100 that activates non-canonical NF-κB signaling. Taken together, these findings suggest TRAPPC9 may be a potential therapeutic target to decrease inflammation and matrix degradation during OA pathology.

People with HIV (PWH) experience higher rates of cardiovascular events (CVEs) compared with the general population. A substantial body of evidence supports that select biomarkers of inflammation (soluble CD14 [sCD14], soluble CD163 [sCD163], highly sensitive C-reactive protein [hs-CRP], interleukin-6 [IL-6]), and coagulation (D-dimer) are elevated in PWH and related to increased rates of CVEs. Our previous work showed that smoking compared with nonsmoking was associated with significantly elevated sCD14, a biomarker of monocyte activation. We aimed to explore the effect of electronic cigarette (EC) provision on inflammatory biomarkers in PWH who smoked daily and then switched to an EC. Nineteen PWH were enrolled in a pilot study in which an EC and e-liquid were provided weekly or 8 weeks. Blood specimens for inflammatory biomarker analysis were obtained at baseline (BL) and at week 8. Biomarker levels were high at BL and did not differ significantly at week 8. There were small nonsignificant reductions in sCD163 and CRP levels. Non-significant increases in IL-6, D-dimer and sCD14 levels were also noted. Use of ECs for 8 weeks does not appear to significantly increase or decrease inflammatory biomarker levels in SWH. Further research with larger samples and a control group is needed.

ABSTRACT: Understanding the basis of osteoarthritis (OA) has seen some interesting advancements in recent years. It has been observed that cartilage degeneration is preceded by subchondral bone lesions, suggesting a key role of this mechanism within the pathogenesis and progression of OA, including the formation of ectopic bone and osteophytes. Moreover, low-grade, chronic inflammation of the synovial lining has gained a central role in the definition of OA pathophysiology, and central immunological mechanisms, innate but also adaptive, are now considered crucial in driving inflammation and tissue destruction. In addition, the role of neuroinflammation and central sensitization mechanisms has been characterized as underlying causes of pain chronicity. This has led to a renewed definition of OA, which is now intended as a complex multifactorial joint pathology caused by inflammatory and metabolic factors underlying joint damage. Since this evidence can directly affect the definition of the correct therapeutic approach to OA, an improved understanding of these pathophysiological mechanisms is fundamental. This review provides an overview of the most updated evidence on OA pathogenesis; it presents the most recent insight on the pathophysiology of OA, describing the interplay between immunological and biochemical mechanisms proposed to drive inflammation and tissue destruction, as well as central sensitization mechanisms. Moreover, although the therapeutic implications consequent to the renewed definition of OA are beyond this review scope, some suggestions for intervention have been addressed.

Purinergic signaling is that nucleotides (especially ATP) and adenosine are utilized as transmitter molecules, which play an important role in the immune system. In the extracellular ventricle, ATP plays a significant role of pro-inflammatory molecules mainly through activating P2 receptors, while adenosine plays the role as anti-inflammatory molecule mainly through activating P1 receptors. As we know，neutrophils are the most abundant immune cells in our circulation and have become an essential part of coordinating a series of complex events during inflammatory diseases. However, due to the destruction of inflammatory substances from neutrophils, the activation of neutrophils is fine-tuned, and purinergic signaling is associated with this process. As a matter of fact, altering the balance between P2 and P1 signals is of great importance for neutrophils to exert immune activities properly. Here, we review the role of purinergic signaling in regulatory function of neutrophils during inflammatory disease, and then discuss the potential contribution of targeted purinergic signals in the treatment of the neutrophil during inflammatory diseases.

Metformin（Met） is a commonly used drug in the treatment of type 2 diabetes. Currently, it has been found that Met can effectively reduce the incidence of stroke and exert anti-inflammatory effects. However, its role in ischemia-reperfusion (I/R) induced nerve injury remains unclear. This study aims to investigate the neuroprotective effects of Met in I/R-induced neuron injury as well as the underlying mechanism.A middle cerebral artery occlusion (MCAO) model was established in SD rats, which were then treated with different doses of Met.Neurological deficits of rats were measured at different times post-surgery. TTC staining to observe the volume of cerebral infarction.HE staining was performed to observe pathological changes of brain tissues .Immunohistochemistry was performed to observe the expression of inflammatory factors in the cerebral tissues .qRT-PCR method was used to detect the relative expression of PI3K、Akt mRNA in cells after 24 h of drug action.Western blot method was used to detect the expression of PI3K、p-PI3K、Akt and p-Akt in hippocampus.What’s more, in vitro experiments were performed on BV2 microglia to verify the role of Met against oxygen-glucose deprivation (OGD). As a result, Met dose-dependently attenuated neurological deficits and neuronal apoptosis. Besides, Met administration also significantly reduced BV2 cells apoptosis and inflammatory response. Mechanistically, Met inactivated PI3K/Akt pathway induced by I/R and OGD, while upregulated PI3K. In conclusion, Met protected rats from cerebral I/R injury via reducing neuronal apoptosis and microglial inflammation through PI3K/Akt pathway.

Aims: Clinical evidence indicates that innate immune cells may contribute to the onset and outcome of acute coronary syndrome (ACS). Our prospective study aimed at analysing neutrophil phenotypes in ACS and their role in predicting 1-year major cardiovascular events. Methods: Blood neutrophil phenotypes were analysed by flow cytometry. Differential blood cell count and plasma levels of soluble markers were recorded at admission and at 6-month follow-up. Results: 108 patients categorized in chronic stable coronary artery disease (n=37), unstable angina (UA) (n=19), Non-ST-Elevation Myocardial Infarction (NSTEMI) (n=25), and ST-Elevation Myocardial Infarction (STEMI) (n=27) were included. STEMI and NSTEMI patients displayed higher neutrophil count and neutrophil-to-lymphocyte ratio (NLR) than stable and UA patients (P<0.0001), which normalized at 6-month after MI. STEMI patients were characterized by elevated percentages of band cells in low-density neutrophils (P=0.007) and in high-density neutrophils (P=0.019) compared to the other patients. Multivariable logistic regression analysis revealed that plasma levels of total MPO was associated with STEMI when compared to stable (OR: 1.434; 95% CI: 1.119-1.837; P<0.0001), UA (1.47; 1.146-1.886; P=0.002), and NSTEMI (1.213; 1.1-1.134; P=0.0001) patients, while increased neutrophil SSC signal intensity was associated with NSTEMI compared to stable patients (3.828; 1.033-14.184; P=0.045). Based on multivariable Cox regression analysis, elevated plasma levels of PCSK9 and low-density neutrophil percentage predicted 1-year outcome independently of cardiovascular risk factors (c-index: 0.915; IQR: 0.908-0.929). Conclusions: Changes in neutrophil phenotype are concomitant to ACS. These changes may differ between STEMI and NSTEMI. They may also contribute to ACS risk and patient outcome.

Acidic glycosphingolipids, gangliosides are highly and consistently expressed in nervous tissues of vertebrates at high levels. Therefore, they have been believed to be largely involved in the development and function of nervous systems. Recent studies with genetic engineering of glycosyltransferase genes have revealed novel aspects of roles of gangliosides in the regulation of nervous tissues with substantial basis. In this review, novel findings on the ganglioside functions and their modes of action elucidated mainly by studies of gene knockout mice have been summarized. In particular, roles of gangliosides in the regulation of lipid rafts to maintain the integrity of nervous systems have been reported with a focus on the roles in the regulation of neuro-inflammation and neurodegeneration via complement systems. In addition, recent advances in the studies of congenital neurodisorders due to the genetic mutaions of ganglioside synthase genes, and also in the techniques for the analysis of ganglioside functions have been introduced.

A widely discussed topic in the pathophysiology of thyroid nodules is the role of obesity that leads to increased systemic inflammatory markers. Leptin plays a vital role in forming thyroid nodules and cancer through several mechanisms. Together with chronic inflammation, there is an augmentation in the secretion of tumor necrosis factor (TNF) and cytokines interleukin 6 (IL-6), contributing to cancer development, progression and metastasis. In addition, leptin exerts a modulatory action in the growth, proliferation and invasion of thyroid carcinoma cell lines via activating various signal pathways, such as Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) and/or phosphoinositide 3-kinase (PI3K) /protein kinase B (Akt). Through several proposed mechanisms, aberrant endogenous estrogen levels have been suggested to play a vital role in the development of both benign and malignant nodules. Metabolic syndrome triggers the development of thyroid nodules by stimulating thyroid proliferation and angiogenesis due to hyperinsulinemia, hyperglycemia and dyslipidemia. Insulin resistance influences the distribution and structure of the thyroid blood vessels. Insulin growth factor -1 (IGF-1) and insulin affect the regulation of the expression of thyroid genes and the proliferation and differentiation of thyroid cells. TSH can promote the differentiation of pre-adipocytes to mature adipocytes, but also, in the presence of insulin, TSH possesses mitogenic properties. This review aims to summarize the underlying mechanisms explaining the role of obesity in the pathophysiology of thyroid nodules and discuss potential clinical implications.

Background: We aimed to assess the association between DII and PD and the mediation effect of DII in the association of PD with systemic inflammation. Using the National Health and Nutrition Examination Survey (NHANES) 2009-2010, 2011-2012 and 2013-2014, participants that received periodontal exam and provided dietary recall data were included. The inflammatory potential of diet was calculated via DII. Periodontitis was defined according to the 2012 case definition. The clinical outcomes of interest were mean periodontal probing (PPD), mean clinical attachment loss (CAL) and thresholds of PPD and CAL. White blood cells (WBC), segmented neutrophils and C-reactive protein (CRP) were used as proxies for systemic inflammation. The periodontal measures were regressed across DII values using adjusted multivariate linear regression. Adjusted mediation analysis appraised the influence of DII in the association of periodontitis and systemic inflammation. 10,178 participants were included. DII was significantly correlated with mean PPD, mean CAL, thresholds of PPD and CAL, WBC, segmented neutrophils and DII (p&lt;0.01). A linear regression logistic adjusted for multiple confounding variables confirmed the association between DII and mean PPD (B = 0.02, Standard Error [SE]: 0.02, p&lt;0.001) and CAL (B = -0.02, SE: 0.01, p&lt;0.001). The association of mean PPD and mean CAL with both white blood cells and segmented neutrophils were mediated by DII (from 2.1 to 3.5%, p&lt;0.001). In the 2009-2010 subset, the association of mean CAL with serum CRP was mediated by DII (52.0%, p&lt;0.01). In conclusion, inflammatory diet and PD may be associated. Also, the inflammatory diet significantly mediated the association of leukocyte counts and systemic inflammation with periodontitis.

Clinical ketosis is a crucial metabolic disease in dairy cows that is often accompanied by severe lipolysis and inflammation in adipose tissue. Our previous study suggested that the fold change of calmodulin (CaM) was upregulated 2.401-fold in the adipose tissue of cows with clinical ketosis. Therefore, we hypothesize that CaM may regulate lipolysis and inflammatory responses in clinical ketosis cows. To verify the hypothesis, we conducted a thorough veterinary assessment of clinical symptoms and serum β-hydroxybutyrate (BHB) concentration before collecting subcutaneous adipose tissue samples from six healthy and six clinically ketotic Holstein cows at 17 ± 4 days postpartum. Commercial kits were used to test the abundance of BHB, Non-esterified fatty acid (NEFA), Liver function index (LFI), interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). We found that Clinical ketosis cows had higher levels of BHB, NEFA, LFI, IL-6, IL-1β, TNF-α, and lower glucose levels compared to healthy cows. Furthermore, the abundance of CaM, toll-like receptor 4 (TLR4), inhibitor of nuclear factor κB kinase subunit β (IKK), phosphorylated nuclear factor κB/nuclear factor κB, (p-NF-κB/NF-κB), adipose triglyceride lipase (ATGL) and phosphorylated hormone-sensitive lipase/hormone-sensitive lipase (p-HSL/HSL) were increased, while that of perilipin-1 (PLIN1) was decreased in the adipose tissue of cows with clinical ketosis. To investigate the mechanistic underlying the responses, we isolated the primary bovine adipocytes from the adipose tissue of healthy cows and induced the inflammatory response mediated by TLR4/IKK/NF-κB with lipopolysaccharide (LPS), in addition to treating with CaM overexpression adenovirus and CaM small interfering RNA. In vitro, LPS upregulated the abundance of CaM, TLR4, IKK, NF-κB, ATGL, p-HSL/HSL, and CaM and downregulated PLIN1. CaM silencing downregulated the abundance of LPS-activated p-HSL/HSL, TLR4, IKK, and NF-κB and upregulated PLIN1 in bovine adipocytes, except for ATGL. By contrast, CaM overexpression upregulated the abundance of LPS-activated p-HSL/HSL, TLR4, IKK, and NF-κB and downregulated PLIN1 expression in bovine adipocytes. In summary, these data suggest that CaM promotes lipolysis in adipocytes through HSL and PINL1 while activating the TLR4/IKK/NF-κB inflammatory pathway to promote an inflammatory response. There is a positive feedback loop between CaM, lipolysis, and inflammation. Overall, inhibiting CaM may act as an adaptive mechanism to alleviate metabolic dysregulation in adipose tissue, contributing to relief from lipolysis and inflammatory response.

Spinal cord injury is a traumatic injury that causes a catastrophic state in patients due to neuronal deficits, loss of motor and sensory function, and this is due to secondary deleterious events subsequent to mechanical damage that expands the death of neural cells beyond the initial trauma. One of the most important events is inflammation, which activates molecules like pro-inflammatory cytokines (IL-1beta, IFN-gamma, TNF-alpha) that provoke a toxic environment, inhibiting axonal growth and exacerbating CNS damage. As there is no effective treatment, one of the strategies developed is neuroprotection to preserve healthy neural tissue and reduce neuroinflammation. Some of the neuroprotective treatments that have been practiced are the use of cell therapy, the administration of peptides and molecules or supplements that have been shown to favor an anti-inflammatory environment, and help to preserve the cells and tissues surrounding the injured area, favoring axonal growth and improving locomotor function. In this review we will explain some of these strategies used in different animal models of spinal cord injury, their activity as modulators of the immune system and the benefits they have shown.

Several studies have identified a relationship between air pollution and depression, particularly in relation to fine particulate matter (PM2.5) exposure. However, the strength of this association appears to be moderated by variables such as age, gender, genetic vulnerability, physical activity and climatic conditions, and has not been assessed at a cross-national level to date. The current study examines the association between the prevalence of depression in each country, based on the most recent Global Burden of Disease Study data, and the average national level of PM2.5 based on the World Health Organization’s database. The observed associations were adjusted for age, gender, level of physical activity, income, education, population density, climate, and type of depression. It was observed that there was a modest but significant positive correlation between PM2.5 level and the prevalence of depression even after adjusting for the above confounders. This association was more marked above a certain threshold and applied chiefly to major depressive episodes. These findings are of significant public health importance in terms of preventive strategies aimed at reducing the population-level burden of depression.

Air pollution has become the world’s single biggest environmental health risk of the past decade, causing about 7 million yearly deaths worldwide. One of the dominant air pollutants is fine particulate matter (PM2.5), a product of combustion. Exposure to PM2.5 has been associated with decreased lung function, impaired immunity, and exacerbations of lung disease. Accumulating evidence suggests that many of the adverse health effects of PM2.5 exposure are associated with lung inflammation and oxidative stress. While the physical structure and surface chemistry of PM2.5 are surrogate measures of particle oxidative potential, little is known about their contributions to negative health effects. In this study, we used functionalized carbon black particles as surrogates for atmospherically aged combustion formed soot to assess the effects of PM2.5 surface chemistry in lung cells. We exposed the BEAS-2B lung epithelial cell line to different soot at a range of concentrations, and assessed cell viability, inflammation, and oxidative stress. Our results indicate that exposure to soot with varying particle surface composition results in differential cell viability rates, expression of pro-inflammatory and oxidative stress genes, and protein carbonylation. We conclude that particle surface chemistry, specifically oxygen content, in soot modulates lung cell inflammatory and oxidative stress responses.

The chemopreventive effects of various mixed cereal grain (MCG) samples on azoxymethane (AOM, 10 mg/kg) and dextran sulfate sodium (DSS, 2% w/v)-induced colorectal cancer (CRC) in C57BL/6J mice were studied. The main MCG preparation consisted of fermented brown rice (FBR), glutinous brown rice, glutinous Sorghum bicolor, glutinous Panicum miliaceum, Coix lacryma-jobi and black soybean at an appropriate mixing ratio. Other MCG preparations contained rice coated with 5% Phellinus linteus and 5% Curcuma longa (MGR-PC), or 10% Phellinus linteus (MCG-P), or 10% Curcuma longa (MCG-C). Consumption of dietary MCG-PC by CRC mice significantly increased colon length, decreased the ratio of colon weight to length, and reduced the number of colon tumors. Similar effects, although to a lower extent, were observed in CRC mice fed with MCG-P, followed by those fed with MCG-C, MCG, FBR or white rice (WR). MCG-PC significantly suppressed colonic neoplasia, and decreased the levels of various cytokines (tumor necrosis factor: Tnf, interleukin 1 beta: Il1b, interleukin 6: Il6, and interferon gamma: Ifng) in serum and colon tissue of the CRC mice. In addition, MCG-PC increased the mRNA expressions of tumor protein p53(Tp53) and cyclin-dependent kinase inhibitor 1A(Cdkn1a), activated pro-apoptotic caspase 3(Casp3), and reduced expression of both mRNA and protein of inducible inducible nitric oxide synthase 2 (Nos2), prostaglandin-endoperoxide synthase 2 (Ptgs2), and cyclin D1(Ccnd1) in colon tissue. These findings suggest that than compared with other cereal grain preparations, MCG-PC had a greater activity against AOM/DSS-induced CRC by reducing intestinal inflammation, and modulating the expression of certain carcinogenesis related factors (Nos2, Ptgs2, Tp53, Cdkn1a, Ccnd1 and Casp3) in colon tissue of CRC mice.

Microglia are the resident immune cells of the central nervous system. Upon stimulus presentation microglia polarize from a resting to an activated state. Microglial translocator protein 18 kDa (TSPO) is considered as a marker of inflammation. Here, we characterized the role of TSPO by investigating the impact of TSPO deficiency on human microglia. We used TSPO knockout (TSPO-/-) variants of the human C20 microglia cell line. We found a significant reduction in the TSPO-associated protein VDAC1 in TSPO-/- compared to control cells. Moreover, we assessed the impact of TSPO deficiency on calcium levels and the mitochondrial membrane potential. Cytosolic and mitochondrial calcium concentrations were increased in TSPO-/- cell lines, whereas the mitochondrial membrane potential tended to be lower. Assessment of the mitochondrial DNA copy number via RT-PCR revealed a decreased amount of mtDNA in the TSPO-/- cells when compared to controls. Moreover, metabolic profiles of C20 cells were strongly dependent on the glycolytic pathway. However, TSPO depletion did not affect the cellular metabolic profile. Measurement of the mRNA expression levels of the pro-inflammatory mediators revealed an attenuated response to proinflammatory stimuli in TSPO-depleted cells, implying a role of the TSPO protein in the process of microglial polarization.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease that affects about 1% of the global population, with a female-male ratio of 3:1. To date, genetic predisposition, the involvement of a deficient immune system and lifestyle are known to be the major responsible for the onset of the disease. RA preferably affects the joints, with consequent joint swelling and deformities followed by ankylosis. Patients suffering from rheumatoid arthritis can also develop extra-articular manifestations, which mainly affect the cardiovascular system, the nervous system, the skin, the eye, the respiratory system, the kidney and the gastrointestinal system. It has been shown that about 20% of RA patients can develop neuropathies, multiple mononeuritis, distal sensory neuropathies and sense motor neuropathies. Neurological involvement occurs as a consequence of vasculitis of the nerve vessels leading to vascular ischaemia, axonal degeneration and neuronal demyelination. In RA, the risk of developing cardiovascular disease is very high and depends, most probably, on vascular damage resulting from endothelial dysfunction. Hence, it is reasonable to assume that the integrity of the endothelium is also involved in the neurological disorders resulting from RA. This review aims to highlight the main characteristics of the extra-articular manifestations at the nervous level resulting from rheumatoid arthritis. To this end, the literature main results on these pathological manifestations have been collected with particular focus on the involvement of endothelial dysfunction. In fact, the endothelium could be considered a valuable target for minimizing the incidence of extra-articular neurological manifestations in RA.

The biogeography of inflammation in ulcerative colitis (UC) suggests a proximal to distal concentration gradient of a toxin. Hydrogen sulfide (H2S) has long been considered one such toxin candidate, and dietary sulfur along with the abundance of sulfate reducing bacteria (SRB) were considered the primary determinants of H2S production and clinical course of UC. The metabolic milieu in the lumen of the colon, however, is the result of a multitude of factors beyond dietary sulfur intake and SRB abundance. Here we present an updated formulation of the H2S toxin hypothesis for UC pathogenesis, which strives to incorporate the interdependency of diet composition and the metabolic activity of the entire colon microbial community. Specifically, we suggest that the increasing severity of inflammation along the proximal-to-distal axis in UC is due to dilution of beneficial factors, concentration of toxic factors, and changing detoxification capacity of the host, all of which are intimately linked to the nutrient flow from the diet.

Research into the causes of neurotoxicity in Alzheimer’s Dementia (AD) has focused on neurofibrillary tangles and beta amyloid (Aβ) plaques. This paper proposes the heterodox theory that these hallmarks of AD are the visible effects, not direct causes of neuronal necrosis. Rather AD results from a combination of age-induced, disproportional decline in physiological support for aerobic metabolism, and dysregulation of the sleep cycle processes. The hypothesis is that the decimation of neurons in AD results from a combination of neurotoxicity and increased apoptosis caused by: 1. direct damage from toxic waste products of anaerobic glycolysis due to a progressive decline in the capacity of neurons to perform oxidative phosphorylation (OXPHOS) and an increased reliance on anaerobic glycolysis to meet metabolic needs; 2. impaired cellular repair and effluent release due to dysregulation of non-rapid eye movement (NREM) sleep allowing damage to cell membranes and synaptic junctions to accumulate inducing a chronic inflammatory response; 3. indirect damage from products produced by inflammatory reaction to toxic metabolites; 4. neuronal apoptosis from the AβPP-mediated pathway due to the age-induced decline of growth hormone (GH), GH-releasing hormone (GHRH) and insulin-like growth factor (IGF).

Our recent study detected the expression of a tissue Renin-Angiotensin System (tRAS) in human intervertebral discs (IVDs). The present study sought to investigate the impact of angiotensin II receptor type 1 (AGTR1) antagonist losartan on human nucleus pulposus (NP) cell inflammation and degeneration induced by tumor necrosis factor-α (TNF-α). Human NP cells (4 donors, Pfirrmann grade 2-3, 30-37 years old, male) were isolated and expanded. TNF-α (10 ng/mL) was used to induce inflammation and degeneration. We examined the impact of losartan supplementation and measured gene expression of tRAS, anabolic, catabolic, and inflammatory markers in NP cells after 24 h and 72 h of exposure, respectively. T0070907, a PPAR-gamma antagonist, was applied to examine the regulatory pathway of losartan. Losartan (1 mM) significantly impaired TNF-α induced increase of pro-inflammatory (nitric oxide and TNF-α), catabolic (matrix metalloproteinases), and tRAS (AGTR1a and Angiotensin Converting Enzyme) markers. Further, losartan maintained the NP cell phenotype by upregulating aggrecan and downregulating collagen type I expression. In summary, losartan showed anti-inflammatory, anti-catabolic, and positive phenotype modulating effects on human NP cells. These results indicate that tRAS signaling plays an important role in IVD degeneration, and tRAS modulation with losartan could represent a novel therapeutic approach.

β-hydroxy β-methylbutyrate (HMB) is a bioactive metabolite formed from breakdown of the branched-chain amino acid leucine. Given the popularity of HMB supplements among different athletes, specifically, those who engage in regular resistance training, this review was performed to summarize current literature on some aspects of HMB supplementation that have received less attention. Because of the small number of published studies, it has not been possible to conclude the exact effects of HMB on cardiovascular parameters, oxidative stress and inflammatory markers. Thus, the interpretation of outcomes should be taken cautiously. However, the data presented here suggest that acute HMB supplementation may attenuate pro-inflammatory response following an intense resistance exercise in athletes. Also, the available findings collectively indicate that chronic HMB consumption in conjunction with resistance training has no more adaptive advantages associated with decreasing cardiovascular risk factors and oxidative stress markers. Taken together, there is clearly a need for further well-designed, longer duration studies to support these findings and determine whether HMB supplementation affects the adaptations induced by resistance training associated with body’s inflammatory condition, antioxidative defense system, and cardiovascular risk factors in humans.

Background/Aim: microRNAs (miRNAs) are key regulators of both physiological and pathophysiological mechanisms in diabetes and gastrointestinal (GI) dysmotility. Our previous studies have demonstrated the therapeutic potential of miR-10a-5p mimic and miR-10b-5p mimic (miR-10a/b mimics) in rescuing diabetes and GI dysmotility in murine models of diabetes. In this study, we elucidated the safety profile of a long-term treatment with miR-10a/b mimics in diabetic mice. Methods: Male C57BL6 mice were fed a high-fat, high-sucrose diet (HFHSD) to induce diabetes and treated by five subcutaneous injections of miR-10a/b mimics for a 5-month period. We examined the long-term effect of the miRNA mimics on diabetes and GI dysmotility, including an assessment of cancer risk as well as liver and colon inflammation using cancer and inflammatory biomarkers. Results: HFHSD-induced diabetic mice subcutaneously injected with miR-10a/b mimics monthly for 5 months exhibited a marked reduction in fasting blood glucose levels with restoration of insulin and significant weight loss, improved glucose and insulin intolerance, and restored GI transit time. In addition, the miR-10a/b mimic treated diabetic mice showed no indication of risk for cancer development and inflammation induction in the liver, colon, and blood for the 5 months post injections. Conclusion: This longitudinal study demonstrates that miR-10a/b mimics, when subcutaneously administered in diabetic mice, effectively alleviate diabetes and GI dysmotility for 5 months with no discernible risk for cancer or inflammation in the liver and colon. The sustained efficacy and favorable safety profiles position miR-10a/b mimics as promising candidates in miRNA-based therapeutics for diabetes and GI dysmotility.

Hyperandrogenism and insulin resistance are co-pathologies of polycystic ovary syndrome (PCOS). Recent evidence has suggested that elevated local cortisol levels are associated with ovarian and endometrial insulin resistance in hyperandrogenic PCOS patients, but the molecular mechanisms underlying these clinical findings remain unclear. We and others have used chronic treatment with human chorionic gonadotropin (hCG) and insulin to create an in vivo rodent model for the onset and development of PCOS-like phenotypes. Here, we aimed to determine whether the molecular mechanisms of glucocorticoid receptor (GR) signaling, mitochondrial function, and local inflammation in the ovary and uterus are intrinsically different in PCOS-like rats compared to controls. In both the ovary and the uterus, decreased expression of two GR protein isoforms was concurrent with increased expression of Fkbp51 but not Fkbp52 mRNA in PCOS-like rats compared to controls. However, PCOS-like rats exhibited an opposite regulation of Hsd11b1 or Hsd11b2 mRNAs in the two tissues. Further, the expression of several oxidative phosphorylation-related protein components was decreased in the PCOS-like ovary and uterus, but surprisingly the expression of many genes involved in mitochondrial function and homeostasis was increased in the same tissues and animals. Additionally, PCOS-like rats showed the increased expression of ovarian and uterine NFκB signaling proteins and Tnfaip3 mRNA. In PCOS-like rats, while similar decreased expression of Il1b, Il6, and Mmp2 mRNAs was seen in the ovary and uterus, the opposite regulation of Tnfa, Ccl2, Ccl5, and Mmp3 mRNA expression was observed in the two tissues. Both ovaries and uteri from PCOS-like animals showed increased collagen deposition compared to controls. Collectively, our observations suggest that hyperandrogenism and insulin resistance disrupt ovarian and uterine GR activation and trigger compensatory or adaptive effects for mitochondrial homeostasis, allowing tissue-level maintenance of mitochondrial function in order to limit ovarian and uterine dysfunction. Our study also suggests that hyperandrogenism and insulin resistance-induced activation of NFκB signaling resulting in aberrant regulation of inflammation-related gene expression might be tissue specific in female reproductive tissues.