The majority of skin cancers are caused by over exposure to ultraviolet (UV) radiation. The effects of UV radiation on the expression of drug transporters expressed in human skin has never been studied. In this the effects of UVA and UVB irradiation on the expression of ATP-binding cassette (ABC) transporters and Solute carrier (SLC) transporters was evaluated in normal human epidermal keratinocytes (NHEK) and normal human dermal fibroblasts (NHDF) in primary culture. First experiments were intended to validate the inflammatory reaction in response to stimulation by lipopolysaccharide (LPS) in NHEK, NHDF and 3D-reconstructed human epidermis (3D-RHE) model. LPS treatment has shown to increase the expression of IL-8 and TNF-alpha in all three in vitro models. Expression of the most expressed ABC and SLC transporters was then measured in NHEK and NHDF after UVA (30 J/m²) and UVB (40 mJ/m²) irradiation. The most striking result was a significant 29-fold increase of the expression of SLCO4A1 in normal human dermal fibroblasts. In summary, this study shows for the first time a significant regulation of the expression of SLCO4A1 in human dermal fibroblasts induced by UVA irradiation. This finding is of particular interest as most of skin cancers are caused by over exposure to ultraviolet radiation and need to be considered in pharmacokinetic evaluation of topical drugs.

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<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<0.001) and CAL (B = -0.02, SE: 0.01, p<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<0.001). In the 2009-2010 subset, the association of mean CAL with serum CRP was mediated by DII (52.0%, p<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.

COVID-19 pandemic represents an unprecedented sanitary threat: antiviral and host-directed medications to treat the disease are still urgently needed.A great effort has been paid to find drugs and treatments for hospitalized, severely ill patients. However, medications used for the domiciliary management of initial symptoms, notwithstanding their importance, have not been and are not presently regarded with the same attention. In analogy with other respiratory viral infections, COVID-19 patients in the early phase require specific antivirals (still lacking) and non-etiotropic drugs to lower pain, fever and control inflammation. Non-steroidal antinflammatory drugs (NSAIDs) and paracetamol (PAC) are widely used as non-etiotropic agents in these conditions and hence are both theoretically repurposable for COVID-19. However, a warning from some research reports and National Authorities raised NSAIDs safety concerns because of the supposed induction of ACE2 protein levels (the receptor used by SARS-CoV2 to enter host airways cells), the risk of bacterial superinfections and masking of disease symptoms. As a consequence, the use of NSAIDs was, and is, strongly discouraged while the alternative adoption of paracetamol is still preferred.On the basis of novel data and hypothesis on the possible role of scarce glutathione (GSH) levels in the exacerbation of COVID-19 and of the GSH depleting activity of PAC, this commentary raises the question of whether PAC may produce an oxidative imbalance which could be detrimental in COVID-19 clinical outcomes.

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.

Mental stress represents a pivotal factor in cardiovascular diseases. The mechanism by which stress produces its deleterious effects is still under study but one of the most explored pathway is cell senescence. In this scenario, circulating microRNAs appear to be mobile regulatory elements of the telomerase activity and alternative splicing within the ”senectome” network. Anti-stress techniques seem to be able to slow-down aging process. As we have recently verified how the practice of Relaxation Response (RR), counteracting psychological stress, determines favorable changes of some inflammatory genes expression, of some neurotransmitters, hormones, cytokines and inflammatory circulating microRNAs, we aimed to verify a possible change even in serum levels of 4 senectome micro-RNAs (SE-miRNAs -20, -30, -410, -515), testing the activity of telomerase in peripheral blood mononuclear cells-PBMCs. We analyzed also alternative splicing microRNAs 134 and 183. According to our data, miRNA-20 and -30 levels and PBMCs-telomerase activity increase during the RR while -410 and -515 levels decrease. Moreover, during the RR sessions both miRNA-134 and -183 decrease. The mediators considered in this work seem to vary rapidly according to a (stress)-relaxation condition showing that psychic activity should be part of the study of aging factors.

In atherosclerosis patients, vascular endothelial dysfunction is commonly observed with damage of vascular endothelial glycocalyx, an extracellular matrix-bound to and encapsulating the endothelial cell lining the blood vessel wall. Unfavorable lifestyle; smoking and physical inactivity, also induces glycocalyx degradation. Moreover, the vascular endothelial glycocalyx is damaged by various unfavorable disease conditions like as dehydration, acute infectious disease, trauma, sepsis, ARDS, Kawasaki disease, preeclampsia, gestational diabetes mellitus, hypertension, diabetes, chronic kidney disease, atherosclerosis, stroke, dementia, microvascular angina, acute coronary syndrome, and heart failure. The vascular endothelial glycocalyx has been shown to be important not only as a physical cytoprotective barrier for vascular endothelial cells but also as a mechanism that regulates intracellular cell signaling. Therefore, vascular endothelial glycocalyx has great potential to explore new strategies for assessing the benefit conditions of our healthy vasculature.

Smoking is a risk factor for respiratory infections and there is reasonable concern that it may affect COVID-19 susceptibility and severity. Recent studies have focused on the interaction between smoking (and nicotine) and ACE2 expression, suggesting that ACE2 up-regulation could contribute to enhanced viral cell entry. However, case series have shown that there is an unexpectedly low prevalence of smoking among hospitalized COVID-19 cases. Since early April, we were the first to hypothesize that dysfunction of the nicotinic cholinergic system (NCS) may be implicated in the pathophysiology of severe COVID-19. We recently reported that many of the clinical manifestations of severe COVID-19 could be explained by dysregulation of the NCS. In this study, we present an amino acid sequence in the receptor binding domain of the SARS-CoV-2 Spike glycoprotein which is homologous to a sequence of a snake venom toxin. We present the 3D structural location of this “toxin-like” sequence on the Spike Glycoprotein. These findings suggest that SARS-CoV-2 could potentially interact with acetylcholine receptors causing dysregulation of the NCS and the cholinergic anti-inflammatory pathway.

Background: The purpose of this study was to examine the prevalence and effects of current smoking on adverse outcomes among hospitalized COVID-19 patients. Methods: We performed a systematic review of the literature (PubMed) for studies published until April 25. Studies were included into the analysis if they satisfied all of the following criteria: 1. To present hospitalized patients with COVID-19. 2. To classify patients into less and more severe disease, irrespective of the severity definition (defined as “adverse ourtcome”). 3. To present data on the smoking status, separately for each severity classification. We identified 18 (from a total of 1398) relevant studies. Pooled current smoking prevalence was compared with the gender-adjusted, population-based expected prevalence by calculating Prevalence Odds Ratio (POR). The association between current, compared to non-current and former, smoking and adverse outcome was examined by calculating Odds Ratio (OR). All analyses were performed using random-effects meta-analysis. Results: Among 6515 patients, 440 of whom were current smokers, the pooled prevalence of current smoking was 6.8% (95%CI: 4.8-9.1%) and the POR was 0.21 (95%CI: 0.16-0.26, P < 0.001). In Chinese studies only, the POR was 0.22 (95%CI: 0.17-0.27, P < 0.001). Current smokers were more likely to have an adverse outcome compared to non-current smokers (OR: 1.53, 95%CI: 1.06-2.20, P = 0.022). However, they were less likely to have an adverse outcome compared to former smokers (OR: 0.42, 95%CI: 0.27-0.74, P = 0.003). Conclusion: An unexpectedly low prevalence of current smoking was observed among hospitalized patients with COVID-19. Hospitalized current smokers had higher odds compared to non-current smokers but lower odds compared to former smokers for an adverse outcome. The possibility that nicotine may have a protective effect in COVID-19 which may be masked by smoking-related toxicity and by the abrupt cessation of nicotine intake when smokers are hospitalized should be explored.

Buerger's disease or Thromboangiitis Obliterans (TAO) is a nonatherosclerotic segmental vascular disease which affects small and medium arteries and veins in the upper and lower extremities. Based on pathological findings, TAO can be considered as a distinct form of vasculitis that is most prevalent in young male smokers. There is no definitive cure for this disease as therapeutic modalities are limited in number and efficacy. Surgical bypass has limited utility and 24% of patients will ultimately require amputation. Recently, studies have shown that therapeutic angiogenesis and immunomodulatory approaches through the delivery of cells to target tissues are potential options for ischemic lesion treatment. In this review, we summarize the current knowledge of TAO treatment and provide an overview of stem cell-based treatment modalities.

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.

In this paper we propose a novel theoretical framework, which was previously developed for major depression and bipolar disorder, namely the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first episode psychosis (FEP), acute relapses, chronic and treatment resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1β, IL-6 and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17) and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-β1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway as well as chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3 and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-a receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin and other acute phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic and deficit schizophrenia indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor which may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Components of the CIRS may offer promising therapeutic targets for schizophrenia.

Inflammatory Bowel Disease (IBD) is characterized by chronic remitting and relapsing inflammation of the lower gastrointestinal tract. The etiology underlying IBD remains unknown but is thought to involve a hypersensitive immune response to environmental antigen, including the microbiota. Diagnosis and monitoring of disease is heavily reliant on endoscopy, which is invasive and does not provide information regarding specific mediators. This review describes recent developments in imaging of IBD with a focus on PET and SPECT imaging of inflammatory mediators, and how this may be applied to the microbiota.

The vertebrate annexin superfamily (AnxA) consists of 12 members of a calcium (Ca²⁺) and phospholipid binding protein family which share a high structural homology. In keeping with this hallmark feature, annexins have been implicated in the Ca²⁺-controlled regulation of a broad range of membrane events. In this review, we identify and discuss several themes of annexin actions that hold a potential therapeutic value, namely the regulation of the immune response and the control of tissue homeostasis, and that repeatedly surface in the annexin activity profile. Our aim is to identify and discuss those annexin properties which might be exploited from a translational science and specifically clinical point of view.

Tea (Camellia sinenesis) is a health beneficial beverage and is also a source for extracting bioactive components such as theanine, tea polyphenols (TPP) and tea polysaccharides (TPS). TPS is a group of hetero-polysaccharides bounded with proteins. There were tests showing that TPS had various bioactivities, such as antioxidant, antitumors, antihyperglycemia, anti-inflammation and improving immunity. However, inconsistent results concerning chemical composition and bioactivity of TPS were published in recent years. The advances in chemical composition and bioactivities of TPS were reviewed in the present paper. The inconsistent and controversial results regarding composition and bioactivities of TPS were also discussed.

The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases, and psychiatric disorders. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants, and immunomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses, and chronic diseases. KYN, kynurenic acid, xanthurenic acid, and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2, 3-oxygenases, and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro- and anti-inflammatory cytokines, and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric, including depressive disorder, bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia, and autism spectrum disorder.

Spinal Cord (SC) Anatomy is often assimilated to a morphologically encapsulated neural entity, but its functional anatomy remains only partially understood. We hypothesized that it could be possible to reexplore SC neural networks by performing live electrostimulation mapping, based on “super-selective” Spinal Cord Stimulation (SCS), originally designed as a therapeutical tool to address chronic refractory pain. As a starting point, we initiated a systematic SCS lead programming approach using live electrostimulation mapping on a chronic refractory perineal pain patient, previously implanted with multicolumn SCS at the level of the conus medullaris (T12-L1). It appeared possible to (re)explore the classical anatomy of the conus medullaris using statistical correlations of paresthesia coverage mappings, resulting from 165 different electrical configurations tested. We highlighted that sacral dermatomes were not only located more medially but also deeper than lumbar dermatomes at the level of the conus medullaris, in contrast with classical anatomical descriptions of SC somatotopical organization. As we were finally able to find a morpho-functional description of ‘Philippe-Gombault’s triangle’, in 19th century historical textbooks of neuroanatomy, matching remarkably with these conclusions, the concept of “Neuro-Fiber-Mapping” was introduced.

Accurate prediction of mercury content emitted from fossil-fueled power stations is of utmost importance for environmental pollution assessment and hazard mitigation. In this paper, mercury content in the output gas of power stations’ boilers was predicted using an adaptive neuro-fuzzy inference system (ANFIS) method integrated with particle swarm optimization (PSO). The input parameters of the model include coal characteristics and the operational parameters of the boilers. The dataset has been collected from 82 power plants and employed to educate and examine the proposed model. To evaluate the performance of the proposed hybrid model of ANFIS-PSO model, the statistical meter of MARE% was implemented, which resulted in 0.003266 and 0.013272 for training and testing, respectively. Furthermore, relative errors between acquired data and predicted values were between -0.25% and 0.1%, which confirm the accuracy of the model to deal nonlinearity and representing the dependency of flue gas mercury content into the specifications of coal and the boiler type.

Acute Respiratory Distress Syndrome (ARDS) is a severe lung condition with a high mortality rate for which there are no effective therapeutics. The failure of the alveolar-capillary barrier, composed of lung endothelial (EC) and alveolar epithelial (AEC) cells, is a critical factor leading to excessive inflammation and edema characteristics of acute lung injury (ALI). Phosphodiesterases (PDE) are enzymes well-recognized for their roles in regulating endothelial permeability and inflammation. Although PDE inhibitors are used as therapeutics for inflammatory diseases like COPD (chronic obstructive pulmonary disease), their efficacy in treating ARDS has not yet been established. In this study, we investigate the effects of ensifentrine, an FDA-approved novel dual PDE 3/4 inhibitor, on lung endothelial and epithelial dysfunction caused by methicillin-resistant S. aureus (MRSA), a pathogen involved in bacterial ARDS. Human primary lung endothelial cells and alveolar epithelial cell lines (A549 and immortalized AEC) were treated with heat-killed MRSA, and their responses were assessed in the presence or absence of ensifentrine. Ensifentrine given either pre- or post exposure attenuated MRSA-induced increased lung endothelial permeability. VE-cadherin junctions, which serve to stabilize the EC barrier, were disrupted by MRSA; however, ensifentrine effectively prevented this disruption. Pre-treatment with ensifentrine protected against MRSA-induced EC pro-inflammatory signaling by inhibiting the expression of VCAM-1, ICAM-1, and by reducing the IL-6 release. In AEC, MRSA caused upregulation of ICAM-1, activation of NF-kB and production of IL-8, all of which were inhibited by ensifentrine. These results indicate that dual inhibition of phosphodiesterases 3 and 4 by ensifentrine is barrier protective and attenuates MRSA-induced inflammation in both lung endothelial and epithelial cells. The PDE3/4 inhibitor ensifentrine may represent a promising novel strategy for the treatment of ALI.

Chikungunya (CHIKV) and Mayaro (MAYV) viruses are arthritogenic alphaviruses that promote an incapacitating and long-lasting inflammatory muscle-articular disease. Despite studies pointing out the importance of skeletal muscle (SkM) in viral pathogenesis, the long-term consequences on its physiology after acute injury and the mechanism of persistence of symptoms are still poorly understood. Combining molecular, morphological, Nuclear Magnetic Resonance Imaging, and histological analysis, we conduct a temporal investigation of CHIKV and MAYV replication in a wild-type mice model, focusing on the impact on SkM composition, structure, and repair in the acute and late phases of infection. We found that viral replication and induced-inflammation promote fast loss of muscle mass and reduction of fibers cross sectional area, by inducing muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin expression, that trigger protein breakdown, resulting in acute SkM fibers atrophy. After temporal reduction of inflammation and clearance of infectious viral particles, SkM atrophy persists until the late phase of infection. The genomic CHIKV and MAYV RNAs were still detected in SkM at the late phase, along with increased levels of chemokines and anti-inflammatory cytokines expression. In agreement with the involvement of inflammatory mediators on induced atrophy, neutralization of TNF and the reduction of oxidative stress using monomethyl fumarate, an agonist of Nrf2, decreases atrogens expression and atrophic fibers, while increasing weight gain in treated mice. Taken together, these data indicate that arthritogenic alphavirus infection could chronically impact body SkM composition and also harm repair machinery, contributing to a better understanding of mechanisms of arthritogenic alphaviruses pathogenesis and with description of potentially new targets of therapeutic intervention.

The Ro60 autoantigen is an RNA-binding protein, and a core component of nucleocytoplasmic ribonucleoprotein (RNP) complexes. Ro60 is essential in RNA metabolism, cell stress response pathways, and cellular homeostasis. It stabilises and mediates quality control and cellular dis-tribution of YRNAs, retroelement transcripts, and misfolded RNAs. Ro60 transcriptional dysregulation or loss of function can result in the generation and release of RNA fragments from YRNAs and other small RNAs. Small RNA fragments can instigate an inflammatory cascade through endosomal TLRs and cytoplasmic RNA sensors, which typically sense patho-gen-associated molecular patterns (PAMPs) and mount the first line of defence against invading pathogens. However, recognition of host-originating RNA moieties from Ro60 RNP complexes can activate inflammatory response pathways and compromise self-tolerance. Autoreactive B cells may produce antibodies targeting extracellular Ro60 RNP complexes. Ro60 autoantibodies serve as diagnostic markers for various autoimmune diseases including Sjögren's disease (SjD) and systemic lupus erythematosus (SLE), and they may also act as predictive markers for an-ti-drug antibody response among rheumatic patients. Understanding Ro60’s structure, function, and role in self-tolerance can enhance our understanding of the underlying molecular mecha-nisms of autoimmune conditions.

Pygeum africanum bark has been shown to inhibit the production of pro-inflammatory prostaglandins in the prostate and reduce the production of leukotrienes and other 5-lipoxygenase (5-LO) metabolites. It has been suggested that inflammation plays an important role in the pathophysiology of benign prostatic hyperplasia (BPH). In clinical trials, P. africanum improved the symptoms and objective measures of BPH. This in vitro study aimed to assess the anti-inflammatory potential of a proprietary Pygeum bark standardized extract (Prunera®) on cytokine release by lipopolysaccharide-simulated human peripheral blood mononuclear cells (PBMCs). PBMCs were obtained from four donors and a bead-based assay (ProcartaPlex™ panel) was used for the detection and quantitation of cytokines. Pygeum africanum bark standardized extract (PABE) showed the following effects: IL-2 was lowered in all donors in absence of a clear dose–response relationship; IL-4, IL-5, IL-6, IL-9, and IL-13 levels were decreased in most donors; IL-22 levels seemed to be suppressed only for donor 4 at lower and medium concentrations; and IL-27 and levels of TNF-α decreased at all PABE concentrations in all donors. The anti-inflammatory effect of PABE supports the potential use of this natural compound in the management of BPH and other conditions in which pro-inflammatory cytokines are involved in their underlying pathophysiological mechanisms.

Fermented foods and ingredients, including fermentates derived from lactic acid bacteria (LAB) in dairy products, can modulate the immune system. Here we describe the use of reconstituted skimmed milk powder to generate novel fermentates from Lactobacillus helveticus strains SC232, SC234, SC212, and SC210, and from Lacticaseibacillus casei strains SC209 and SC229, and demonstrate using in vitro assays that these fermentates can differentially modulate cytokine secretion by bone marrow derived dendritic cells (BMDCs) when activated with either the viral ligand, loxoribine, or an inflammatory stimulus, lipopolysaccharide. Specifically, we demonstrate that SC232 and SC234 increase cytokines IL-6, TNF-α, IL-12p40, IL-23, IL-27 and IL-10, and decreased IL-1β in primary bone marrow derived dendritic cell (BMDCs) stimulated with a viral ligand. In contrast exposure of these cells to SC212 and SC210 resulted in increased IL-10, IL-1β, IL-23, and decreased IL-12p40 following activation of the cells with the inflammatory stimulus LPS. Interestingly SC209 and SC229 had little or no effect on cytokine secretion by BMDCs. Overall, our data demonstrates that these novel fermentates have specific effects and can differentially enhance key immune mechanisms that are critical to viral immune responses, or can suppress responses involved in chronic inflammatory conditions, such as Ulcerative Colitis (UC), and Crohn’s disease (CD).

IBD, encompassing CD and UC, are characterized by chronic gastrointestinal inflammation due to abnormal immune responses to gut microflora. The bidirectional communication between the gut and the brain, known as the GBA, is disrupted in IBD, leading to neurobiological imbalances and affective symptoms. Systemic inflammation in IBD affects the brain's inflammatory response system, hormonal axis, and BBB integrity, influencing gut microbiota and clinical responses to probiotics. This review aims to explore the links between dysregulations in the GBA, serum biomarkers, and the development of MCI and NDDs. The objective is to identify potential correlations and propose future research directions to understand the impact of altered microbiomes and intestinal barrier functions on NDDs. Studies suggest a potential link between IBD and extraintestinal complications such as MCI and NDDs. Mechanisms include systemic inflammation, BBB dysfunction, autoimmune responses, GBA dysfunction, medication effects, and comorbidities. Serum biomarkers, including vitamin D3, C-reactive protein, high-sensitivity C-reactive protein, vitamin B12, homocysteine, serum amyloid, neuron-specific enolase, neurofilament light chain, S100 proteins, brain-derived neurotrophic factor, IL-6, LP-2 associated phospholipase, prostaglandin E2, IL-1β, and TNF-α, have been investigated for their potential to predict MCI but current results are lacking clarity.

Background Popular movement-based injury risk screens have been shown to lack predictive precision, leading to interest in multifactorial models. Furthermore, there is a lack of research regarding injury risk assessment for those currently or planning to be recreationally active. This study aims to provide injury risk insights by analyzing multifactorial injury risk models and as-sociated clinical measures in the U.S. population. Methods Data related to injury, inflammatory markers, physical functioning, body composition, physical activity, and other variables from 21,033 respondents were extracted from NHANES. Odds ratios for self-reported injury were calculated for single predictors and risk models. Case-control and principal component analyses (PCA) were conducted to elucidate confounders and identify risk factor clusters, respectively. Receiver operating characteristic analysis was used to test the precision of a risk factor cluster to identify pain points and functional difficulties. Results Sociodemographic, individual, and lifestyle factors were strongly associated with higher odds of injury. Increases in fibrinogen and C-reactive protein were significantly associated with all risk groups. Membership to the high-risk group (age over 40, obesity, no muscle-strengthening activities, sedentary lifestyle, and low back pain) predicted at least one functional difficulty with 67.4% sensitivity and 87.2% specificity. In the injury group, bone turnover markers were higher, yet confounded by age and there was a significantly higher prevalence of self-reported osteoporosis compared to the control. In males, low testosterone was associated with injury, and higher estradiol was associated with pain and functional difficulties. In females, higher levels of follicle-stimulating hormone were associated with functional difficulties. PCA revealed four high-risk profiles, with markers and activities showing distinct loadings. Conclusion A comprehensive approach to injury risk assessment should consider the nexus of aging, lifestyle, and chronic disease to enhance tailored injury prevention strategies, fostering safe and effective physical activity participation and reducing the burden of musculoskeletal disorders.

We propose that a dietary reduction of Lipopolysaccharide (LPS) could reduce risk and slow the progression of cognitive decline and Alzheimer’s disease. LPS is a component of the highly inflammatory cell membrane of Gram-negative bacteria. The highest dietary sources of LPS are processed meat and dairy products, which can sharply raise plasma LPS within one to two hours. The LPS in these foods is packaged into chylomicrons, which enter the bloodstream. Smaller amounts of LPS from colonic microbiota do not account for the sharp postprandial increase of plasma LPS. Once in the bloodstream, LPS can trigger the release of inflammatory cytokines within three hours. LPS can increase cytokines via LPS binding protein and cluster of differentiation-14, triggering toll-like receptor-4, and activating nuclear factor kappa-B. Nuclear factor kappa-B can increase cytokine levels, including interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha. LPS and inflammatory cytokines are higher in Alzheimer’s disease, both in plasma and in the central nervous system. These cytokines can enter the brain via active transport and induce microglial activation and inflammatory damage in the brain, including loss of synapses and neurons. Elevated brain inflammation from dietary LPS can contribute to cognitive impairment and increased risk of dementia.

Marine microalgae are a rich reservoir of natural compounds, including bioactives. Nonetheless, these organisms remain fairly unexplored despite their potential biotechnological applications. Culture collections with diverse taxonomic groups and lifestyles are a good source to unlock this potential and discover new molecules for multiple applications such as the treatment of human pathologies or the production of aquaculture species. In the present work extracts from 33 strains (including 20 dinoflagellates, 4 diatoms and 9 strains from other 7 algal classes), cultivated under identical conditions were examined for antiviral, antibacterial, anti-inflammatory and anti-cancer activities. Among these, antiviral and anti-inflammatory activities were detected in a few strains while antibacterial tests showed positive results in most assays. In turn, most trials did not show any anti-cancer activity. Wide differences were observed between species within the same class, in particular dinoflagellates which were better represented in this study. These preliminary findings pave the way for in-depth characterization of extracts with highest signals in each test, identification of compounds responsible of the biological activities found, and a further screening of the CCVIEO culture collection.

Chronic fatigue syndrome (CFS) is a disease in which fatigue that interferes with daily life persists for six months or longer. The number of patients with CFS is increasing, as CFS-like symptoms have been reported to occur in the sequelae of both COVID-19 infection and the SARS-CoV-2 vaccine, both of which have become significant issues in recent years. While the pathogenesis mechanism is not yet fully understood, research suggests that oxidative stress (OS) may play a role in the development of CFS. In this paper, we discuss the antioxidant potential of the antioxidant formulation Twendee M® (TwM) and the results of a questionnaire that monitored changes in symptoms before and after TwM in a total of 23 men and women diagnosed with CFS. TwM is a supplement containing 15 different ingredients, and has a strong antioxidant capacity that cannot be achieved with a single antioxidant ingredient. The results of the questionnaire showed that TwM significantly improved all of the major symptoms of CFS, including fatigue, muscle pain, joint pain, sleep disturbance, decreased memory and concentration, and headache. TwM was shown to alleviate various symptoms of CFS and improve quality of life.

Background: We aimed to explore microvascular changes evaluated with optical coherence tomography angiography (OCTA) in patients undergoing epiretinal membrane (ERM) pars-plana vitrectomy (PPV) combined with intravitreal Ozurdex implantation, compared with standard PPV. (2) Methods: Prospective interventional analysis on 25 eyes undergoing PPV+Ozurdex (Group A) and 25 eyes undergoing PPV alone. Best corrected visual acuity (BCVA) and OCTA parameters, such as vessel density (VD) of the superficial and deep capillary plexi (SCP and DCP) in the whole 6.4x6.4 mm and fovea area, were evaluated preoperatively and 3 months after surgery. (3) Results: Postoperative BCVA significantly improved in both groups. No cases of post-operative cystoid macular edema (CME) were reported in Group A vs. 2 eyes in Group B. In Group A we found a statistically significant increase of SCP’s VD in either the whole image (from 42.1±4.1 to 45.6±4.3 %, p=0.01) and the fovea image (from 38.5±7.5 to 41.7±4.2%, p=0.03). In Group B, we reported no significant variations in the SCP’s VDs. In the DCP, VD significantly increased only in the whole image in Group A. Stage 4 ERMs showed the greatest improvement in VD, especially in Group A. (4) Conclusions: In conclusion, intraoperative Ozurdex prompted a significant BCVA recover and limited the occurrence of postoperative CME compared to the standard procedure. Moreover, Ozurdex implant is associated with a better restoration of microvascular structure in either SCP and DCP.

The aim of this review was to search in literature, data regarding the inflammasome, involvement in, oral pathologies (mainly periodontitis) and other diseases and the approaches to control the inflammasome-related pathogenic mechanisms. The review also investigated how phytochemicals and pharmaceutical substances could be used to inhibit the inflammasome activity. Inflammasomes are involved in inflammatory, autoimmune and autoinflammatory diseases. Pharmaceutical substances can control the inflammasome by three mechanisms: inhibiting of intracellular signaling pathways (Allopurinol and SS-31), blocking inflammasome components (VX-765, Emricasan and VX-740), and inhibiting cytokines mediated by the inflammasome (Canakinumab, Anakinra and Rilonacept). Phytochemical inhibit the inflammasome, by neutralization of reactive oxygen species. Biomaterials functionalized by the adsorption of therapeutic agents on different nanomaterials may represent a future research direction to facilitate multimodal and sequential treatment in oral pathologies.

Today, air pollution is the greatest threat to organismal healthspan. The environment of our planet earth, the habitat of over eight billion humans and estimated twenty billion billions other animals, is contaminated with a wide variety of pollutants. Unfortunately, humans, out of billions and billions of living organisms on earth, are solely responsible for polluting the environment through emitting pollutants like particulate matter from industry, fuel engine vehicles, biomass combustion, toxic fumes from blasting, and wildfire. In the modern world, human-caused air pollutants induce massive oxidative stress and inflammation, the major contributors in initiation and progression of many diseases including pulmonary, cardiovascular, renal, hepatic, reproductive, neurological, mental, and accelerated biological aging. The provocative question is the following: how can we solve this human-created problem? As it is not realistic to clean the environment at once from human-caused pollution, initiatives have been undertaken to develop novel therapeutic approaches to control air-pollutant-induced oxidative stress and inflammation to protect humans from pollution-induced devastating diseases. In this article, I discuss the key findings of numerous recent preclinical studies documenting first, the role of air pollutant PM2.5 in augmentation of inflammation, oxidative stress, and associated diseases; and second, the efficacies of different natural and synthetic compounds in amelioration of PM2.5-induced oxidative stress, inflammation, pyroptosis, and associated pathologies.

Inflammation is a conserved process that involve the activation of immune and non-immune cells aiming at protecting the host from bacteria, viruses, toxins and injury. However, unresolved inflammation and permanent release of pro-inflammatory mediators are responsible for the promotion of a condition called “low-grade systemic chronic inflammation”, characterized by tissue and organ damages, metabolic changes and increased susceptibility to non-communicable diseases. Several studies have demonstrated that different dietary components may influence modifiable risk factors for diverse chronic human pathologies. Marine n-3 polyunsaturated fatty acids (n-3 PUFAs), mainly eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), are well recognized anti-inflammatory and immunomodulatory agents able to influence many aspects of the inflammatory process. The aim of this article is to review the recent literature that relates to the modulation of human disease, such as rheumatoid arthritis, by n-3 PUFAs.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a complex gastrointestinal disorder with a multifactorial etiology, including environmental triggers, autoimmune mechanisms, and genetic predisposition. Despite advancements in therapeutic strategies for IBD, its associated mortality rate continues to rise, which is often attributed to unforeseen side effects of conventional treatments. In this context, we explored the potential of Ecklonia cava extract (ECE) derived from an edible marine alga known for its anti-inflammatory and antioxidant properties in mitigating IBD. This study investigated the effectiveness of ECE as a preventive agent in a murine model of dextran sulfate sodium (DSS)-induced colitis. Our findings revealed that pretreatment with ECE significantly ameliorated colitis severity as evidenced by increased colon length, reduced spleen weight, and histological improvements demonstrated by immunohistochemical analysis. Furthermore, ECE significantly attenuated the upregulation of inflammatory cytokines and mediators and the infiltration of immune cells known to be prominent features of colitis in mice. Notably, ECE restored dysbiosis of intestinal microflora and aided in the recovery of damaged intestinal mucosa. Mechanistically, ECE exhibited protective effects against pathogenic colitis by inhibiting the NLRP3/NF-κB pathway known to be pivotal regulators in the inflammatory signaling cascade. These compelling results suggest that ECE holds promise as a potential candidate for IBD prevention. It might be developed into a functional food for promoting gastrointestinal health. This research sheds light on the preventive potential of natural compounds like ECE in the management of IBD, offering a safer and more effective approach to combating this challenging disease.

Obesity affects nearly 660 million adults worldwide and is known for its many comorbidities. Although the phenomenon of obesity is not fully understood, science regularly reveals new determinants of this pathology. Among them, the persistent organic pollutants (POPs) have been recently highlighted. Mainly lipophilic, POPs are normally stored in adipose tissue and can lead to adverse metabolic effects when released into the bloodstream. The main objective of this narrative review is to discuss the different pathways by which physical activity may counteract POPs adverse effects. The research that we carried out seems to indicate that physical activity could positively influence several pathways negatively influenced by POPs, such as insulin resistance, inflammation, lipid accumulation, adipogenesis and gut microbiota dysbiosis that are associated with the development of obesity. This review also indicates how, through the controlled mobilization of POPs, physical activity could be a valuable approach to reduce the concentration of POPs in the bloodstream. These findings suggest that physical activity should be used to counteract the adverse effects of POPs. However, future studies should accurately assess its impact in specific situations such as bariatric surgery where weight loss promotes POPs blood release.

The purpose of this work was to investigate whether two-months supplementation with 100% sea buckthorn juice (SBJ) would modify blood lipids, LDL subfractions and other markers of cardiovascular risk in hypercholesterolemic women. A group of 28 hypercholesterolemic non-medicated adult women with a mean age of 50.58 ± 5.76 years consumed 50 mL of 100% SBJ daily for two-months. We observed a significant reduction of body weight (BW; p < 0.05), body mass index (BMI; p < 0.05), body fat mass (BFM; p < 0.001) and visceral fat area (VFA; p < 0.001), on the contrary, a significant increase of skeletal muscle mass (SMM; p < 0.05) and fat-free mass (FFM; p < 0.05). Supplementation with 100% SBJ significantly increased the level of high-density lipoprotein (HDL; p < 0.05), reduced the level of low-density lipoprotein (LDL; p < 0.05), atherogenic LDL subfractions (LDL3–7; p < 0.05) and improved LDL/HDL ratio (p < 0.001). After the SBJ consumption, significant reduction of C-reactive protein (CRP; p < 0.001), orosomucoid (ORM; p < 0.001) and interleukin 6 (IL-6; p < 0.05) were found. In conclusion, consumption of SBJ showed an indication of beneficial effects on cardiovascular risk factors in hypercholesterolemic women.

Inflammation can regulate hepatic drug metabolism enzymes and transporters. The impact of inflammation on renal drug transporters remains to be elucidated. We aimed to quantify the effect of inflammation (caused by acute pyelonephritis) on the in vivo activity of renal OAT1/3, using the probe drug furosemide. Pregnant women (2nd or 3rd trimester) received a single oral dose of furosemide 40 mg during acute pyelonephritis (Phase 1; n = 7) and after its resolution (Phase 2; n = 7; by treatment with intravenous cefuroxime 750 mg TID for 3-7 days), separated by 10 to 14 days. IL-6, IFN-γ, TNF-α, MCP-1, and C-reactive protein plasma concentrations were higher in Phase I vs Phase II. The pregnant women had a lower geometric mean [CV%] furosemide CLsecretion (3.9 [43.4] vs 6.7 [43.8] L/h) and formation clearance to the glucuronide (1.1 [85.9] vs 2.3 [64.1] L/h) in Phase 1 vs. Phase 2. Inflammation reduced the in vivo activity of renal OAT1/3 (mediating furosemide CLsecretion) and UGT1A9/1A1 (mediating the formation of furosemide glucuronide) by approximately 40% and 54%, respectively, presumably by elevating plasma cytokine concentrations. The dosing regimens of narrow therapeutic window OAT drug substrates may need to be adjusted during inflammatory conditions.

The metabolism of lipoproteins, which regulates the transit of the lipid to and from tissues, is crucial to maintaining cholesterol homeostasis. Cardiac remodeling is referred to as a set of molecular, cellular, and interstitial changes that, following injury, affect the size, shape, function, mass, and geometry of the heart. Acetyl coenzyme A (acetyl CoA), which can be made from glucose, amino acids, or fatty acids, is the precursor for the synthesis of cholesterol. In this article, authors explain concepts behind cardiac remodeling, its clinical ramifications, and the pathophysiological roles played by numerous various components, such as cell death, neurohormonal activation, oxidative stress, contractile proteins, energy metabolism, collagen, calcium transport, inflammation, and geometry. The levels of cholesterol are traditionally regulated by two biological mechanisms at the transcriptional stage. First, the SREBP transcription factor family regulates the transcription of crucial rate-limiting cholesterogenic and lipogenic proteins, which in turn limits cholesterol production. Immune cells become activated, differentiated, and divided, during an immune response with the objective of eradicating the danger signal. In addition to creating ATP, which is used as energy, this process relies on metabolic reprogramming of both catabolic and anabolic pathways to create metabolites that play a crucial role in regulating the response. Because of changes in signal transduction, malfunction of the sarcoplasmic reticulum and sarcolemma, impairment of calcium handling, increases in cardiac fibrosis, and progressive loss of cardiomyocytes, oxidative stress appears to be the primary mechanism that causes the transition from cardiac hypertrophy to heart failure. De novo cholesterol production, intestinal cholesterol absorption, and biliary cholesterol output are consequently crucial processes in cholesterol homeostasis. In the article's final section, the pharmacological management of cardiac remodeling is explored. The route of treatment is explained into different steps: including, promising, and potential strategies. This chapter offers a brief overview of the history of the study of cholesterol absorption as well as the different potential therapeutic targets.

Organ transplantation remains the only treatment option for patients with end-stage organ dysfunction. However, there are numerous limitations that challenge its clinical application, including the shortage of organ donations, the quality of donated organs, injury during organ preservation and reperfusion, primary and chronic graft dysfunction, acute and chronic rejection, infection, and carcinogenesis in post-transplantation patients. Acute and chronic inflammation and cell death are two major underlying mechanisms for graft injury. Necroptosis is a type of programmed cell death involved in many diseases and has been studied in the setting of all major solid organ transplants, including the kidney, heart, liver, and lung. It is determined by the underlying donor organ conditions (e.g., age, alcohol consumption, fatty liver, hemorrhage shock, donation after circulatory death, etc.), preservation conditions and reperfusion, as well as allograft rejection. Specific molecular mechanisms of necroptosis have been uncovered in the organ transplantation setting, and potential targeting drugs have been identified. We hope this review article will promote more clinical research to determine the role of necroptosis and other types of programmed cell death in solid organ transplantation to alleviate the clinical burden of ischemia-reperfusion injury and graft rejection.

Autism Spectrum Disorder (ASD) is characterized by varying degrees of difficulty in social interaction and communication. These deficits are often associated with gastrointestinal symptoms, indicating alterations in both intestinal microbiota composition and metabolic activities. The intestinal microbiota influences the function and development of the nervous system. In individuals with ASD, there is an increase in bacterial genera such as Clostridium, as well as species involved in the synthesis of branched-chain amino acids (BCAA) like Prevotella copri. Conversely, decreased amounts of Akkermansia muciniphila, and Bifidobacterium spp. are observed. Epigallocatechin gallate (EGCG) is one of the polyphenols with the greatest beneficial activity on microbial growth and its consumption is associated with reduced psychological distress. Therefore, the objective of this review is to analyze how EGCG and its metabolites can improve the microbial dysbiosis present in ASD and its impact on the pathology. The analysis reveals that EGCG inhibits the growth of pathogenic bacteria like Clostridium perfringens and Clostridium difficile. Moreover, it increases the abundance of Bifidobacterium spp. and Akkermansia spp. As a result, EGCG demonstrates efficacy in increasing the production of metabolites involved in maintaining epithelial integrity and improving brain function. This identifies EGCG as highly promising for complementary treatment in ASD.

The purpose of this study was to investigate the effect that Glycine max hydrolyzed with enzymes from Bacillus velezensis KMU01 has on dextran sulfate sodium (DSS)-induced colitis in mice. Hydrolysis improves functional health through the bioconversion of raw materials and increase in intestinal absorption rate and antioxidants. Therefore, G. max was hydrolyzed in this study using a food-derived microorganism, and its anti-inflammatory effect observed. Enzymatically hydrolyzed G. max (EHG) was orally administered once daily for four weeks before DSS treatment. Colitis was induced in mice through consumption of 5% (w/v) DSS in drinking water for eight days. Results showed that EHG treatment significantly alleviated DSS-induced body weight loss and decreased the disease activity index and colon length. In addition, EHG markedly reduced tumor necrosis factor-a, interleukin (IL)-1b, and IL-6 production, and increased that of IL-10. EHG improved DSS-induced histological changes and intestinal epithelial barrier integrity in mice. Moreover, we found that the abundance of 15 microorganisms changed significantly; that of Proteobacteria and Escherichia coli, which are upregulated in patients with Crohn’s disease and ulcerative colitis, decreased after EHG treatment. These results suggest that EHG has a protective effect against DSS-induced colitis and is a potential candidate for colitis treatment.

Gram-negative bacterial infections pose a significant threat to public health. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and induces innate immune responses, autophagy and cell death, which have major impacts on the body physiological homeostasis. However, the role of TLR4 in bacterial LPS-induced autophagy and apoptosis in large mammals remains unknown, which are closer to humans than rodents in many physiological characteristics. So far, few reports focus on the relationship between TLR, autophagy and apoptosis in large mammal levels. We urgently need more tools to further explore their crosstalk. Here, we generated a TLR4-enriched mammal model (sheep) and found that a high-dose LPS treatment blocked autophagic degradation and caused strong innate immune responses and severe apoptosis in PBMCs of transgenic offspring. Excessive accumulation of autophagosomes/autolysosomes might contribute to LPS-induced apoptosis in PBMCs of transgenic animals. Further study demonstrated that inhibiting TLR4 downstream NF-κB or p38 MAPK signaling pathways reversed the LPS-induced autophagy activity and apoptosis. These results indicate that the elevated TLR4 aggravates LPS-induced PBMCs apoptosis by leading to lysosomal dysfunction and impaired autophagic flux, which is associated with TLR4 downstream NF-κB and MAPK signaling pathways. This study provides a novel TLR4-enriched mammal model to study its potential effects on autophagy activity, inflammation, oxidative stress and cell death. These findings also enriched the biological functions of TLR4 and provided powerful evidence for bacterial infection.

Tryptophan is an essential nutrient required to produce niacin (vitamin B3), which is needed for energy metabolism and DNA production. Alterations in tryptophan metabolism could have significant effects on aging and musculoskeletal health. The kynurenine pathway, the main catabolic route of tryptophan, is modulated by inflammatory factors, which are increased in older persons, a process known as inflammaging. Osteoporosis, sarcopenia, osteosarcopenia and frailty have also been linked with chronic increased levels of inflammatory factors. Due to the disruption of the kynurenine pathway by chronic inflammation and/or changes in the gut microbiota, serum levels of toxic kynurenines are increased and have been associated with osteoporosis, sarcopenia and frailty. In contrast, anabolic end products of this pathway, such as picolinic acid, have demonstrated a beneficial effect on bone and muscle. In addition, recent studies have shown that physical activity can modulate this pathway by promoting the secretion of anabolic kynurenines. According to the evidence collected, kynurenines could have a promising role as biomarkers for osteoporosis sarcopenia, osteosarcopenia and frailty in older persons. In addition, some of these metabolites could become important targets for developing new pharmacological treatments for these conditions.

Background: primary sclerosing cholangitis (PSC) is a chronic cholestatic disease characterized by inflammation and fibrosis of the bile ducts. Cholestasis may lead to hepatic inflammation and fibrosis, and amelioration of cholestasis may allow recovery from inflammatory and fibrotic pathological damage. Prevotella copri (P. copri) intervention have been reported could significantly improve cholestasis and liver fibrosis in DDC-induced PSC mice model. Despite alone P. copri treatment could not recover DDC-induced inflammation, it increased the abundance of Lactobacillus murinus (L. murinus) compared to DDC treatment, which has been reported to have anti-inflammatory effects. The abundance of L. murinus still not recover to normal level may underlie hepatic inflammation in P. copri+DDC mice. Method: alone or in combination interventions of P. copri and L. murinus were used to investigate the molecular mechanism of improvement of PSC inflammation and fibrosis. Results: P. copri and L. murinus significantly reduced the hepatic inflammatory cell aggregation and inflammatory factor expression, as well as the hepatic collagen content and fibrin factor expression in PSC mice. Further analysis of phosphorylation and dephosphorylation levels revealed that P. copri and L. murinus combined intervention in PSC mice inhibited the activity of DDC-activated TGF-β1/Smad pathway, thereby reducing liver inflammation and fibrosis. Conclusion: combination of P. copri and L. murinus inhibits the TGF-β1/Smad pathway and reduces inflammation and fibrosis in PSC.

Bronchial asthma (BA) is considered a chronic inflammatory disorder associated with airway hyperresponsiveness (AHR). Increased oxidative stress (OS) is a clinical feature of BA, which promotes the inflammatory responses in bronchial/airway epithelial cells. Smokers and nonsmokers with asthma have been shown to have increases in several OS and inflammatory biomarkers. A few studies suggest a relationship between antioxidant intake from diet/supplements and BA in smoking and nonsmoking asthmatics. Dietary carotenoids and vitamin C (VC) intake might reduce BA risk in smokers and/or non-smokers. Evidence is lacking on the protective role of antioxidant vitamin and/or mineral consumption against BA in smokers and nonsmokers with respect to inflammation and OS biomarkers. Therefore, the aim of this review is to highlight current knowledge regarding the relations between antioxidant intake, BA and its associated biomarkers in smokers and nonsmokers.

Oxidative stress and inflammation are basic pathogenic factors involved in tissue injury, pain, as well as acute and chronic diseases. Since long-term uses of steroids and non-steroidal anti-inflammatory drugs (NSAIDs) cause severe adverse effects, novel effective materials with minimal side effects are required. In this study, polyphenol content and antioxidative activity of rosebud extracts from 24 newly-crossbred Korean roses were analyzed. Among them, Pretty Velvet rosebud extract (PVRE) were found to contain high polyphenols and to show in vitro antioxidative and anti-inflammatory activities. In RAW 264.7 cells stimulated with lipopolysaccharide (LPS), PVRE down-regulated mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and thereby decreased nitric oxide (NO) and prostaglandin E2 (PGE2) production. In an air-pouch inflammation model, treatment with PVRE decreased λ-carrageenan-induced tissue exudation, infiltration of inflammatory cells including neutrophils, monocytes and lymphocytes, and tumor necrosis factor-α and interleukin-1β concentrations, as achieved with dexamethasone (a steroid). Notably, PVRE also inhibited PGE2, similar to dexamethasone and indomethacin (an NSAID). The anti-inflammatory effects of PVRE were confirmed by microscopic findings, attenuating tissue erythema, edema, and inflammatory cell infiltration. These results indicate that PVRE exhibits dual (steroid- and NSAID-like) anti-inflammatory activities by blocking both the iNOS ― NO and COX-2 ― PG pathways, and that PVRE could be a promising anti-inflammatory material for diverse issue injuries.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been linked to changes in amino acid (ΑΑ) levels. The current observational study sought to investigate the relationship between plasma AA concentrations in a NAFLD population and MRI parameters reflecting inflammation and fibrosis, inflammatory and oxidative stress markers, and disease-related anthropometric and biochemical indicators. Approach & Results: Plasma AA levels were quantified with liquid chromatography in 97 NAFLD patients from the MAST4HEALTH study. Medical, anthropometric and lifestyle characteristics were collected and biochemical parameters, as well as inflammatory and oxidative stress biomarkers were measured. In total, males and subjects with higher MRI-proton density fat fraction (MRI-PDFF) exhibited higher plasma AA levels compared to females and subjects with lower PDFF respectively. Several associations of AAs with disease related markers were revealed, with the more prominent ones being those of aromatic amino acids with log-PDFF (beta: 1.190E-02, p-Value: 0.001) and log-ALT (beta: 7.55E-03, p-Value: 0.001), of branched amino acids with log-insulin (beta: 1.97E-03, p-Value: 1.16E-04) and of ethanolamine (beta: 0.036, p-Value: 3.65E-04) and L-ornithine (beta: 5.4E-04, p-Value: 0.021) with log-total antioxidant status (TAS). Conclusions: Plasma AA levels varied according to sex, BMI, and several MRI clinical factors. Furthermore, significant relationships were demonstrated between AA and several disease indicators, such as MRI parameters, biochemical and oxidative stress indices, showing the potential utility of AAs as diagnostic dis-ease-related indicators activity.

Obesity is characterized by chronic low-grade inflammation. Caveolin-1 (CAV1), a structural and functional protein found in adipose tissues (AT), is augmented in obese individuals. We aimed to define the inflammatory mediators that influence CAV1 gene regulation and associated mechanism in obesity. Using subcutaneous AT from 27 (7 lean/20 obese) normoglycemic individuals, in vitro human adipocyte models, and in vivo mice models, we found elevated CAV1 expression in obese AT and a positive correlation between the gene expression of CAV1, tumor necrosis factor alpha (TNF-α), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). CAV1 gene expression was associated with that of proinflammatory cytokines/chemokines, and their cognate receptor (r ≥ 0.447, p ≤ 0.030) but not with anti-inflammatory markers. CAV1 expression was correlated with CD163, indicating a prospective role for CAV1 in adipose inflammatory microenvironment. Unlike wild-type animals, mice lacking TNF-α exhibited reduced levels of CAV1 mRNA/proteins, which were elevated by administering exogenous TNF-α. Mechanistically, TNF-α induces CAV1 gene transcription by mediating NF-kB binding to its two regulatory elements located in the CAV1 proximal regulatory region. The interplay between CAV1 and TNF-α signaling pathway is interesting and has potential as a target for therapeutic interventions in obesity and metabolic syndromes.

Low back pain is a clinically highly relevant musculoskeletal burden and is associated with inflammatory as well as degenerative processes of the intervertebral disc. However, the pathophysiology and cellular pathways contributing to this devastating condition are still poorly understood. Based on previous evidence, we hypothesize that tissue renin-angiotensin system (tRAS) components, including the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2), are present in human nucleus pulposus (NP) cells and associated with inflammatory and degenerative processes. Experiments were performed with NP cells from 4 human donors. The existence of angiotensin II, angiotensin II type 1 receptor (AGTR1), AGTR2, MAS-receptor (MasR), and ACE2 in human NP cells was validated with immunofluorescent staining and gene expression analysis. Hereafter the cell viability was assessed after adding agonists and antagonists of the target receptors as well as angiotensin II in different concentrations for up to 48 hours of exposure. A TNF-α-induced inflammatory in vitro model was employed to assess the impact of angiotensin II addition and the stimulation or inhibition of the tRAS receptors on inflammation, tissue remodeling, expression of tRAS markers, and the release of nitric oxide (NO) into the medium. Further, protein levels of IL-6, IL-8, IL-10, and intracellular as well as secreted angiotensin II were assessed after exposing the cells to the substances, and inducible nitric oxide synthase (iNOS) levels were evaluated utilizing Western Blot. The existence of tRAS receptors and angiotensin II were validated in human NP cells. Cell viability analysis revealed no cytotoxic effects of angiotensin II. The AGTR1 inhibitor Candesartan and the MAS receptors AVE0991 showed cytotoxic effects at high concentrations (100 µM). The addition of angiotensin II only showed a mild impact on gene expression markers. However, there was a significant increase in NO secreted by the cells. The gene expression ratios of pro-inflammatory/anti-inflammatory cytokines IL-6/IL--10, IL-8/IL-10, and TNF-α /IL-10 were positively correlated with the AGTR1/AGTR2 and AGTR1/MAS1 ratios, respectively. The stimulation of the AGTR2 MAS-receptor and the inhibition of the AGTR1 receptor revealed beneficial effects on the gene expression of inflammatory and tissue remodeling markers. This finding was also present at the protein level. We did not find alterations in iNOS protein concentrations after adding the drugs. The current data showed that tRAS components are expressed in human NP cells and are associated with inflammatory and degenerative processes. Further characterization of the associated pathways is warranted. The findings indicate that tRAS modulation might be a novel therapeutic approach to intervertebral disc disease.

Worldwide, the prevalence of surgery under general anaesthesia has increased significantly, on one hand because of modern anaesthetic and pain control techniques, and on the other hand because of better diagnosis and increased complexity of surgical technique. Together with the development of new concepts in the surgical field, the attention of researchers and clinicians turned to minimizing the impact of surgical trauma and offering minimal invasive procedures. This fact is due to the recent discoveries in the field of cellular and molecular mechanisms, that have revealed a systemic inflammatory and pro-oxidative impact that not only lasts in the perioperative period, but also impacts the long term, contributing to more difficult recovery, increased morbidity, and mortality, and finally a negative financial impact. Detailed molecular and cellular analysis have shown an overproduction of inflammatory and pro-oxidative species, that are responsible for an augmentation of the systemic inflammatory status and more difficult postoperative recovery. Moreover, it was shown that there are a series of changes in certain epigenetic structures, the most important being the microRNAs. Based on these findings, a series of modern, targeted therapeutic approaches have been proposed, with the final goal of blocking these mechanisms and reducing the redox state. Recent studies carried out had a positive clinical impact regarding antioxidant therapy and have shown that it can be used in the perioperative period with beneficial clinical impact. This review describes and details the most important molecular and cellular mechanisms that impact the surgical patient undergoing general anaesthesia, and it presents a series of antioxidant therapies that can reduce systemic inflammation.

The neural-crest derived enteric nervous system (ENS) is the intrinsic nervous system of the gastrointestinal (GI) tract and controls all gut functions, including motility. Lack of ENS neurons causes various ENS disorders such as Hirschsprung Disease. One treatment option for ENS dis-orders includes the activation of resident stem cells to regenerate ENS neurons. Regeneration in the ENS has mainly been studied in mammalian species using surgical or chemically-induced injury methods. These mammalian studies showed a variety of regenerative responses with generally limited regeneration of ENS neurons, but (partial) regrowth and functional recovery of nerve fibers. Several aspects might contribute to the variety in regenerative responses, including observation time after injury, species, and gut region targeted. Zebrafish have recently emerged as a promising model system to study ENS regeneration as larvae possess the ability to generate new neurons after ablation. As the next steps in ENS regeneration research, we need a detailed under-standing of how regeneration is regulated on a cellular and molecular level both in animal models with high and low regenerative capacity. Understanding the regulatory programs necessary for robust ENS regeneration will pave the way for using neural regeneration as a therapeutic approach to treating ENS disorders.

The interrelationship between periodontal disease, obesity-related hyperlipidemia and mechanical forces as well as their modulating effects on the epigenetic profile of periodontal ligament (PdL) cells are assumed to be remarkably complex. The PdL serves as connective tissue between teeth and alveolar bone for pathogen defense and inflammatory response to mechanical stimuli occurring during tooth movement. Altered inflammatory signaling could promote root resorption and tooth loss. Hyperinflammatory COX2/PGE2 signaling was reported for human PdL fibroblasts (HPdLF) concomitantly stressed with P. gingivalis lipopolysaccharides and compressive force after exposure to palmitic acid (PA). The aim of this study was to investigate to what extent this is modulated by global and gene-specific changes in histone modifications. Quantitative expression of epigenetic key players and global H3Kac as well as H3K27me3 levels were evaluated in dual stressed HPdLF exposed to PA revealing a decreased force-related reduction in repressive H3K27me3. UNC1999-induced H3K27me3 inhibition reversed the hyperinflammatory response of dual-stressed PA-cultures characterized by COX2 expression, PGE2 secretion and THP1 adhesion. Reduced expression of the anti-inflammatory cytokine IL10 and increased association of H3K27me3 at its promoter-associated sites were reversed by inhibitor treatment. Thus, the data highlight an important epigenetic interplay between different stimuli to which the PdL is exposed.

Type 2 Diabetes Mellitus is being increasingly associated with dysfunction of cognition. Dementia, including vascular dementia and Alzheimer’s disease, is being recognized as comorbidities of this metabolic disorder. The progressive hallmarks of this cognitive dysfunction include mild impairment of cognition and cognitive decline. Dementia and mild impairment of cognition appear in older patients primarily. Studies on risk factors, neuropathology, and brain imaging have provided important suggestions for mechanisms that lie behind the development of dementia. It is a significant challenge to understand the disease processes related to diabetes which affect the brain and lead to dementia development. The connection between Diabetes Mellitus and dysfunction of cognition has been observed in many human and animal studies that have noted mechanisms related to Diabetes Mellitus are possibly responsible for aggravating cognitive dysfunction. This article attempts to narrate the possible association between type 2 diabetes and Dementia, reviewing studies that have noted this association in vascular dementia and Alzheimer’s disease and helping to explain the potential mechanisms behind the disease process. The Google search for ‘Diabetes Mellitus and Dementia’ was carried out. Also, the search was done using ‘Diabetes Mellitus,’ ‘Vascular Dementia,’ ‘Alzheimer’s Disease.’ The literature search was done from Google Scholar, Pubmed, Embase, ScienceDirect, and MEDLINE. Keeping in mind the increasing rate of Diabetes Mellitus, it is important to establish the type 2 diabetes effect on the brain and diseases of neurodegeneration. This narrative review aims to build awareness regarding different types of dementia and their relationship with diabetes.

Hyperleptinemia potentiates the effects of many atherogenic factors, such as inflammation, platelet aggregation, migration, hypertrophy, proliferation of vascular smooth muscle cells, and endothelial cell dysfunction. The present study analysed the effects of long-term hyperleptinemia in an in vivo myocardial ischemia-reperfusion model to demonstrate whether the in vivo deleterious effect also affects cardiac structure and function. Rats by were subcutaneously administered leptin for 8 days to estimate the involvement of the JAK/STAT pathway. Data from 58 male Wistar rats were included in the final analysis. Myocardial infarction (MI) was modelled by the 30-minute ligation of the main left coronary artery followed by 120-minute reperfusion. Hemodynamic measurements, electrocardiography monitoring, echocardiography, myocardial infarct size and area at risk, blood biochemical parameters, leptin, IL-6, TNF-alpha, FGF-21, and cardiomyocyte morphology were measured. Statistical analyses were performed using IBM SPSS Statistics v.26. Seven-day hyperleptinemia in rats led to increased an blood pressure and heart rate, myocardial hypertrophy, impaired LV function, an increased frequency of ischemic arrhythmias, dyslipidaemia, systemic inflammation, and an increased size of induced myocardial infarction. The blockade of the JAK/STAT signalling pathway effectively reversed the negative effects of leptin, including increased blood pressure and total cholesterol.

The increased global incidence of myopia requires the establishment of therapeutic approaches. Previous studies have suggested that inflammation plays an important role in the development and progression of myopia. We used human retinal pigment epithelial cell to study the molecular mechanisms on how FJE and PVE lowering the inflammation of the eye. The effect of FJE and PVE in MFD induced hamster model and explore the role of inflammation cytokines in myopia. Expression levels of IL-6, IL-8, and TNF-α were upregulated in retinal pigment epithelium (RPE) cells treated with IL-6 and TNF-α. FJ extract (FJE) + PV extract (PVE) reduced IL-6, IL-8, and TNF-α expression in RPE cells. Furthermore, FJE and PVE inhibited inflammation by attenuating the phosphorylation of protein kinase B (AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) pathway. In addition, we report two resveratrol + ursolic acid compounds from FJ and PV and their inhibitory activities against IL-6, IL-8, and TNF-α expression levels in RPE cells treated with IL-6 and TNF-α. FJE, PVE, and FJE + PVE were applied to MFD hamsters and their axial length was measured after 21 days. The axial length showed statistically significant differences between phosphate-buffered saline- and FJE-, PVE-, and FJE + PVE-treated MFD eyes. FJE + PVE suppressed expressions of IL-6, IL-8, and TNF-α. They also inhibited myopia-related transforming growth factor-beta (TGF)-β1, matrix metalloproteinase (MMP)-2, and NF-κB expression while increasing type Ⅰ collagen expression. Overall, these results suggest that FJE + PVE may have a therapeutic effect on myopia and be used as a potential treatment option.

Inside Central Nervous System (CNS) appears neurons and glia cells. There are more glial cells than neurons and have more functions than neurons. Glia name represents different kind of cells, ones from neural origin (astrocytes, radial glia, and oligodendroglia), and others from blood monocytes (microglia). During ontogeny, neurons appear first (rat fetal 15th) and after astrocytes (rat fetal 21th) indicating a bigger importance function in the CNS. Also, during the phylogeny, reptiles have less astrocytes compared to neurons and in humans, astrocytes are double in number than neurons. This data, perhaps means that astrocytes are more special cells and work in memory and learning? Astrocytes have an important role in different mechanisms protecting CNS across the production of antioxidant and anti-inflammatory proteins, cleaning extracellular medium and helping neurons to communicate with each other correctly. Inflammatory mediators production are important to prevent changes in normal physiology. But, excessive or continue production leads to many diseases, such as Alzheimer's disease (AD), Sclerosis Lateral Amyotrophic (ELA), Multiple sclerosis (MS), and neurodevelopment diseases, like Bipolar disorder, Schizophrenia, and Autism's symptomatology. Different drugs and thecniques can reverse oxidative stress and/or inflammatory excess. This review is intended to serve as an approximation to the field.

Apoptosis, the programmed and intentional death of senescent, damaged, or otherwise superfluous cells, is the natural end-point for most cells within multicellular organisms. Apoptotic cells are not inherently damaging, but if left unattended they can lyse through secondary necrosis. The resulting release of intracellular contents drives inflammation in the surrounding tissue and can lead to autoimmunity. These negative consequences of secondary necrosis are avoided by efferocytosis—the phagocytic clearance of apoptotic cells. Efferocytosis is a product of both apoptotic cell and efferocyte mechanisms, which cooperate to ensure the rapid and complete removal of apoptotic cells. Herein, the processes used by apoptotic cells to ensure their timely removal, and the receptors, signaling, and cellular processes used by efferocytes to identify, remove, and process the apoptotic cells, are reviewed.

Long-haul COVID-19 illness first gained widespread recognition among social support groups and later in scientific and medical communities. This illness is mysterious as it affects COVID-19 survivors at all levels of disease severity, even younger adults and children. While the precise definition may be lacking, the defining symptoms are fatigue, dyspnea, and headache that last for months after hospital discharge. The less typical symptoms may include cognitive impairments, chest and joint pains, myalgia, smell and taste dysfunctions, cough, mood changes, and gastrointestinal and cardiac issues. Presently, there is limited literature discussing the possible pathophysiology, risk factors, and treatments in long-haul COVID-19, which the current review aims to address. In brief, long-haul COVID-19 may be driven by long-term lung and brain damage and unresolved inflammation from multiple sources. The associated risk factors may include female sex, more than five early symptoms, early dyspnea, and specific biomarkers like D-dimer. While only rehabilitation training has been useful for long-haul COVID-19, therapeutics repurposed from mast cell activation syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, and pulmonary fibrosis also hold potential. In sum, this review hopes to provide the current understanding of what is known about long-haul COVID-19.

HLA class I alleles constitute established risk factors for non-infectious uveitis and preemptive genotyping of HLA class I alleles is standard practice in the diagnostic work-up. The HLA-A29 serotype is indispensable to Birdshot Uveitis (BU) and renders this enigmatic eye condition a unique model to better understand how the antigen processing and presentation machinery contributes to non-infectious uveitis or chronic inflammatory conditions in general. This review will discuss salient points regarding the protein structure of HLA-A29 using and how key amino acid positions impact the peptide binding preference and interaction with T cells. We discuss to what extent the risk genes ERAP1 and ERAP2 uniquely affect HLA-A29 and how the discovery of a HLA-A29-specific submotif may impact autoantigen discovery. We further provide a compelling argument to solve the long-standing question why BU only affects HLA-A29-positive individuals from Western-European ancestry by exploiting data from the 1000 Genomes Project. We combine novel insights from structural and immunopeptidomic studies and discuss the functional implications of genetic associations across the HLA class I antigen presentation pathway to refine the etiological basis of Birdshot Uveitis.

Indoor dusts are collectively formed from anthropogenic and atmospheric activities. Particle matter 10 (PM10) is inhalable and causes significant inflammation by interaction with the pulmonary epithelial barrier. The mediators involved in bronchial epithelial cells response to dust are remined unknown. The air-liquid interface of our lung on chip model was exposed to indoor dust collected from highly polluted houses in Delhi, India. The media were collected after 4 days and cytokine levels were measured. We found that the concentration of IFN, IFNγ, Interleukin-6 (IL-6), IL1b, TNFa, and Granulocyte monocyte colony stimulating factor (GM-CSF) were significantly increased after exposure to indoor dust. IFN type I pathways were a major response from dust exposure. Further investigation is needed to determine the mechanism of action and targets of dust in bronchial epithelial cells.

High-frequency near-infrared diode laser provides high peak output, low heat accumulation, and efficient biostimulation. Although these characteristics are considered suitable for osteoarthritis (OA) treatment, the effect of high-frequency near-infrared diode laser in in vitro or in vivo OA models has not yet been reported. Therefore, we aimed to assess the biological effects of high-frequency near-infrared diode laser irradiation on IL-1β-induced chondrocyte inflammation in an in vitro OA model. Normal Human Articular Chondrocyte-Knee (NHAC-Kn) cells were stimulated with human recombinant IL-1β and irradiated with high-frequency near-infrared diode laser (910 nm, 4 or 8 J/cm2). The mRNA and protein expression of relevant inflammation- and cartilage destruction-related proteins was analyzed. IL-1β treatment significantly increased the mRNA levels of IL-1β, IL-6, TNF-α, MMP-1, MMP-3, and MMP-13. High-frequency near-infrared diode laser irradiation significantly reduced the IL-1β-induced expression of IL-1β, IL-6, TNF-α, MMP-1, and MMP-3. Similarly, high-frequency near-infrared diode laser irradiation decreased the IL-1β-induced increase in protein expression and secreted levels of MMP-1 and MMP-3. These results highlight the therapeutic potential of high-frequency near-infrared diode laser in OA.

Major Depression Disorder (MDD) is accompanied by an immune response characterized by increased levels of pro-inflammatory and immune-regulatory cytokines and cytokine-induced stimulation of indoleamine-2,3-dioxygenase (IDO). There is also some evidence that anti-inflammatory drugs may have a clinical efficacy in MDD.The aim of this study is to examine the clinical effects of an eight-week combinatorial treatment of ketoprofen (a nonsteroidal anti-inflammatory drug) combined or not with sertraline, on serum levels of IDO, interferon (IFN)-γ, interleukin (IL)-4 and transforming growth factor (TGF)-β1 in association with changes in the Beck-Depression Inventory-II (BDI-II). The study included 140 MDD patients and 40 normal controls. The pre-treatment serum levels of IDO, IFN-γ, TGF-β1 and IL-4 were significantly higher in MDD patients compared with the control group. Treatment with sertraline with or without ketoprofen significantly reduced the increased baseline production of all 4 biomarkers to levels which were similar as those of normal controls. Ketoprofen add-on had a significantly greater effect on IDO and BDI-II as compared with placebo. The reductions in IDO, IL-4 and TGF-β1 during treatment were significantly associated with those in the BDI-II.In conclusion, the clinical efficacy of both sertraline + ketoprofen may be ascribed at least in part to attenuated IDO levels and immune-inflammatory responses in MDD. Moreover, add-on treatment with ketoprofen may augment the efficacy of sertraline by attenuating IDO. However, these treatments may also significantly reduce the more beneficial properties of T helper-2 and T regulatory (Treg) immune subsets. Future research should develop immune treatments that target the immune-inflammatory response in MDD, while enhancing the compensatory immune-regulatory system (CIRS).

Increased gut permeability (leaky gut) with increased translocation of Gram-negative bacteria plays a role in the gut-brain axis through effects on systemic immune-inflammatory processes. Deficit schizophrenia is characterized by an immune-inflammatory response combined with a deficit in natural IgM antibodies to oxidative specific epitopes (OSEs), which are a first line defense against bacterial infections. This study measured plasma IgA/IgM responses to 5 Gram-negative bacteria in association with IgM responses to malondialdehyde (MDA) and azelaic acid in 80 schizophrenia patients (40 with the deficit syndrome and 40 without) and in 38 healthy controls.Deficit schizophrenia was characterized by significantly increased IgA responses to Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii and Klebsiella pneumoniae as compared with non-deficit schizophrenia. The presence of deficit schizophrenia was highly predicted by increased IgA responses to Pseudomonas putida and IgM responses to all 5 Gram-negative bacteria and lowered natural IgM to MDA and azelaic acid with a bootstrap area under the ROC curve of 0.960 (2000 random curves). A large proportion of the variance (41.5%) in the PANSS negative score was explained by the regression on IgA responses to K. pneumoniae and IgM responses to the 5 enterobacteria coupled with lowered IgM antibodies to azelaic acid. There were significant associations between IgA levels to Gram-negative bacteria and Mini Mental State Examination, Boston naming test, Verbal Fluency and Word List Memory test scores.These findings provide further evidence that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by an increased impact of Gram-negative commensal bacteria coupled with a deficit in natural IgM, pointing to aberrations in B1 cells. It is concluded that increased bacterial translocation and deficits in the compensatory immune-regulatory system (CIRS) may drive negative symptoms and neurocognitive impairments, which are hallmarks of deficit schizophrenia.

Inflammatory bowel disease (IBD) is a CC chemokine receptor 6 (CCR6) - associated immune mediated disorder which has attracted an extensive superfluity of experimental analyses. IBD has come to the fore of varied scrutinizing owing to its complexity by nature for comprising of two synergistic sub phenotypes; Crohn’s disease (CD) and Ulcerative colitis (UC). Both these disease entities cause potent immune dysregulation followed by intense tissue damage within the gut mucosal system, initiating symptoms which are severely debilitating. Multiple causative factors are said to be responsible for IBD but direct immune dysfunction is kindled by overplay of innate and adaptive immune responses produced against a pathogenic microbial attack through the weakened or leaky gut epithelial barrier. Once immune homeostasis is not achieved by tolerating agents, the self-assertive adaptive immunity mobilize its various T and B cell cohorts initializing their allied immune mechanisms by vigorously deploying them towards the site of infection. CCR6 and its unique solitary ligand CC-chemokine ligand 20 (CCL20) are small protein molecules which are abundantly expressed by T and B lymphocytes and act as chemotactic immune-modulatory envoys that help in the deployment of the effector lymphocyte arm of the immune system, producing two directly opposing outcomes in IBD. This dichotomous immunity consists of either immune tolerance or inflammation which then develops into a chronic state, remaining catatonic to inherent immunity or targeted clinical therapy. In this review, we have chronologically identified a plethora of experimental studies radiating into 14 different compartments highlighted in the visual depiction which have employed both mouse models and clinical subjects spanning a period of nearly two decades. In doing so, we expect the research community would further benefit by tracing through the history, thereby understanding the CCR6 –CCL20 axis in IBD and identifying the gaps in literature which can be fortuitously filled in the future.

Introduction. The use of probiotics demonstrate efficacy against obesity and metabolic syndrome (MetS). Detection effective probiotic strains for hyperglycemia and immunity associated with is important task. The aim of the study was to evaluate an influence of Lactobacillus casei IMV B-7280 separately and composition L. casei IMV B-7280 / Bifidobacterium animalis VKB / B. animalis VKL on the levels of blood glucose and immunity in obese mice. Meterials and methods. Obesity was induced by fat-enriched diet (FED) in male BALB/c mice. Obese mice were transferred to standard diet and received per os probiotic strains daily during 10 days. We measured tumor necrosis factor-a (TNF-a) in blood serum using enzyme-linked immunosorbent assay and functional activity of peritoneal exudate macrophages (PEMs). Glucose levels in blood was defined with glucometer. Results. We ascertained that all probiotic strains induced reducing mice weight and visceral fat, normalization of TNF-a production and functional activity of PEMs. Treatment with L. casei IMV B-7280 was associated with decreasing blood glucose levels. No normalization of glucose and TNF-a levels in obese mice, transferred to standard diet without probiotic treatment, although we revealed decreasing their weight and visceral fat and partial recover of functional activity of PEMs. Conclusions. Probiotic strain L. casei IMV B-7280 (separately) and composition L. casei IMV B-7280 / B. animalis VKB / B. animalis VKL can re-equilibrate metabolic and inflammation indices in mouse obesity model. L. casei IMV B-7280 alone was more efficient in decreasing glucose levels than composition of strains.

Metabolic disorders have become among the most serious threats to human health, leading to severe chronic diseases such as obesity, type 2 diabetes, non-alcoholic fatty liver disease, as well as cardiovascular diseases. Interestingly, despite the fact that each of these maladies has different physiological and clinical symptoms, they appear to share certain pathological traits such as intracellular stress and inflammation induced by metabolic derangements stemmed from over nutrition frequently aggravated by modern sedentary life style. These modern ways of living inundate cells and organs with saturating levels of sugar and fat, leading to glycotoxicity and lipotoxicity that induce intracellular stress signaling ranging from oxidative to ER stress response to cope with the metabolic insults [1]. In this review, we discuss the roles played by cellular stress and its responses in shaping metabolic disorders. We have summarized here current mechanistic insights explaining the pathogenesis of these disorders. These are followed by a discussion of the latest therapies targeting the stress response pathways.

Alzheimer’s Disease (AD) is a neurodegenerative condition that currently has no known cure. The principles of the expanding field of network medicine (NM) have recently been applied to AD research. The main principle of NM proposes that diseases are much more complicated than one mutation in one gene, and incorporate different genes, connections between genes, and pathways that may include multiple diseases to create full scale disease networks. AD research findings as a result of the application of NM principles have suggested that functional network connectivity, myelination, myeloid cells, and genes and pathways may play an integral role in AD progression, and may be integral to the search for a cure. Different aspects of the AD pathology could be potential targets for drug therapy to slow down or stop the disease from advancing, but more research is needed to reach definitive conclusions. Additionally, the holistic approaches of network pharmacology in traditional Chinese medicine (TCM) research may be viable options for the AD treatment, and may lead to an effective cure for AD in the future.

Curcumin, a hydrophobic polyphenol compound derived from the rhizome of the Curcuma genus, has a wide spectrum of biological and pharmacological applications. Previously, curcumin nanoparticles with different stabilizers had been produced successfully in order to enhance solubility and per oral absorption. In the present study, we tested the anti-inflammatory effect of D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS)-stabilized curcumin nanoparticles in vivo. Lambda-carrageenan (λ-carrageenan) was used to induce inflammation in rats; it was given by an intraplantar route and intrapelurally through surgery in the pleurisy test. In the λ-carrageenan-induced edema model, TPGS-stabilized curcumin nanoparticles were given orally one hour before induction and at 0.5, 4.5, and 8.5 h after induction with two different doses (1.8 and 0.9 mg/kg body weight (BW)). Sodium diclofenac with a dose of 4.5 mg/kg BW was used as a standard drug. A physical mixture of curcumin-TPGS was also used as a comparison with a higher dose of 60 mg/kg BW. The anti-inflammatory effect was assessed on the edema in the carrageenan-induced paw edema model and by the volume of exudate as well as the number of leukocytes reduced in the pleurisy test. TPGS-stabilized curcumin nanoparticles with lower doses showed better anti-inflammatory effects, indicating the greater absorption capability through the gastrointestinal tract.

Solar energy is a renewable resource of energy that is broadly utilized and has the least emissions among the renewable energies. In this study, machine learning methods of artificial neural networks (ANNs), least squares support vector machines (LSSVM), and neuro-fuzzy are used for advancing prediction models for thermal performance of a photovoltaic-thermal solar collector (PV/T). In the proposed models, the inlet temperature, flow rate, heat, solar radiation, and the sun heat have been considered as the inputs variables. Data set has been extracted through experimental measurements from a novel solar collector system. Different analyses are performed to examine the credibility of the introduced approaches and evaluate their performance. The proposed LSSVM model outperformed ANFIS and ANNs models. LSSVM model is reported suitable when the laboratory measurements are costly and time-consuming, or achieving such values requires sophisticated interpretations.

Post-exercise recovery is fundamental to optimizing athletic performance, focusing on muscle repair, glycogen replenishment, rehydration, and reducing exercise-induced inflammation. This review examines the evolving landscape of recovery nutrition, highlighting the transition from conventional supplements—such as protein, carbohydrates, creatine, and branched-chain amino acids (BCAAs)—to functional foods rich in bioactive compounds. Emerging evidence supports the efficacy of functional foods like tart cherry juice, turmeric, and omega-3 fatty acids in mitigating oxidative stress and inflammation, thus accelerating recovery. Additionally, probiotics and prebiotic-rich foods are gaining recognition for enhancing gut health, promoting nutrient absorption, and strengthening immune function, which are crucial in recovery processes. The concept of personalized nutrition, guided by genetic and metabolic profiling, is explored as a promising approach to tailor recovery strategies to individual physiological needs. Continued research into the long-term effects of supplements, the role of functional foods, and nutrient interactions is essential for developing more comprehensive and individualized recovery protocols. Integrating functional foods with personalized nutrition offers a holistic strategy to enhance recovery, optimize performance, and promote long-term health in athletes.

The blood-brain barrier (BBB) serves as an interface between the bloodstream and central nervous system. It limits the movement of molecules and immune cells, regulates the entry of nutrients, and removes waste products from the brain. The dysfunction of the BBB has been identified in Parkinson´s disease (PD) but the role of the BBB and endothelial cells (ECs) has not been well studied. LRRK2 G2019S mutation is the most common PD causing mutation with similar pathophysiology than in sporadic cases. How the mutation affects EC function has not been investigated previously in patient’s cells. In the study, we used iPSC-derived ECs from PD patients with the LRRK2 mutation as well as cells from healthy individuals. We report that PD ECs have higher levels of α-synuclein, altered mitochondrial respiration and response to inflammatory exposure, especially to TNFα. In addition, transcriptomic analysis showed upregulation of fatty acid synthesis related pathways in PD ECs and downregulation of lncRNA MEG3, both of which have been associated with PD. Altogether, PD ECs manifest some of the PD related hallmarks and are likely to contribute to the pathogenesis of PD.

To evaluate new circulating markers related to macrovascular complications (MVC) in type 2 diabetes mellitus (T2DM), we recruited 30 controls (CG), 34 patients with T2DM (DG), and 28 patients with T2DM and vascular complications (DG+C), among them, 22 presented MVC. Pe-ripheral blood was used to determine redox status (superoxide dismutase, SOD; catalase, CAT; glutathione reductase, GRd; glutathione peroxidase, GPx; glucose-6-phosphate dehydrogenase, G6PD) and markers of oxidative damage (advanced oxidation protein products, AOPP; lipid pe-roxidation, LPO). Inflammatory markers (IL-1β, IL-6, IL-10, IL-18, MCP-1, TNF-α) and the relative expression of c-miRNAs were analyzed. The real-time PCR results showed that the expressions of miR-155-5p, miR-21-5p, miR-146a-3p, and miR-210-3p were significantly higher in the DG group compared to CG. DG+C group presented statistically relevant differences with CG for four miRs: the increased expression of miR-484-5p, miR-21-5p, and miR-210-3p, and decreased for miR-126a-3p. Moreover, miR-126a-3p was significantly less expressed in DG+C compared to DG. The application of binary logistic regression analysis and construction of receiving operator characteristic curves (ROC) revealed two models with high predictive value for vascular complications presence: 1) HbAc1, creatinine, total cholesterol (TC), LPO, GPx, SOD, miR-126, miR-484. 2) HbAc1, creatinine, TC, IL-6, LPO, miR-126, miR-484. Moreover, our data demonstrated that gender, TC, GPx, CAT, and miR-484 were associated with MVC and exhibited higher predictive values than classical variables. miR-126, miR-484, IL-6, SOD, CAT, and GPx participate in vascular damage development in the studied diabetic population and should be considered for future studies.

Background/Objectives: Meconopsis has long been used in traditional Tibetan medicine to treat various diseases. However, blue-flowered Meconopsis (M. betonicifolia) is becoming increasingly scarce due to overharvesting. As a potential alternative, yellow-flowered Meconopsis (M. integrifolia) shows promise but requires comprehensive characterization. This study aimed to evaluate and compare the anti-inflammatory potential of yellow- and blue-flowered Meconopsis species. Methods: LC-MS was used to analyze the chemical profiles of yellow- and blue-flowered Meconopsis. Putative targets of shared constituents were subjected to GO and disease enrichment analysis. The LPS-induced RAW264.7 macrophage model was employed to assess anti-inflammatory effects. Metabolomics was applied to gain mechanistic insights. Results: LC-MS revealed over 70% chemical similarity between species. Enrichment analysis associated targets with inflammation-related pathways. In macrophage assays, both species demonstrated dose-dependent anti-oxidative and anti-inflammatory activities, with yellow Meconopsis exhibiting superior efficacy. Metabolomics showed modulation of key inflammatory metabolic pathways. Conclusions: This integrative study validated yellow-flowered Meconopsis as a credible alternative to its blue-flowered counterpart for anti-inflammatory applications. Metabolic profiling provided initial clues regarding their multi-targeted modes of action, highlighting clinical relevance and potential for sustainable utilization and biodiversity conservation.

Type 2 Diabetes mellitus (T2DM) and cancer share common risk factors including obesity, in-flammation, hyperglycemia, and hyperinsulinemia. High insulin levels activate PI3K/Akt/mTOR signaling pathway promoting cancer cell growth, survival, proliferation, metastasis, and an-ti-apoptosis. The inhibition of PI3K/Akt/mTOR signaling pathway for cancer remains a promising therapy, however, the combination of therapeutic inhibitors may solve the resistance to such agents. Understanding the metabolic link between diabetes and cancer can assist in improving the therapeutic strategies used for the management of cancer patients with diabetes and vice versa. This review provides an overview of shared molecular mechanisms between diabetes and cancer as well as discusses established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management.

This communication is to summarize our single center experience on applications of anti-IL-1 biologic response modifiers on autoimmune and autoinflammatory conditions in children. We present our rationale for off-label utilization of Anakinra and discuss evolving treatment paradigms that warrants further research and validation. Based on our observations and successful treatment outcomes, we advocate future multilateral efforts to liberate access to anti-IL-1 medications to control inordinate and detrimental inflammation in children.

Decompression sickness (DCS) with neurological disorders is the leading cause of diving accidents. Exposure to high levels of CO2 during diving is a safety concern for occupational , groups at risk of DCS. However, the effects of prior exposure to CO2 have never been evaluated. The purpose of this study was to evaluate the effect of CO2 breathing prior to a provocative dive on the occurrence of DCS in mice. 50 mice were exposed to a maximum CO2 concentration of 70 hPa for one hour at atmospheric pressure. Another 50 mice breathing air under similar conditions served as controls. In the AIR group (controls), 22 out of 50 mice showed post-dive symptoms compared to 44 out of 50 in the CO2 group. We found that CO2 breathing is associated with a decrease in body temperature in mice and that CO2 exposure dramatically increases the incidence of DCS. More unexpectedly, it appears that a lower temperature of the animals even before exposure to the accident-prone protocol leads to an unfavorable prognosis. This study also suggests that the composition of the microbiota may influence thermogenesis and thus accidentology. Depending on prior exposure, some bacteria identified in this work could be perceived as protective or pathogenic.

Hirschsprung disease (HSCR, incidence 1/5000 live births) is caused by failure of neural crest-derived precursors to migrate, survive, proliferate or differentiate during the embryonic development of the Enteric Nervous System (ENS), which could be disrupted by many factors, in-cluding inflammatory processes. The NF-κB family controls several biological processes includ-ing inflammation, neurogenesis and cell migration. With the aim of studying the potential role of NF-κB in HSCR, we have analyzed the expression of the NF-κB main subunits and other NF-κB-related genes by RT-qPCR in HSCR tissue samples (sub-divided in ganglionic and agan-glionic segments). We found a decreased gene expression of the NF-κB main subunit RelA/p65, but also of IkBα, TNF-α, TFGBR2 and ERBB3 in the pathologic distal aganglionic segments com-pared to the proximal ganglionic segments. Moreover, we could also confirm the lower protein expression of RelA/p65 in the aganglionic distal segments by immunofluorescence staining. Fur-ther, we show that the expression of RelA/p65 in the proximal segments concurs with lymphocyte infiltration in the bowel tissue, indicating a pro-inflammatory activation of p65 in the proximal ganglionic HSCR tissue in the patients analyzed. In all, our findings suggest that the modulation of NF-κB signaling in the neuro-enteric system does obviously contribute to the pathological ef-fects in HSCR.

Background and Objectives: To investigate the relationship between the SII index and the micro-macro complications and death that develop in the first year and the following 3 years, following the calculation of the index in type 2 diabetic retinopathy patients. Materials and Methods: This study was performed retrospectively with 523 type 2 diabetic retinopathy patients admitted to the endocrinology outpatient clinic of our hospital between January 2019 and December 2019. The demographic, and clinical characteristics of the patients were evaluated using descriptive statistics. Shapiro-Wilk test was used for the normal distribution of quantitative data; Mann-Whitney U, Mc Nemar Chi-square, and Cochran's Q tests were used to analyze SII values between groups and complication rates by years; sensitivity and specificity were determined by ROC analysis and considered statistically significant with a significance level of P

Our report presents the findings from a treatment program that involved plant-based diets (PBDs) and supplements for 1,750 elderly cardiology patients diagnosed with COVID-19 between April 2020 and June 2023. At the start of the program, there was no published data supporting the use of PBDs for COVID-19 patients. However, after 18 months, studies were released that indicated the effectiveness of PBDs in decreasing the incidence and severity of COVID-19. Our treatment protocol differed from these studies in several ways. We carefully controlled the quality, quantity, and processing method of the foods we provided, opting for raw instead of cooked vegetables. Additionally, we incorporated supplementation that complemented the nutrients lacking in a PBD and enhanced the anti-viral, anti-inflammatory, antioxidant, antithrombotic, and immunomodulatory properties of a PBD. Our patients recovered faster (12±1.4 days vs. 20.9±4.3 days), with lower severity (2% vs. 10-20%), hospitalizations (0 vs. 5-10%), and deaths (0 vs. 15-17%) compared to the general population. These favorable outcomes are particularly noteworthy given Indonesia's high COVID-19 morbidity and mortality rates, among the highest in Asia. The findings of this report provide valuable insights for practitioners in managing high-risk elderly COVID-19 patients, particularly in avoiding severity and mortality.

This general review assesses the impact of physical exercise on oxidative and nitrosative stress and the counteractive role of antioxidants, drawing from a systematic literature search up to March 2024 in databases like PubMed and Web of Science. The review highlights studies on the effect of exercise on the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and antioxidant responses in both human and animal models based on rigorous inclusion and exclusion criteria. Due to the variety of exercise types and participants' characteristics, a narrative synthesis approach was adopted. The findings indicate that moderate exercise boosts antioxidant defenses, known as hormesis, whereas excessive physical activity may increase oxidative and nitrosative damage. The review also explores the complex effects of antioxidant supplementation, revealing that while natural dietary antioxidants support health, high-dose supplements could potentially hinder positive adaptations to exercise. Recommendations for athletes and the general active population highlight the importance of balancing exercise and dietary intake to optimize health benefits. The review concludes with a call for more detailed research on tailored exercise and nutrition plans to dissect these intricate relationships further.

Inflammatory bowel disease (IBD), a heterogeneous group of recurring inflammatory condi-tions of the digestive system that encompass both ulcerative colitis (UC) and Crohn’s disease (CD), pose a significant public health challenge, currently lacking a definitive cure. The specif-ic etiopathogenesis of IBD is not yet fully understood, but a multifactorial interplay of genetic and environmental factors is suspected. A growing body of evidence supports the involve-ment of intestinal dysbiosis in the development of IBD, including the effects of dysbiosis on the integrity of the intestinal epithelial barrier, modulation of the host immune system, alter-ations in the enteric nervous system, and the perpetuation of chronic inflammation. A com-prehensive understanding of these mechanisms is important to define preventive measures, to develop new effective and lasting treatments and to improve disease outcome. This review examines the complex tri-directional relationship between gut microbiota, mucosal immune system, and intestinal epithelium in IBD. In addition, nonpharmacological and behavioral strategies aimed at restoring a proper microbial-immune relationship will be suggested.

Abstract: Background: Aging is an important risk factor for cardiovascular diseases and con-vincing data has shown that chronic low-grade inflammation, which develops with advanced age, contributes significantly to cardiovascular risk. Objectives: The present study aimed to use ¹⁸F-FDG/¹⁸F-NaF-PET/CT imaging to respectively gauge arterial inflammation and microcalcifi-cation in healthy elderly and to assess the potential benefits of a tyrosol- and hydroxytyrosol-rich diet on these two markers of atherosclerotic plaque fragility. Methods: Eleven healthy partici-pants (mean age 75 ± 5.67 years) were supplemented for 6 months with high polyphenol-rich extra virgin olive oil (HP-EVOO), extra virgin olive oil (EVOO), or refined olive oil (ROO). The partic-ipants underwent PET/CT imaging with ¹⁸F-FDG and ¹⁸F-NaF radiotracers at baseline and after 6 months. ¹⁸F-FDG and ¹⁸F-NaF uptakes were quantified using standardized uptake values (SUV) and were categorized based on artery calcification and olive oil type. Results: A total of 324 slices of the aortas of the imaged participants were analyzed for arterial inflammation and 327 slices were analyzed for microcalcification. 18F-FDG uptake was significantly higher in the non-calcified segments than in the calcified segments (SUVmax = 2.70  0.62 and SUVmax = 2.54  0.44, respectively, p<0.042). Conversely, the non-calcified segments displayed significantly lower 18F-NaF uptake than the calcified segments (SUVmax = 1.90 0.37 and 2.09  0.24, respec-tively, p<0.0001). The 6-month supplementation with HP-EVOO induced a significant reduction in 18F-FDG uptake in both the non-calcified (2.93  0.23 to 2.75  0.38, p<0.004) and calcified seg-ments of the aortas (2.25  0.29 to 2.15  0.19, p<0.02). 18F-NaF uptake was also significantly low-er in patients supplemented with HP-EVOO (SUVmax = 1.98  0.33 at baseline compared to 1.85  0.28, after the 6-month supplementation, p<0.004), whereas no significant effect was observed with EVOO. Conversely, participants supplemented with ROO displayed a significant increase in 18F-NaF uptake (SUVmax = 1.78  0.34 to 1.95  0.34, p<0.0001). Conclusion: The present study confirmed that ¹⁸F-FDG/¹⁸F-NaF-PET/CT imaging is a valuable approach for assessing age-related arterial damage and demonstrated that a phenolic compound-rich diet reduces both arterial inflammation and atherosclerotic lesion microcalcification.

Sporadic inclusion body myositis (sIBM) is the most common muscle disease of older people and is clinically characterized by slowly progressive asymmetrical muscle weakness, predominantly affecting quadriceps, deep finger flexors and foot extensors. At present there are no enduring treatments for this relentless disease that eventually leads to severe disability and wheelchair dependency. Although sIBM is considered a rare muscle disorder, its prevalence is certainly higher as the disease is often undiagnosed or misdiagnosed. The histopathogical phenotype of sIBM muscle biopsy includes muscle fiber degeneration and endomysial lymphocytic infiltrates that mainly consist of cytotoxic CD8+ T cells surrounding nonnecrotic muscle fibers expressing MHCI. Muscle fiber degeneration is characterized by vacuolization and accumulation of congophilic misfolded multi-protein aggregates, mainly in their non-vacuolated cytoplasm. Many players have been identified in sIBM pathogenesis including environmental factors, autoimmunity, abnormalities of protein transcription and processing, accumulation of several toxic proteins, impairment of autophagy and ubiquitin proteasome system, oxidative and nitrative stress, endoplasmic reticulum stress, myonuclear degeneration, and mitochondrial dysfunction. Aging has been also proposed as a contributor to the disease. However, the interplay between these processes and the primary event that leads to the coexistence of autoimmune and degenerative changes is still under debate. Here, we outline our current understanding of disease pathogenesis, focusing on degenerative mechanisms, and discuss the possible involvement of aging.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to an infection. Recent in-vitro studies have investigated the effects of CytoSorb hemoadsorption on endothelial function in sepsis showing a reduction in markers of endothelial dysfunction, but to this day there is a lack of clinical studies showing whether this approach could actually positively influence the disturbed vascular barrier function in septic conditions. We analyzed the data on administered fluid volumes and catecholamines to determine the potential benefit of CytoSorb hemoadsorption therapy on endothelial function in a clinical scenario. We performed a retrospective analysis of 124 septic shock patients who had undergone adjunctive treatment with CytoSorb hemadsorption therapy. We collected volume requirements, and calculated the volume balance within different time periods to obtain an assumption on the stability of the vascular barrier. We also calculated catecholamine requirements. With regard to the entire study cohort our findings revealed a significant reduction in fluid balance at 72 hours (T72) compared to both baseline (T0) and the 24-hour mark (T24). Fluid balances from T72 – T0 were significantly lower in hospital survivors compared to non-survivors. Patients who received a second catecholamine had a significantly lower in-hospital mortality. Our findings showed that use of hemoadsorption therapy results in a reduced positive fluid balance paralleled by reductions in vasopressor needs suggesting a positive effect on endothelial integrity. These results, derived from a large cohort of patients, provide valuable insights that may greatly improve our understanding of the multiple effects of hemoadsorption treatment in septic shock patients.

Post-operative pain is the unpleasant sensory and emotional experience after surgery, its origin being both the inflammatory reaction induced by the surgical trauma on the abdominal wall, and the splanchnic pain, induced by the activation of nociceptors of the viscera, which are highly sensi-tive to distension, ischemia and inflammation. Nowadays, it is well recognized that there is a close relationship between the gut microbiome and pain perception, and that microbiome is highly af-fected by both anaesthesia and surgical manipulation. Thus, efforts to restore the disturbed micro-biome by supplementation with beneficial bacteria, namely probiotics, seems to be effective. In this article the knowledge gained mainly from experimental research on this topic is analyzed, the con-cluding message being that each probiotic strain works in its own way towards pain relief.

: For a long time, atherosclerosis has been regarded as a mere lipid deposit in the blood vessels. However, in the recent years a growing body of experimental and clinical evidence have highlighted the role of inflammation and immunity as a central mechanism of disease. Moreover, in the last decade the coming of next-generation sequencing and its application to large human population has broken the barrier between inflammation and cancer. Indeed, acquired mutation in key genes related to the control of hematopoiesis and myeloproliferation have paved the way to establish the new concept of clonal hematopoiesis of indeterminate potential. This phenomenon is being considered not such “indeterminate”, but as an emerging cardiovascular risk factor. Thus, this may explain the mechanisms of myeloproliferation and inflammation in atherosclerosis. And in a bidirectional journey, it has helped to explain the extremely high cardiovascular risk in cancer survivors, in particular in myeloprolfierative neoplasm patients. A deeper understanding of these mechanisms may pave the way for the future early diagnosis and potential preemptive treatments of the leading worldwide cause of death.

Polycystic ovary syndrome (PCOS) is increasingly being viewed as an evolutionary mismatch disorder that manifests in women after exposure to a range of lifestyle and environmental factors. Although there is ongoing debate regarding the pathogenesis, international guidelines recommend lifestyle treatment, with diet and exercise, as the first line of management in all women with PCOS. In addition, accumulating evidence suggests that environmental factors such as endocrine disrupting chemicals (EDC) may be involved in the pathogenesis of PCOS due to their known hormonal and metabolic effects. As a result, international professional bodies have recommended that all pregnant women be advised of the risks of EDC and that education programs be developed to inform health professionals. Microparticulate air pollution (MAP) is also a significant environmental exposure that has been associated with a variety of chronic diseases, including PCOS. We performed a systematic review of studies examining the relationship between MAP and PCOS using the PRISMA methodology. The review identified 214 records from PubMed, Cochrane, and Scopus databases, and 4 studies that met the inclusion criteria for qualitative assessment. Preliminary data suggest that MAP may contribute to the pathogenesis of PCOS via a number of mechanisms. This review highlights the need for greater awareness and further research on the effects of MAP in women with PCOS.

Premenstrual syndrome is characterized by pain and symptoms affecting the women´s quality of life. We aimed to evaluate the safety and effectiveness of an oral fixed dose combination containing naproxen 220 mg + paracetamol 300 mg + pamabrom 25 mg tablet (Analgen Fem®) during the routine clinical practice. A prospective, open-label, multicenter, observational post-marketing study was conducted from December 2017 to December 2019 including 270 women older than 18 years. Primary endpoint was the proportion of adverse events, meanwhile the pain intensity, premenstrual syndrome symptoms, and patient proportion with a pain score reduction by at least 50% were secondary endpoints. The mean age of population was 28.9 ± 8.8 years. Among the 270 women, 8 (3%) experienced 10 adverse events. These were headache (5/8), gastritis (2/8) dyspepsia (1/8), diarrhea (1/8) and nausea (1/8). The investigator discontinued the study medication in 3/8 patients because of adverse events. The median of differences between the pain intensity at baseline and at last observation (-4.5, 95%CI; -5, -4) demonstrated that naproxen 220 mg + paracetamol 300 mg + pamabrom 25 mg fixed dose combination reduced pain intensity (p<0.001). In addition, the proportion of patients with pain reduction by at least 50% at the end of the treatment was 70.7%. The study demonstrated that this drug represents a safe and tolerated treatment, reducing pain intensity and premenstrual symptoms.

Glaucoma, a group of diseases characterized by progressive retinal ganglion cell loss, cupping of the optic disc and by a typical pattern of visual field defects, is a leading cause of severe visual impairment and blindness worldwide. Elevated intraocular pressure (IOP) is the leading risk factor for glaucoma development. However, glaucoma can also develop at normal pressure levels. An increased susceptibility of retinal ganglion cells to IOP, systemic vascular dysregulation, endothelial dysfunction and autoimmune imbalances have been suggested to play a role in the pathophysiology of normal tension glaucoma. Since inflammation and oxidative stress play a role in all forms of glaucoma, the goal of this review article is to resent an overview on the inflammatory and prooxidant mechanisms in the pathophysiology of glaucoma and to discuss immunomodulatory and antioxidant treatment approaches.

Abstract Sickle cell anaemia (SCD) is a life-threatening haematological disorder which is predominant in sub-Saharan Africa and is triggered by a genetic mutation of the β-chain haemoglobin gene resulting in the substitution of glutamic acid with valine. This mutation leads to the production of an abnormal haemoglobin molecule called haemoglobin S (HbS). When deoxygenated, haemoglobin S (HbS) polymerizes and results in a sickle-shaped red blood cell which is rigid and has a significantly shortened life span. Various reports have shown a strong link between oxidative stress, inflammation, the immune response, and the pathogenesis of sickle cell disease. The consequence of these processes lead to the development of vasculopathy (disease of the blood vessels) and several other complications. The role of the immune system, particularly the innate immune system, in the pathogenesis of SCD has become increasingly clear in recent years of research, However, little is known about the roles of the adaptive immune system in this disease. This review examines the interaction between the immune system, inflammation, oxidative stress, blood transfusion, and their effects on the pathogenesis of sickle cell anaemia

Angiotensin II (Ang II) plays a role in several inflammatory diseases and is capable of inducing the release of inflammatory mediators in several cell types. The objective was to investigate the potential of Ang II to induce mRNA expression of inflammatory mediators by cultured primary human periodontal cells. A synergistic effect of a co-treatment with Ang II and IL1β on mRNA expression of inflammatory mediators was also explored. Primary cultures of human fibroblast-like cells isolated from gingival and periodontal ligament tissues from 3 subjects were established using explant techniques. Immunophenotyping of STRO-1, Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) was performed by flow cytometry analysis. Cell cultures were challenged with Ang II (1M) for 3, 6 and 24h with or without a co-treatment with IL1β (0.1ng/mL) for 24h. mRNA expression of inflammatory mediators was performed by real time quantitative polymerase chain reaction (RT-qPCR). We present, for the first time, a precise quantification for AT1R and AT2R on human gingival and periodontal fibroblast-like cell types; the percentage of positive immunostaining compared to the total population of cells varied from 3.35% through 5.29% for AT1R and 2.97% through 4.57% for AT2R. Ang II slightly upregulated mRNA expression of IL6 and CCL2/MCP1 in gingival cells and IL8 and PTGS2/COX2 in periodontal ligament cells. IL1β induced upregulation of IL8, IL6 CCL2/MCP1, PTGS2/COX2 and IL1β mRNA in both cell types. Co-treatment with Ang II and IL1β did not show a synergistic effect under these experimental conditions. Ang II shows a low potential to induce mRNA upregulation of inflammatory mediators in cultured primary human gingival and periodontal ligament cells, most likely due to the low percentage of Ang II receptors in such cells, and no synergistic effect with the co-treatment with IL1β.

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which has now become a severe public health problem worldwide. β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous study has demonstrated that Bruton's tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-β related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by β-AR overactivation;(2) Methods: In vivo: Male C57BL/6J mice were treated with or without the β-AR agonist isoproterenol (ISO) to establish cardiac fibrosis animal model. Here, results showed that BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by β-AR. In vitro: Results showed that ZB alleviated β-AR-induced cardiac fibroblast activation and macrophage proinflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited β-AR-induced cardiac fibrosis and inflammation by BTK、STAT3、NF-κB and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates β-AR-induced cardiac fibrosis and inflammation.

Type 2 diabetes mellitus may be complicated with chronic complications including diabetic neuropathy (DN). Timely diagnosis is crucial in treatment and maybe reversal of this complication. C reactive protein to albumin ratio (CAR) is considered as a marker of inflammation in various diseases that characterized with acute or chronic inflammation. Since diabetic neuropathy and type 2 diabetes mellitus are also associated with chronic, low grade inflammation, we aimed to study CAR levels of type 2 diabetic subjects with diabetic neuropathy and to compare to those in patients without diabetic neuropathy. Type 2 diabetic patients presented to our institutional outpatient clinics were divided into two according to the presence of DN. Subjects with DN were listed as DN group and others were as non-DN group. Characteristics and laboratory data, including CAR, in DN and non-DN groups were compared. Median CAR of the DN and non-DN groups were 2,19 (0,2-49)% and 0,56 (0,02-5,8)%, respectively (p&lt;0.001). CAR was significantly and positively correlated with age (r=0.15, p&lt;0.001), weight (r=0.19, p=0.01), BMI (r=0.11, p=0.03), waist circumference (r=0.10, p=0.046), fasting plasma glucose (r=0.14, p=0.004), serum creatinine (r=0.25, p&lt;0.001), triglyceride (r=0.17, p&lt;0.001), and LDL-cholesterol (r=0.13, p=0.001) levels. Moreover, CAR was inversely correlated with eGFR levels (r=-0.16, p&lt;0.001). The sensitivity and specificity of CAR (when higher than 1,02%) in predicting diabetic neuropathy were 78% and 73%, respectively (AUC: 0.84, p&lt;0.001, 95% CI: 0,82-0,87). Moreover, high CAR level was an independent risk factor of diabetic neuropathy (p&lt;0.001, OR: 1.34, 95% CI: 0.48-1.62). In conclusion, elevated CAR levels could be considered as a marker of diabetic neuropathy.

Microglial dysfunction is one of the hallmarks and leading causes of common neurodegenerative diseases (NDD), including Alzheimer’s disease (AD) and Parkinson’s disease (PD). All these pathologies are characterized by aberrant aggregation of disease-causing proteins in the brain, which can directly activate microglia, trigger microglia-mediated neuroinflammation, and increase oxidative stress. Inhibition of glial activation may represent a therapeutic target to alleviate neurodegeneration. Recently, 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormone (TH) able to interact directly with a specific GPCR known as trace amine-associated receptor 1 (TAAR1), gained interest for its ability to promote neuroprotection in several models. Nevertheless, T1AM’s effects on microglial disfunction remain still elusive. In the present work we investigated whether T1AM could inhibit the inflammatory response of human HMC3 microglial cells to LPS/TNFα or β-amyloid peptide 25-35 (Aβ25-35) stimuli. The results of ELISA and qPCR assays revealed that T1AM was able to reduce microglia-mediate inflammatory response by inhibiting the release of proinflammatory factors, including IL-6, TNFα, NF-kB, MCP1 and MIP1, while promoting the release of anti-inflammatory mediators, such as IL-10. Notably, T1AM anti-inflammatory action in HMC3 cells resulted to be a TAAR1-mediated response, further increasing the relevance of the T1AM/TAAR1 system in the management of NDD.

Inflammation is the response of the innate immune system to any type of injury. Although acute inflammation is critical for survival, dysregulation of innate immune response leads to chronic in-flammation. Many synthetic anti-inflammatory drugs have side effects, and thus, natural an-ti-inflammatory compounds are still needed. Cannabis sativa L. may provide a good source of in-flammation-reducing molecules. Here, we tested the anti-inflammatory properties of cannabis ex-tracts and pure cannabinoids in lipopolysaccharide (LPS)-induced inflammation in human THP-1 macrophages. We found that pre-treatment with cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), or extracts containing high levels of CBD or THC reduce the level of induction of various cytokines. The CBD was more efficient than THC, and the extracts were more efficient than pure cannabinoids. Finally, IL-6, IL-10 and monocyte chemoattractant protein-1 (MCP-1) were most sensitive to pre-treatments with CBD and THC, while IL-1β, IL-8 and TNF-α were less responsive. Thus, our work demonstrates the potential of use of cannabinoids or/and cannabis extracts for the reduction of inflammation and establishes IL-6 and MCP-1 as the sensitive markers for the analysis of the effect of cannabinoids on inflammation in macrophages.

Alcoholic Liver Disease (ALD) and Non-Alcoholic Fatty Liver Disease (NAFLD) are the most common causes of chronic liver disease and are increasingly emerging as a global health problem. Such disorders can lead to liver damage, resulting in the release of pro-inflammatory cytokines and the activation of infiltrating immune cells. These are some of the common features of ALD progression in ASH (alcoholic steatohepatitis) and NAFLD to NASH (non-alcoholic steatohepa-titis). Hepatic steatosis and subsequent fibrosis, whose continuous progression is accompanied by angiogenesis, lead to hypoxia, inducing the activation of vascular factors, which in turn triggers pathological angiogenesis and subsequent fibrosis, resulting in a vicious cycle. This condition further exacerbates liver injury and may contribute to the development of comorbidities, such as metabolic syndrome as well as hepatocellular carcinoma. Increasing evidence suggests that antiangiogenic therapy may have beneficial effects on these hepatic disorders and their exacerbation. Therefore, there is a great interest to deepen the knowledge of the molecular mechanisms of natural antiangiogenic products that could both prevent and control liver diseases. In this review, we focus on the role of major natural antian-giogenic compounds against steatohepatitis and determine their potential therapeutic benefits in the treatment of liver inflammation.

Oxidative stress driven by several environmental and local airway factors associated with chronic obstructive bronchiolitis, a hallmark feature of COPD, plays a crucial role in the disease pathomechanism. Unbalance between oxidants and antioxidant defense mechanisms not only amplifies the local inflammatory processes, but it also worsens cardiovascular health and contribute to the COPD related cardiovascular dysfunctions and mortality. The current review summarizes recent developments in our understanding of different mechanisms contributing to oxidative stress and its countermeasures with special attention to those that link local and systemic processes. Major regulatory mechanisms orchestrating these pathways are also introduced together with some suggestions for further research on the field.

Angiotensin II (Ang II) plays a role in several inflammatory diseases and is capable of inducing the release of inflammatory mediators in several cell types. The objective was to investigate the potential of Ang II to induce mRNA expression of inflammatory mediators by cultured primary human periodontal cells. A synergistic effect of a co-treatment with Ang II and IL1β on mRNA expression of inflammatory mediators was also explored. Primary cultures of human fibroblast-like cells isolated from gingival and periodontal ligament tissues from 3 subjects were established using explant techniques. Immunophenotyping of STRO-1, AT1 and AT2 receptors was performed by flow cytometry analysis. Cell cultures were challenged with Ang II (1M) for 3, 6 and 24h with or without a co-treatment with IL1β (0.1ng/mL) for 24h. mRNA expression of inflammatory mediators was performed by real time quantitative polymerase chain reaction (RT-qPCR). We present, for the first time, a precise quantification for AT1 and AT2 receptors on human gingival and periodontal fibroblast-like cell types; the percentage of positive immunostaining compared to the total population of cells varied from 3.35% through 5.29% for AT1 and 2.97% through 4.57% for AT2. Ang II slightly upregulated mRNA expression of IL6 and CCL2/MCP1 in gingival cells and IL8 and PTGS2/COX2 in periodontal ligament cells. IL1β induced upregulation of IL8, IL6 CCL2/MCP1, PTGS2/COX2 and IL1β mRNA in both cell types. Co-treatment with Ang II and IL1β did not show a synergistic effect under these experimental conditions. Ang II shows a low potential to induce mRNA upregulation of inflammatory mediators in cultured primary human gingival and periodontal ligament cells, most likely due to the low percentage of Ang II receptors in such cells, and no synergistic effect with the co-treatment with IL1β.

Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). In murine models, chronic SF can impair endothelial function and induce cognitive declines. These deficits are likely mediated, at least in part, by alterations in Blood-Brain Barrier (BBB) integrity. Male C57Bl/6J mice were randomly assigned to SF or sleep control (SC) conditions for 4 or 9 weeks, and in a subset 2 or 6 weeks of normal sleep recovery. Presence of inflammation and microglia activation were evaluated. Explicit memory function was assessed with the novel object recognition (NOR) test, while BBB permeability was determined by systemic dextran-4kDA-FITC injection and Claudin 5 expression. SF exposures resulted in decreased NOR performance and in increased inflammatory markers and microglial activation as well as enhanced BBB permeability. Explicit memory and BBB permeability were significantly associated. BBB permeability remained elevated after 2 weeks of sleep recovery (p<0.01) and returned to baseline values only after 6 weeks. Chronic SF exposures mimicking the fragmentation of sleep that characterizes patient with OSA elicits evidence of inflammation in brain regions and explicit memory impairments in mice. Similarly, SF is also associated with increased BBB permeability, the magnitude of which is closely associated with cognitive functional losses. Despite normalization of sleep patterns, BBB functional recovery is a protracted process that merits further investigation.

Accumulating literature demonstrates that omega-3 polyunsaturated fatty acid (N3PUFA) can be incorporated into the phospholipid bilayer of cell membrane in the human body to positively affect the cardiovascular system, including improving epithelial function, decreasing coagulopathy, and attenuating uncontrolled inflammatory responses and oxidative stress. Moreover, it has been proven that the N3PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of some potent endogenous bioactive lipid mediators that mediate some favorable effects attributed to their parent substances. A linear dose-response relationship between increased EPA and DHA intake and reduced thrombotic outcomes have been reported. The excellent safety profile of dietary N3PUFA makes them a prospective adjuvant treatment for people exposed to a higher risk of cardiovascular problems associated with COVID-19. This review presented the potential mechanisms that might contribute to the beneficial effect of N3PUFA and the optimal form and dose applied.

Background: Hepatic erythrophagocytosis is augmented in NASH and amplifies inflammation and fibrosis. Although various pro-phagocytic signals have been identified on erythrocytes of NASH patients, the role of bound thrombospondin-1 (TSP-1), which acts as an “eat-me” signal, arginase-1, which regulates the levels of nitric oxide in erythrocytes, and phosphatidylethano-lamine (PE) which can amplify erythrophagocytosis and hepatic inflammation have not been explored. Hence, we sought to investigate the levels of arginase-1 and TSP-1 in erythrocyte lysate and PE in erythrocyte membranes of NASH patients. Methods: Twenty-four patients and 14 healthy controls participated in our study. The levels of TSP-1 and arginase were quantified by ELISA in erythrocyte lysates, and the levels of PE in erythrocyte membranes by thin layer chro-matography. Results: Erythrocytes of NAFLD patients exhibit lower levels of arginase-1 and TSP-1 (p<0.01). Erythrocyte-bound TSP-1 levels correlated with the levels of erythrocyte surface CD47. Phosphatidylethanolamine was increased in erythrocytes of NASH patients and was accompanied by increased release, indicating exposure. Conclusion: Our results imply reduced TSP-1 binding by erythrocytes which could allow free TSP-1 molecules to act on macrophages, enhancing erythrophagocytosis. Increased PE which could amplify inflammation after efferocytosis, while downregulation of arginase-1 could lead to defective efferocytosis.

Gossypol is a complex plant polyphenol reported to be cytotoxic and anti-inflammatory, but little was known about its effect on gene expression in macrophages. The objective was to explore gossypol’s toxicity and its effect on gene expression involved in inflammatory responses, glucose transport and insulin signaling pathway in mouse macrophages. Mouse RAW264.7 macrophages were treated with multiple concentrations of gossypol for 2-24 h. Gossypol toxicity was estimated by MTT assay and soluble protein content. qPCR analyzed the expression of anti-inflammatory tristetraprolin family (TTP/ZFP36), proinflammatory cytokine, glucose transporter (GLUT) and insulin signaling genes. Cell viability was greatly reduced by gossypol, accompanied with dra-matic reduction of soluble protein content in the cells. Gossypol treatment resulted in an increase of TTP mRNA level 6-20 fold and increased ZFP36L1, ZFP36L2 and ZFP36L3 mRNA levels by 26-69 fold. Gossypol increased proinflammatory cytokine TNF, COX2, GM-CSF, INFγ and IL12b mRNA levels up to 39-458 fold. Gossypol treatment upregulated mRNA levels of GLUT1, GLUT3 and GLUT4 genes as well as INSR, AKT1, PIK3R1 and LEPR but not APP genes. This study demonstrated that gossypol induced macrophage death and reduced soluble protein content that was accom-panied with massive stimulation of anti-inflammatory TTP family and proinflammatory cytokine gene expression as well as elevation of gene expression involved in glucose transport and insulin signaling pathway in mouse macrophages.