Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in pre-clinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultra-high throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified 5 selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These are the most selective inhibitors of meprin α to date.

Cassava Solid waste (Onggok) is a solid waste from the cassava-based tapioca industry, the starch content in Onggok is still 50-80 wt.% of residual starch, which can be used to produce maltodextrin for foods application. Furthermore, using cassava solid waste is beneficial in terms of the cost of raw materials. The starch content in cassava can be modified through enzymatic hydrolysis using α-amylase and β-amylase enzymes at 80oC and pH 5.5. Enzymatic hydrolysis was done using mixed enzymes that varied the concentration of α-amylase at 0,.1% and the β-amylase enzymes at 0.05, 0.1, and 0.5%. the concentration of cassava waste (Onggok) varied from 4%, 7%, 10%, and 13%. The optimum concentration of α-amylase and β-amylase enzymes are 0.1% and 0.1% respectively at time intervals of 1 minute resulting in a dextrose equivalent (DE) value 0f 5.7. The characteristics of maltodextrin were studied using scanning electron microscopy (SEM) to determine the morphology of the starch structure which had changed due to the enzyme hydrolysis. Simultaneous thermal analysis (STA) was studied to determine the Thermal stability of hydrolysis products. Maltodextrin produced from cassava waste (Onggok) has a DE value < 10, which has the potential to be used in the pharmaceutical industry

The β-thalassemias are hereditary monogenic diseases characterized by low or absent production of adult hemoglobin and excess in the content of α-globin. This excess is cytotoxic for the erythroid cells and responsible of the β-thalassemia associated ineffective erythropoiesis. Therefore, the decrease of α-globin excess is a relevant clinical effect for these patients and can be obtained by induction of fetal hemoglobin, by autophagy, or both. The in vivo effects of sirolimus (rapamycin) and analogues on induction of fetal hemoglobin (HbF) is of key importance for therapeutic protocols in a variety of hemoglobinopathies, including β-thalassemia. In this research communication, we report data showing that decrease of autophagy-associated p62 protein, increased expression of ULK-1 and reduction of the excess of α-globin is operating in erythroid precursors (ErPCs) stimulated in vitro with low dosages of sirolimus. In addition, increased ULK-1 mRNA content and decrease of α-globin content were found in ErPCs isolated from β-thalassemia patients recruited for the NCT03877809 clinical trial and treated with 0.5-2 mg/day sirolimus. Our data support the concept that autophagy, ULK1 expression and α-globin chain reduction should be considered important endpoints in sirolimus-based clinical trials for β-thalassemia.

Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). In part II we report the optimization of a potent and selective hydroxamic acid meprin α inhibitor probe which may help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition.

Differences in fish assemblages’ structure and their relation with environmental variables (due to the variations in sampled seasons, habitats, and zones), were analyzed in two adjacent estuaries on the north Pacific coast of Mexico. Environmental variables and fish catches were registered monthly between August 2018 and October 2020. Multivariate analyses were conducted to define habitats and zones based on their environmental characteristics, and the effect of this variability on fish assemblages’ composition, biomass, and diversity (α and β) was evaluated. A total of 12,008 fish individuals of 143 species were collected using different fishing nets. Multivariate analyses indicated that fish assemblages’ structure was different between zones due to the presence, height, and coverage of distinct mangrove species. Additionally, factors such as depth and salinity showed effects on fish assemblages’ diversity (α and β-nestedness), which presented higher values in the ocean and remained similar in the rest of the analyzed zones and habitats. These results and the differences in species replacement (β-turnover) indicate the singularity of fish assemblages at estuaries (even in areas very close to the ocean), and the necessity to establish local management strategies for these ecosystems.

Substrate binding proteins (SBP) bind to specific ligands in the periplasmic region and bind to membrane proteins to participate in transport or signal transduction. Typical SBPs consist of two α/β domains and recognize the substrate by hinge motion between two domains. Conversely, short length Rhodothermus marinus SBP (named as RmSBP) exists around the methyl-accepting chemotaxis protein. We previously determined the crystal structure of RmSBP consisting of a single α/β domain, but the substrate recognition mechanism is still unclear. To better understand the short length RmSBP, we performed comparative structure analysis, computational substrate docking, and X-ray crystallographic study. RmSBP shares a high level of similarity in α/β domain with other SBP proteins, but it has a distinct topology in the C-term region. The substrate binding model suggested that conformational change in the peripheral region of RmSBP was required to recognize the substrate. We determined the crystal structures of RmSBP at pH 5.5, 6.0, and 7.5. RmSBP showed structural flexibility of the β1-α2 loop, β5-β6 loop, and extended C-term domain based on the electron density map and temperature B-factor analysis. These results provide information that will further the understanding of the function of the short length SBP.

3,4-Dihydroquinolin-2(1H)-ones represent a class of valuable bioactive compounds with six-membered nitrogen-containing heterocyclic structures. The development of simple, mild and efficient synthetic methods has been widely concerned by synthetic chemists. In this review, we have summarized a series of different synthetic strategies for the synthesis of dihydroquinoline-2(1H)-ones via catalytic annulation of α,β-unsaturated N-arylamides in the past decade, including covering electrophilic cyclization, radical initiated cyclization and photochemical cyclization reactions. Besides, the substrate scope and mechanistic details are also discussed. This paper will provide a useful reference for the development of diverse synthesis methodologies of 3,4-dihydroquinolin-2(1H)-ones.

Many biological functions of curcumin have been reported. As certain bioactivities of curcumin are eliminated by antioxidants, reactive oxygen species generated by curcumin have been suggested as a relevant mechanism. In the present study, effects of different types of antioxidants on stability and bioactivities of curcumin were analyzed. High concentrations (>4mM) of the thiol antioxidants including N-acetylcysteine (NAC), glutathione (GSH) and β-mercaptoethanol accelerated decomposition of curcumin and other curcuminoids; Submillimolar levels (<0.5 mM) of GSH and NAC rather improved their stability. Ascorbic acid or superoxide dismutase also stabilized curcumin regardless of their concentration. Cellular levels and bioactivities of curcumin including cytotoxicity and induction of heme oxygenase-1 were significantly reduced in the presence of 8 mM of GSH and NAC. The effects were enhanced in the presence of submillilmolar GSH and NAC, or non-thiol antioxidants. The present results indicate that antioxidants with reduced thiol group could directly interact with α, β-unsaturated carbonyl moiety of curcuminoids and modulate their stability and bioactivity.

The seeds of cultivated peanut, Arachis hypogaea, are an agronomically important crop produced for human nutrition, oilseed and feed stock. Peanut seed is the single most expensive variable input cost and thus producers require seed with excellence performance in terms of germination efficiency. During the maturation process, triglycerides are stored in oil bodies as an energy resource during germination and seedling development. The stability of oil body membranes is essential for nutrient mobilization during germination. This study focused on evaluating the phytosterol composition in seed components including the kernel, embryo (heart), and seed coat or skin. Samples of different maturity classes were analyzed for macronutrient and phytosterol content. The three most abundant phytosterols, β-sitosterol, campesterol, and stigmasterol, comprised 82.29%, 86.39%, and 94.25% of seed hearts, kernels, and seed coats, respectively. Stigmasterol concentration was highest in the seed kernel providing an excellent source of this sterol known to have beneficial effects on human health. Peanut hearts contained the highest concentration of sterols by mass potentially providing protection and resources for the developing seedling. The amount of α-tocopherol increases in peanut hearts during the maturation process providing protection from temperature stress and stability required for seedling vigor. These results suggest that phytosterols may play a significant role in the performance of seeds and provides a possible explanation for the poor germination efficiency of immature seeds.

Beef meat production in Uruguay is based on pasture or concentrate feeding systems, leading to differences in meat quality. The objective of this study was to compare the oxidative and color stability during refrigerated retail display of beef meat from these two systems. For this, ten Aberdeen Angus steers were reared and fed on pasture and other ten were finished on a concentrate diet. After slaughter, the Semimembranosus muscle was cut into slices and put in a refrigerated showcase for 3, 6, and 9 days simulating commercial conditions. The β-carotene, α-tocopherol, and fatty acid content were determined before the display, and the lipid and protein oxidation, color parameters, and heme iron content were determined before and during the display. Meat from steers fed pasture had a lower content of intramuscular fat, monounsaturated fatty acids, n-6/n-3 ratio, lipid and protein oxidation, L* and a* values, and a higher content of linolenic acid, DHA, total n-3, β-carotene, and α-tocopherol. In conclusion, meat from pasture-fed steers was more stable during the retail display, which can probably be explained by a higher content of antioxidant compounds, such as β-carotene and α-tocopherol, and presented a healthier fatty acid profile.

In this work, we explore the intrinsic disorder status of the three members of the synuclein family of proteins - α-, β-, and γ-synucleins. We also analyzed the peculiarities of the amino acid sequences and modeled 3D structures of the human synuclein family members to find potential effects of pathological mutations. Furthermore, we conducted a comparative sequence-based analysis of the synuclein proteins from various evolutionary distant species and evaluated their levels of intrinsic disorder using a set of commonly used bioinformatics tools. Next, we conducted a detailed functional disorder analysis of the proteins in the interactomes of the human synuclein family members using various web-based disorder analysis and prediction tools, such as RIDAO, D2P2 and FuzDrop. We identify that the interactome of human α-synuclein has relatively higher levels of intrinsic disorder, as compared to the interactomes of human β- and γ- synucleins. These observations highlight the critical importance of intrinsic disorder of human α-synuclein and its interactors in neuronal processes as compared to other proteins of the synuclein family.

In this paper, we generalize the problems of finding simple polygons with the minimum area, maximum perimeter and maximum number of vertices so that they contain a given set of points and their angles are bounded by $\alpha+\pi$ where $\alpha$ ($0\leq\alpha\leq \pi$) is a parameter. We also consider the maximum angle of each possible simple polygon crossing a given set of points, and derive an upper bound for the minimum of these angles. The correspondence between the problems of finding simple polygons with the minimum area and maximum number of vertices is investigated from a theoretical perspective. We formulate the three generalized problems as nonlinear programming models, and then present a Genetic Algorithm to solve them. Finally, the computed solutions are evaluated on several datasets and the results are compared with those from the optimal approach.

Understanding the phenomena underlying the non-selective susceptibility to ischemia of py-ramidal neurons in the CA3 area of the hippocampus is important from the point of view of elu-cidating the mechanisms of memory loss and the development of post-ischemic dementia. We used an ischemic model of Alzheimer's disease to study changes in amyloid protein precursor gene expression, its cleavage enzymes and tau protein in the CA3 area of the hippocampus af-ter a 10-minute brain ischemia with 12, 18, and 24-month survival. Quantitative reverse tran-scriptase PCR assay showed that the expression of all the genes that contribute to amyloid pro-duction was dysregulated within 2 years in the CA3 area of the hippocampus after ischemia. The expression of the amyloid protein precursor gene was above the control values at all times of the study. The expression of the α-secretase gene also exceeded the control values throughout the study. In contrast, the expression of the β-secretase gene reaching its maximum increase 12 months after ischemia, was below control values after 18 months and again above control values after 24 months of survival. Presenilin 1 and 2 gene expression was significantly elevated throughout the follow-up period, with peak expression of both genes occurring 12 months after ischemia. This suggests that the genes studied are involved in the non-amyloidogenic processing of amyloid protein precursor. Also, tau protein gene expression was significantly elevated throughout the observation period, and peak gene expression was present 12 months after is-chemia. Data indicate that an episode of brain ischemia with long-term survival causes damage and death of pyramidal neurons in the CA3 area of the hippocampus in a manner dependent on modified tau protein. Thus defining a new and important mechanism of pyramidal neuronal death in the CA3 area after ischemia. In addition tau protein gene modification after brain is-chemia is useful in identifying ischemic mechanisms occurring in Alzheimer's disease.

Ferrocenium (Fc+) inherits a number of molecular/electronic properties from the neutral counterparts’ ferrocene (Fc) including the high symmetry. Both Fc+ and Fc prefer the eclipsed structure (D5h) over the staggered structure (D5d) by an energy of 0.36 kcal·mol-1. The present study using the recently developed excess orbital energy spectrum (EOES) shows that the open shell Fc+ cation exhibits similar conformer dependent configurational changes to the neutral Fc conformer pair. A further energy decomposition analysis (EDA) discloses that the reasons for the preferred structures are different between Fc+ and Fc. The dominant differentiating energy between the Fc+ conformers is the electrostatic energy (EEstat), whereas in neutral Fc, it is the quantum mechanical Pauli repulsive energy (EPauli). Within the D5h conformer of Fc+, the EOES reveals that the -electrons of Fc+ experience more substantial conformer dependent energy changes than the -electrons (assumed the hole is in a β orbital).

The rising incidence of prostate cancer necessitates innovative treatment approaches, particularly as diseases like the COVID-19 pandemic can disrupt traditional cancer care. This study aimed to evaluate the impact of hypofractionated versus conventionally fractionated radiotherapy on prostate cancer cell lines in vitro. Prostate cancer cell lines (PC-3 and DU-145) were exposed to varying doses of radiation alongside non-cancerous BPH-1 cells. We assessed radiation effects on cell proliferation, viability, colony formation, DNA repair, migration, invasion, and cytotoxicity. Results demonstrated that the prostate cell lines exhibited varying responses, with hypofractionation favourably impacting aggressive PC-3 cells while preserving non-cancerous cells. In contrast, conventional fractionation led to increased invasion and cytotoxicity in both prostate cancer cell lines. These findings advocate for personalised radiation therapy approaches that enhance treatment efficacy by considering the distinct behaviours of differing prostate cancer subtypes.

Muscle mass and strength decrease with aging, but habitual exercise can maintain muscle health. β-Hydroxy-β-methyl butyrate calcium (HMB) and black ginger (BG) are anti-oxidants that have been reported to improve muscle protein metabolism and energy production; these molecules may have synergistic effects. The senescence-accelerated mouse-prone 8 (SAMP8) model is a useful model of muscle aging. Therefore, in this study, we explored how the combination of habitual exercise, HMB, and BG affected muscle aging. We used 28-week-old SAMP8 mice divided into five groups: control, exercise (Ex), Ex+BG, Ex+HMB, and Ex+BG+HMB (Ex+Comb). Mice were required to run on a treadmill for 16 weeks at 5 days per week. In 44-week-old mice, grip strength tests and dissection were conducted. Muscle weight was measured, and the gastrocnemius muscle was subjected to quantitative polymerase chain reaction and immunoblotting. Muscle mass and strength were preserved in the Ex+Comb group, and mitochondrial function was preserved through suppressing oxidative stress. Muscle protein synthesis signaling was improved in the Ex+Comb group. Autophagy and the ubiquitin system were normalized by Ex+Comb treatment. Overall, habitual exercise and HMB plus BG treatment maintained muscle health by suppressing oxidative stress, preserving mitochondrial function, and maintaining muscle protein metabolism in SAMP8 mice.

The aim of this study was to investigate the effect of β-Hydroxy-β-methylbutyrate (HMB) supplementation on anti-inflammatory cytokines including IL-4, IL-10 and TGF-β during an acute bout of resistance exercise (RE) in young resistance trained men. Ten resistance-trained men in a randomized, double-blind, placebo-controlled and crossover study, were administered a 7-day HMB supplementation (3×1 g.d-1 of HMB) and placebo (3×1 g.d-1 of Maltodextrin) with a 7 days washout period. After supplementation periods, subjects performed three sets of bench press, lat pull down, leg extension, leg curl, biceps curl, triceps curl and shoulder press to failure with 85% of one repetition to maximum (1RM). Blood samples were obtained before- (Pre), immediately post- (IP) and 1 hour-post RE (1h P) to assess serum concentrations of IL-4, IL-10 and TGF-β1. The data were analyzed using 2 (treatment: HMB and PL) × 3 (time points: Pre, IP and 1hP) repeated measures analysis of variance (ANOVA) followed by the Bonferroni post hoc test with a significant level of p<0.05. Serum IL-4 was significantly higher at IP resistance exercise in HMB compared to placebo. Circulating IL-4 and TGF-β1 were significantly raised at IP compared to Pre in both HMB and placebo treatments. No significant differences between treatments were observed for IL-10 and TGF-β1at any time points. In conclusion, HMB supplementation increased the circulating level of IL-4 during RE in resistance-trained men, which may attenuate inflammation and facilitate adaptation to RE.

Japanese pepper (sansho, Zanthoxylum piperitum) contains several types of sanshools belonging to N-alkylamides. Because of long-chain unsaturated fatty acids present in their structure, sanshools are prone to oxidative deterioration, which poses problems in processing. Here, we evaluated the effects of antioxidants from the genus Zanthoxylum in preventing sanshool degradation using accelerated tests. An ethanolic extract of segment membranes of the sansho fruit pericarp was incubated at 70 °C for 7 days with different antioxidants to determine the residual amount of hydroxy-α-sanshool (HαS) in the extract. α-Tocopherol (α-Toc) showed excellent HαS-stabilizing activity at low concentrations. Among phenolic acids, we noted that the HαS-stabilizing activity increased with the number of hydroxy groups per molecule. For example, gallic acid and its derivatives exhibited excellent sanshool-stabilizing activity. Quercetin was found to be a superior HαS stabilizer compared with hesperetin and naringenin. However, the effective concentration was much higher for phenolic compounds than for α-Toc. These substances are believed to play a role in preventing the decomposition of sanshools in the pericarp of sansho. These sanshool stabilizers should be useful in the development of new beverages, foods, cosmetics, and pharmaceuticals that take advantage of the taste and flavor of sansho.

The aim of this study was to assess if the ovine articular cartilage serine proteinase inhibitors (SPIs) were related to the Kunitz inter-α-trypsin inhibitor (ITI) family. Ovine articular cartilage was finely diced and extracted in 6M urea and SPIs isolated by sequential anion exchange, HA affinity and Sephadex G100 gel permeation chromatography. Selected samples were also subjected to chymotrypsin and concanavalin-A affinity chromatography. Eluant fractions from these isolation steps were monitored for protein and trypsin inhibitory activity and pooled fractions assessed by affinity blotting using biotinylated trypsin to detect active SPIs and by Western blotting using antibodies to α1-microglobulin, bikunin, TSG-6 and 2-B-6 (+) CS stub epitope generated by chondroitinase-ABC digestion. This identified 2-B-6 (+) positive 220-250,120, 58 and 36 kDa SPIs. The 58 kDa SPI contained α1-microglobulin, bikunin and chondroitin-4-sulphate stub epitope consistent with its identity as the α1-microglobulin-bikunin (AMBP) precursor and was also isolated by concanavalin-A lectin affinity chromatography indicating it had N-glycosylation. Kunitz protease inhibitor (KPI) species of 36, 26, 12 and 6 kDa could be autolytically generated by prolonged storage of the aforementioned 120 and 58 kDa SPIs; chymotrypsin affinity chromatography also generated the 6kDa SPI. KPI domain 1 and 2 SPIs were separated by concanavalin lectin affinity chromatography, domain 1 displayed affinity for this lectin indicating it had N-glycosylation. KPI 1 and 2 both displayed potent inhibitory activity towards trypsin, chymotrypsin, kallikrein, leucocyte elastase and cathepsin G. Localisation of versican, lubricin and HA in the surface regions of articular cartilage represented probable binding sites for the ITI SPs with likely importance in the preservation of joint function.

The amyloid fibril formation by $\alpha$-synuclein is a hallmark of various neurodegenerative disorders, most notably Parkinson's disease. Epigallocatechin gallate (EGCG) has been reported to be an efficient aggregation inhibitor of numerous proteins, among them $\alpha$-synuclein. Here we show that this applies only to a small region of relevant parameter space and that under some conditions, EGCG can even accelerate α-synuclein amyloid fibril formation through facilitating its heterogeneous primary nucleation. Furthermore, we show through quantitative seeding experiments that contrary to previous reports, EGCG is not able to re-model α-synuclein amyloid fibrils into seeding-incompetent structures. Taken together, our results paint a complex picture of EGCG as a compound that can under some conditions inhibit the amyloid fibril formation of α-synuclein, but the inhibitory action is not robust against various relevant changes in experimental conditions. Our results are important for the development of strategies to identify and characterise promising amyloid inhibitors.

Over the last decades, the increased incidence of metabolic disorders such as type 2 diabetes and obesity has motivated researchers to investigate new enzyme inhibitors. In this study, the inhibitory effects of synthetic amino acid derivatives (PPC80, PPC82, PPC84, PPC89, and PPC101) on the activity of digestive enzymes was assessed by in vitro assays. The inhibitory effect was determined by the inhibition percentage and the 50% inhibitory concentration (IC50), and the mechanism of action was investigated by Lineweaver–Burk plots. PPC80, PPC82, and PPC84 inhibited pancreatic lipase (IC50 of 1.67–10.23 x 10-1 mmol/L). The activity of pancreatic α-amylase was suppressed by PPC80, PPC82, PPC84, PPC89, and PPC101 (IC50 of 1.62–5.19 x 10-1 mmol/L). Finally, PPC84, PPC89, and PPC101 also showed a potent inhibitory effect on α-glucosidase (IC50 of 0.51–3.53 x 10-1 mmol/L). PPC80 and PPC82 followed a non-competitive inhibition mechanism against pancreatic lipase, while PPC84 acted through competitive inhibition. The inhibition of pancreatic α-amylase by the derivatives was non-competitive, as well as for PPC84, PPC89 and PPC101 against α-glucosidase. The results suggest that these synthetic amino acid derivatives have inhibitory potential against digestive enzymes and may be used as therapeutic agents to control metabolic disorders.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that develops as a consequence of different factors such as oxidative stress and accumulation of the protein amyloid β (Aβ) in the brain, resulting in apoptosis of neuronal cells. The search for a treatment for this disorder is essential as current medications are limited to alleviating symptoms and palliative effects. The aim of this study is to investigate the effects of mint extracts on selected mechanisms implicated in the development of AD. To enable a thorough investigation of mechanisms, including effects on -secretase (the enzyme the leads to the formation of A), on Aβ aggregation, and on oxidative stress and apoptosis pathways, a neuronal cell model, SH-SY5Y cells was selected. Six Mentha taxa were investigated for their in vitro β-secretase (BACE) and Aβ-aggregation inhibition activities. Also, their neuroprotective effects on H2O2-induced oxidative stress and apoptosis in SH-SY5Y cells were evaluated through caspase activity. Real-time PCR and Western blot analysis were carried out for the two most promising extracts to determine their effects on signalling pathways in SH-SY5Y cells. All mint extracts had strong BACE inhibition activity. M. requienii extracts showed excellent inhibition of Aβ-aggregation, while other extracts showed moderate inhibition. M. diemenica and M. requienii extracts lowered caspase activity. Exposure of SH-SY5Y cells to M. diemenica extracts resulted in a decrease in the expression of pro-apoptotic protein, Bax, and an elevation in the anti-apoptotic protein, Bcl-xL, potentially mediated by down-regulation of ASK1-JNK pathway. These results indicate that mint extracts could prevent the formation of Aβ and also could prevent their aggregation if they had already formed. M. diemenica and M. requienii extracts have potential to suppress apoptosis at the cellular level. Hence, mint extracts could provide a source of efficacious compounds for a therapeutic approach for AD.

Research has shown that the consumption of herbal teas is linked with positive effects on the regulation of postprandial blood glucose level. In this study, a comparative analysis of aqueous and ethanol extractions is performed on four herbal teas (Mallotus, Cyclocarya, Rubus, Vine) to evaluate their phytochemical profiles and functional activities. Investigations of phytochemical contents, antioxidant activities, α-glucosidase inhibitory activities and chemical compositions are carried out through colorimetric analyses and UPLC-Q-Orbitrap HRMS/MS, respectively. Results showed that among the studied herbal teas, Vine exhibited the highest glucose re-gulating abilities under both aqueous and ethanol extractions. Overall, ethanol extracted samples yielded higher phytochemicals content, but the compositions of the phytochemicals varied. Meanwhile, aqueous extracts showed surprisingly strong antioxidant activities and comparable α-glucosidase inhibitory activities with ethanol extracts. Phytochemicals contents presented a positive correlation with antioxidant activities and α-glucosidase inhibitory activities. Nevertheless, antioxidant activities displayed a weak positive correlation with α-glucosidase inhibitory activities. Results from this study provided evidence that aqueous extracts from herbal teas possessed valuable phytochemicals composition for antioxidants and the hyperglycemic populations, and are promising candidates for potential applications as functional ingredients with health promoting effects and as natural additives to boost the nutritional value of herbal food products.

The α-glucosidase inhibitor is of interest to researchers due to its association with type-II diabetes treatment by suppressing postprandial hyperglycemia. Hesperidin is a major flavonoid in orange fruit with diverse biological properties. This paper evaluates the effects of hesperidin on α-glucosidase through inhibitory kinetics, fluorescence quenching, and molecular docking methods for the first time. The inhibition kinetic analysis showed that hesperidin reversibly inhibited the α-glucosidase activity with an IC50 value of 18.52 M and the inhibition was performed in an uncompetitive type. Fluorescence quenching studies indicated that the intrinsic fluorescence of α-glucosidase was quenched via a static quenching process and only one binding site was present between hesperidin and α-glucosidase. The interaction between them was spontaneous and mainly driven by hydrogen bonds as well as hydrophobic forces. Furthermore, molecular docking results suggested that hesperidin might bond to the entrance or outlet part of the active site of α-glucosidase through a network of five hydrogen bonds formed between hesperidin and the four amino acid residues (Trp709, Arg422, Asn424, and Arg467) of ?-glucosidase and hydrophobic effects. These results provide new insights into the inhibitory mechanisms of hesperidin on α-glucosidase, supporting the potential application of hesperidin-rich orange product as a hypoglycemic functional food.

Astrocytes have been implicated in a wide range of neurodegenerative diseases, with the literature indicating harmful or beneficial roles on a case-by-case basis. On such conditions, these cells are capable of secreting several inflammatory factors and also promote synapse elimination and remodeling. These responses are possible because they sense their surroundings via several receptors, including metabotropic glutamate receptor (mGluR5). However, mGluR5 activation in astrocytes under neuroinflammatory conditions can be neuroprotective or have the opposite effect. In this work, we investigated the role of mGluR5 in hiPSC-derived astrocytes subjected to pro-inflammatory stimulation by recombinant TNF-α (rTNF-α). Our results show that mGluR5 blockade by CTEP is capable of reducing pro-inflammatory cytokines (IL-6, IL-8 and TNF-α) release in rTNF-α-stimulated astrocytes, but, in contrast, leads to an augmented expression of the pan-reactive marker SERPINA3. Additionally, CTEP enhances synaptoneurosomes phagocytosis by astrocytes in both non-stimulated and TNF-α-stimulated conditions, indicating that mGluR5 blockade alone is enough to drive synaptic material engulfment. Finally, mGluR5 antagonism as well as rTNF-α stimulation leads to a reduction in the expression of synaptogenic molecules. Altogether, these data suggest a complex role for mGluR5 in human astrocytes, since its blockage may have beneficial and detrimental effects under inflammatory conditions.

Some α-Pyrone derivatives isolated from Alternaria phragmospora fungus showed promising anti leukemic activities, while others were inactive. CRM1/XPO1 (chromosome region maintenance 1 protein, also called exportin1 or PO1 in humans) has been chosen as a target for antileukemic molecular docking study for those compounds to understand their modes of interaction and structure activity relationships. The results showed that two (2 and 4), out of six, natural α-Pyrone derivatives exhibited well-established interactions with the amino acids of the receptor, which was in agreement with the experimental anti-leukemic results of these compounds. Moreover, twenty hypothetical chemically modified α-Pyrone derivatives (7-27) have been designed. Compounds 7, 8, 22 and 24 showed more efficient docking properties than the previously considered natural compounds.

Our findings indicate that all five phytocannabinoids reduce HG-HL-induced -cell loss likely through reducing apoptosis and pyroptosis. The protective effects of CBD, THCV, CBC, and CBN were seen in the GSIS impairment by HG-HL. Although all five phytocannabinoids tested in this research demonstrated the capability to inhibit β-cell dedifferentiation induced by HG-HL, CBD seems to be more effective compared to the other phytocannabinoids, as indicated by the specific biomarker responses of β-cells and progenitor cells to CBD.

Background: Identification of cancer biomarkers that are differentially expressed (DE) under two biological conditions is an important task in many microarray studies. There exist several methods in the literature in this regards and most of these methods designed especially for unpaired samples, which does not satisfy the requirements of paired samples where the gene expressions are taken from the same patients before and after treatment. Furthermore, the traditional biomarker identification methods based on either p-values or fold change (FC) values. However, sometimes, p-value based results do not comply with FC based results due to the smaller variance of gene expressions. There are some methods that combine both p-values and FC values to solve this problem. But, these methods also show weak performance for small-sample case in presence of outlying expressions. To overcome this problem, in this paper an attempt is made to develop a hybrid robust SAM-FC approach by combining rank of FC values and rank of p-values based on SAM statistic using minimum β-divergence method, which is designed for paired samples. This method introduces a weight function known as β-weight function. This weight function produces larger weights corresponding to usual/normal expressions and smaller weights for unusual/outlying expressions. The β-weight function plays the significant role on the performance of the proposed method. Results: The proposed method uses β-weight function as a measure of outlier detection by setting β=0.2. We unify both classical and robust estimates using β-weight function such that maximum likelihood estimators (MLEs) are used in absence of outliers and minimum β-divergence estimators are used in presence of outliers to obtain reasonable p-values and FC values in the proposed method. We examined the performance of proposed method in a comparison of some popular methods (t-test, SAM, LIMMA, Wilcoxon, WAD, RP and FCROS) using both simulated and real gene expression profiles for both small-and large-sample cases. From the simulation and a real spike in data analysis results we observed that the proposed method outperforms other methods for small-sample case in presence of outliers and it keeps almost equal performance with other robust methods (Wilcoxon, RP and FCROS) otherwise. From a head-and-neck cancer (HNC) dataset the proposed method identified 2 genes (CYP3A4, NOVA1) that are significantly enriched in linoleic acid metabolism, drug metabolism, steroid hormone biosynthesis and metabolic pathways. The survival analysis through Kaplan-Meier curve revealed that combined effect of these 2 genes has prognostic capability and they might be promising biomarker of HNC. Moreover, we retrieved the 12 candidate drugs based on gene interaction from glad4u and drug bank databases. Conclusion The identified drugs showed statistical significance and critical role of the proteins indicate that these proteins might be therapeutic target in cancer. Thus, elucidating the associations between the drugs identified in the present study require further investigations.

Many cancers utilize L-glutamine as a major energy source. This “L-glutamine addiction” involves a well-characterized pathway whereby L-glutamine is hydrolyzed by a glutaminase (GLS) to L-glutamate, which is then converted to α-ketoglutarate, the carbons of which enter the tricarboxylic acid (TCA) cycle. However, mammalian tissues/cancers possess a rarely mentioned alternative pathway (the glutaminase II pathway): L-Glutamine is transaminated to α-ketoglutaramate (KGM), followed by ω-amidase (ωA)-catalyzed hydrolysis of KGM to α-ketoglutarate. Uncertainty may prevail over the name glutaminase II which may be confused with the enzyme named glutaminase 2 (GLS2). Thus, we recently suggested a new name for the glutaminase II pathway, namely the glutamine transaminase-ω-amidase (GTωA) pathway. Herein, we 1) evaluate three recent articles that mention L-glutamine addiction, but not the GTωA pathway, 2) summarize the metabolic importance of the GTωA pathway, including its role in closing the methionine salvage pathway, and 3) as a source of anaplerotic α-ketoglutarate. An advantage of the GTωA pathway [i.e., L-glutamine + α-keto acid + H2O α-ketoglutarate + L-amino acid + +NH4] is that it is irreversible and that there is no net change in redox status, permitting α-ketoglutarate production during hypoxia. Finally, we discuss possible clinical benefits of GTωA pathway inhibitors.

Gastric cancer is an intractable disease with a high incidence of peritoneal dissemination and obstructive symptoms (e.g. ileus, jaundice, and hydronephrosis) arising from accompanying marked fibrosis. Microenvironmental interactions between cancer cells and stromal cells are the suggested cause of the disease. Transforming growth factor (TGF-β) is an intriguing cytokine exhibiting dual roles in malignant disease, acting as an important mediator of cancer invasion, metastasis, and angiogenesis as well as exhibiting antitumor functions. Moreover, the TGF-β pathway contributes to the generation of a favorable microenvironment for tumor growth and metastasis throughout the steps of carcinogenesis. Among these effects, TGF-β induces the epithelial-to-mesenchymal transition with prometastatic functions, contributes to the conversion of stromal cells to carcinoma-associated fibroblasts, and suppresses the function of immune cells, which compromises the antitumor immune response, leading to cancer progression and stromal fibrosis. In this review, we address the role of the essential TGF-β signaling pathway in the regulation of the activities of components of the tumor microenvironment of gastric cancer and how this contributes to tumor progression and stromal fibrosis. We then explore the potential to optimize therapy that inhibits TGF-β signaling in the preclinical and clinical settings of gastric cancer.

Leucine-rich α-2 glycoprotein1 (LRG1) is a member of the leucine-rich repeat (LRR) family that was implicated in multiple diseases including cancer, aging and heart failure as well as diabetes and obesity. LRG1 plays a key role in diet-induced hepatosteatosis and insulin resistance by mediating the crosstalk between adipocytes and hepatocytes. LRG1 also promotes hepatosteatosis by upregulating de novo lipogenesis in the liver and suppressing fatty acid β oxidation. In this study, we investigated the association of LRG1 with obesity markers including leptin and other adipokines in adolescents (11-14 years; n=425). BMI-for-age classification based on WHO growth charts was used to define obesity. Plasma LRG1 was measured by ELISA while other markers were measured by multiplexing assay. Median (IQR) of LRG1 levels was higher in obese [30 (25, 38) µg/mL] and overweight [30 (24, 39) µg/mL] adolescents, compared to normal-weight participants [27 (22, 35) µg/mL]. The highest tertile of LRG1 had an OR [95%CI] of 2.55 [1.44, 4.53] for obesity. LRG1 was positively correlated to plasma levels of HsCRP (R=0.2), Leptin (R=0.2) and Chemerin (R=0.24) with p<0.001. Additionally, it was positively associated with plasma level of IL6 (R=0.17) and IL10 (R=0.14) but not TNF-α. In conclusion, LRG1 levels are increased in obese kids and associate with increased levels of adipogenic markers. These results suggest the usefulness of LRG1 as an early biomarker for obesity and its related pathologies in adolescents.

Background and objective: Acinetobacter baumannii (A. baumannii) is an important nosocomial pathogen that possesses not only intrinsic resistance to many classes of antibiotics, but also is capable to rapidly develop antimicrobial resistance during treatment. The aim of our study was to determine the production of different types of β-lactamases (AmpC, ESBL, KPC) in A. baumannii strains, to evaluate its association with antimicrobial resistance, and to identify the changes in these characteristics after 5 years. Materials and methods: A total of 233 A. baumannii strains were isolated from different clinical specimens of patients treated at the Hospital of Lithuanian University of Health Sciences in 2016–2017 and 2021–2022. All clinical cultures positive for A. baumannii were analyzed. The type of β-lactamase was detected by phenotypic methods using ESBL plus AmpC screen disk tests and the combination meropenem disk test. Results: In 2016–2017 and 2021–2022, all A. baumannii strains were resistant to ciprofloxacin; more than 80% were resistant to carbapenems, piperacillin/tazobactam, gentamicin, and tobramycin. Comparison of two different period showed that the production of two different types of β-lactamases increased more than 5-fold (from 17.7% to 94.2%, p < 0.001), and the production of all three types of β-lactamases, more than 4-fold (from 1.3% to 5.8%, p < 0.001). A. baumannii strains producing two or three types of β-lactamases were more often resistant to tigecycline, tetracycline, and doxycycline than strains producing one type of β-lactamases (p < 0.001). Conclusions: The frequency of isolation of A. baumannii strains producing two or three β-lactamases types and the resistance rates to ampicillin/sulbactam, tigecycline, tetracycline, and doxycycline increased in 2020–2021 as compared with 2016–2017. The production of two or three types of β-lactamases by A. baumannii strains was associated with higher resistance rates to tetracyclines.

Reducing carbohydrates digestion by having low glycaemic index (GI) foods has been linked to weight loss. Inhibiting related enzymes is an alternative way to decrease carbohydrate digestion. RCM-107, an eight-herb formula that is modified from the RCM-104, has indicated significant weight-loss action in clinical trials. However, no research has been conducted to study its effect on the activity of porcine pancreatic alpha-amylase (PPA), which is involved in carbohydrate absorption. In this paper, we used fluorescence PPA inhibition assay to investigate the inhibitory effects of RCM-107 and the individual herbs present in this herbal mixture on amylase activity. Subsequently, molecular docking predicted the key active compounds that may be responsible for the enzyme inhibition. According to our results, both the RCM-107 formula and several individual herbs displayed α-amylase inhibitory effects. Also, marginal synergistic effects of RCM-107 were also detected. In addition, alisol B, (-)-epigallocatechin-3-gallate (EGCG) and plantagoside have been predicted as the key active compounds that may be responsible for the α-amylase inhibition effect of RCM-107 according to inter-residue contact analysis. Finally, Glu233, Gln63, His305, Asp300 and Tyr151 are predicted to be markers of important areas with which potential amylase inhibitors would interact.

In recent years there has been increasing interest in the discovery of new natural herbal remedies for the treatment of common conditions such as diabetes and inflammatory diseases. In this context, this paper analyzed the antidiabetic and anti-inflammatory potential of two plants of the genus Artemisia: Artemisia absinthium (wormwood) and Artemisia vulgaris (mugwort) and Trigonella foenum-graecum (fenugreek) plants less studied from this point of view. Thus, hydroal-coholic extracts (50% EtOH v/v, 10% mass) were made, which were processed by membrane technologies, micro- and ultrafiltration, in order to concentrate the biologically active principles. The extracts were then analyzed in terms of content in active principles of interest (polyphenols, flavones). The antidiabetic activity of the extracts was analyzed by testing their ability to inhibit α-amylase and α-glucosidase and the anti-inflammatory activity by testing the ability to inhibit hyaluronidase (HYA) and lipoxygenase (LOX). Thus, the T. foenum-graecum extracts showed a high inhibitory activity on α-amylase 3.22 ± 0.3 g / mL (compared to the standard used - IC50 acarbose = 3.5 g / mL) and a high inhibitory activity on LOX: 19.69 ± 0.52 g/mL (compared to all standards used). The concentrated extract of Artemisia vulgaris showed increased activity of inhibition of α-amylase - IC50 = 8.57 ± 2.31g/mL and moderate activity of inhibition of HYA - IC50 = 17.18 g/mL compared to ibuprofen, the standard used - IC50 = 5.73 g/mL. The concentrated extract of Artemisia absinthium showed a pronounced activity of inhibition of LOX - IC50 = 19.71 g / mL, compared to the standard - rutin - IC50 = 22.34 g/mL).

The usability of glass fibers as immobilization support with porous open structure has been explored. We have developed a method for immobilization of β-galactosidase on special glass fiber rolls. The new method provides a simple, non-expensive and industrially applicable method. Glutaraldehyde was used as a non-specific crosslinking agent for covalent binding of β-galactosidase on modified glass fibers. The efficiency of immobilization was tested with the known hydrolysis of lactose. All experiments were performed in a continuous laboratory reactor. The effect of reaction temperature (20, 25, and 30) °C, substrate flow rate (1, 2, and 3) mL/min, and pH of the reaction medium (6, 7, and 8) on the conversion was studied. The reaction efficiency was monitored by measuring the glucose concentration with a spectrophotometer. High immobilization efficiency and enzyme activity and stability were obtained. The optimum reaction temperature, substrate flow rate and pH were found. The activity and stability of the enzyme entrapped on the glass fiber rolls remained almost unchanged during reuse, which is a good prospect for potential industrial applications.

β-glucosidases (BGLs) play a crucial role in the degradation of lignocellulosic biomass as well as in industrial applications such as pharmaceuticals, foods, and flavors. However, the application of BGLs has been largely hindered by issues such as low enzyme activity, product inhibition, low stability, etc. Many approaches have been developed to engineer BGLs to improve these enzymatic characteristics to facilitate industrial production. In this article, we review the recent advances in BGL engineering in the field, including the efforts from our laboratory. We summarize and discuss the BGL engineering studies according to the targeted functions as well as the specific strategies used for BGL engineering.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of cardiotoxicity post-chemotherapeutic exposure, assess how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-β) pathway and discuss its role as a mediator of cardiomyopathy. We highlight recent findings demonstrating TGF-β inhibition as a potent method to prevent cardiac re-modeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-β pathway is associated with negative patient outcomes across 32 types of cancer including TNBC. We then highlight how TGF-β modulation may be a potent method to target mesenchymal (CD44+/CD24-) and epithelial (ALDHhigh) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to plasticity and differential regulation these populations remain difficult to target and persist as a major barrier barring successful therapy. TGF-β inhibition represents an intersection of two fields: cardiology and oncology. Through inhibiting cardiomyopathy, cardiac damage and heart failure may be prevented and through CSC targeting, patient prognosis may be improved. Together, both approaches, if successfully implemented would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy.

Pseudomonas aeruginosa is an adaptable bacterial pathogen that infects various organs, including the respiratory tract, vascular system, urinary tract, and central nervous system leading to high morbidity and mortality. Our primary focus of this study was to characterize P. aeruginosa clinical strains on the basis of pigment color production, determine its association to multidrug resistance behavior and ability to form biofilm. We identified yellow (30.1%), green (39.8%) and no pigment (30.1%) producing strains from a total of 143 clinical isolates. Yellow pigment producing strains presented significant resistance to a class of antibiotics including β-lactam (91.5%), aminoglycosides (70.5%), and carbapenems (51.9%) compared to green and non-pigmented strains. Importantly, 16.3% of yellow pigment producing strains was resistant to colistin where only 2.3% of non-pigmented and 1.8% of green pigmented strains were resistant to this agent. Moreover, yellow pigment producing strain were frequent producers of β-lactamase group of enzymes, ESBL (55.6%), MBL (55.6%), and AmpC (50%) and displayed higher frequency of efflux positive group (64.2%) compared to green (7.14%) and non-pigmented one (28.5%). Notably, green pigment producing strains when compared to non-pigmented groups also displayed antibiotic susceptibility behavior similar to yellow pigment producing strains. Although yellow pigment producing strains were strong biofilm producers, no significant association was identified between pigment and biofilm formation. Among pigmented and non-pigmented strains, majority of yellow pigment producing strains have shown MIC levels greater than the green and non-pigmented strains. Our study has demonstrated the impact of pigment coloration on susceptibility to antimicrobial agents where yellow pigment producing strains represent considerably a serious problem as due to lack of alternative agents against such transformed strain may collectively be associated with multidrug resistance development.

Amyloid β-peptide (Aβ) oligomerization is believed to contribute to the neuronal dysfunction in Alzheimer disease (AD). Despite decades of research, many details of Aβ oligomerization in neurons still need to be revealed. Förster Resonance Energy Transfer (FRET) is a simple but effective way to study molecular interactions. Here we use a confocal microscope with a sensitive Airyscan detector for FRET detection. By live cell FRET imaging, we detect Aβ42 oligomerization in primary neurons. The neurons were incubated with fluorescently labelled Aβ42 in the cell culture medium for 24 hours. Aβ42 were internalized and oligomerized into the lysosomes/late endosomes in a concentration-dependent manner. Both the cellular uptake and intracellular oligomerization of Aβ42 were significantly higher than for Aβ40. These findings provide a better understanding of Aβ42 oligomerization in neurons.

β-glucan is a generic term for insoluble dietary fibers exerting various effects on the immune system. As a group, β-glucans are non-cellulose polysaccharides composed of a glucopyranose as the main constituent sugar with β configuration, having a β- (1,3)-linked glucopyranose main chain as a common feature. β-glucans are absorbed through the intestine. Since the 1980s, there have been many studies reporting various effects of β-glucans on the immune system, including reports on receptors, that have slowly clarified their recognition system and action mechanisms. However, these studies focused mostly on treatments of infectious diseases and tumors; thus, the effects of β-glucans ingested in food as dietary fiber and their mechanisms of action remain largely unknown. The uptake of β-glucan into the body may be resemble that of proteins, which are soluble polymers, and insoluble material such as dietary fiber. Dietary fibers have varied structures, with wide-ranging solubility and physiological effects. Understanding whether these substances are actually taken up, how they exert their effects, and their metabolism after being taken up are important issues when considering the functionality and safety of dietary fibers.

The objective of this study was to evaluate the effects of dietary supplementation with bacteriophage and β-mannanase on health and growth performance in calves. Thirty-six pre-weaning male Holstein calves were randomly allocated to one of four dietary treatments: no supplementation, 0.1% β-mannanase, 0.1% bacteriophage, and both 0.1% bacteriophage and β-mannanase supplementation in a starter. The experiment lasted from 2 weeks before weaning to 8 weeks after weaning. Twenty-two calves survived to the end of the experiment. No interaction was observed between the two methods of supplementation. A 1-kg increase in initial BW resulted in a 1.41-fold increase in the odds ratio of survival (p < 0.01). The bacteriophage supplementation tended to increase the odds ratio of survival (p = 0.09). The number of Escherichia coli in feces significantly decreased one week after weaning. β-mannanase supplementation increased the concentrates intake (p < 0.01) and tended to increase the final BW (p = 0.08). Analysis of repeated measures indicated β-mannanase supplementation increased weekly body weight gain (p = 0.018). We conclude that bacteriophage supplementation may have a positive effect on calf survival rate, while β-mannanase supplementation may increase the growth rate and intake of a starter in calves.

The probability of the evolution of a character depends on two factors: the probability of moving from one character state to another character state and the probability of the new character state fixation. More the evolution of a character is probable more convergent evolution will be witnessed, consequently, convergent evolution could mean that the convergent character evolution result as a combination of these two factors. We investigate this phenomenon by studying the convergent evolution of biochemical functions. We use for the investigation the case of β-lactamases. β-lactamases hydrolyzes β-lactams which are antimicrobials able to block the DD-peptidases involved in bacterial cell wall synthesis. β-lactamase activity is present in two different superfamilies: the metallo-β-lactamase and the serine β-lactamase superfamily. The mechanism used to hydrolyze the β-lactam is different for the two superfamilies. We named this kind of evolution an allo-convergent evolution. We further show that the β-lactamase activity evolved several times within each superfamily, a convergent evolution type that we named iso-convergent evolution. Both types of convergent evolution can be explained by the two evolutionary mechanisms discussed above. The probability of moving from one state to another is explaining the promiscuous β-lactamase activity present in the ancestral sequences of each superfamily, while the probability of fixation is explained in part, by positive selection as the organisms having β-lactamase activity allows them to resist to organism secreting β-lactams. Indeed a mutation increasing the β-lactamases activity will be selected as the organisms having this activity will have an advantage over the others.

With the increasing resistance of bacteria to current antibiotics, novel compounds are urgently needed to treat bacterial infections. Streptozotocin (STZ) is a natural product that has broad-spectrum antibiotic activity, albeit with limited use because of its toxicity to pancreatic β cells. In an attempt to derivatize STZ through structural modification at the C3 position, we performed the synthesis of three novel STZ analogues by making use of our recently developed regioselective oxidation protocol. Keto-STZ (2) shows the highest inhibition of bacterial growth (MIC and viability assays), but is also the most cytotoxic compound. Pre-sensitizing the bacteria with GlcNAc increased the antimicrobial effect, but did not result in complete killing. Interestingly, allo-STZ (3) revealed moderate concentration-dependent antimicrobial activity and no cytotoxicity towards β cells, and deoxy-STZ (4) showed no activity at all.

High degree of polymerisation agave fructans (HDPAF) are presented as a novel encapsulating material. Electrospraying coating (EC) was selected as the encapsulation technique and β-carotene as the model bioactive compound. In case of direct electrospraying, two encapsulation methodologies (solution and emulsion) were proposed to find the formulation which provided a suitable particle morphology and an adequate concentration of β-carotene encapsulated in the particles. SEM images showed spherical particles with sizes ranging from 440 to 880 nm depending on the concentration of HDPAF and processing parameters. FTIR analysis confirmed interaction and encapsulation of β-carotene with HDPAF. Thermal stability of β-carotene encapsulated in HDPAF was evidenced by thermogravimetric analysis (TGA). The study showed that β-carotene encapsulated in HDPAF by the EC method remained stable for up to 50 h of exposure to UV light. Therefore, HDPAF is a viable option to formulate nanocapsules as a new encapsulating material. In addition, EC allowed increasing the ratio β-carotene:polymer as well as its photostability.

Cardamom is plant of the Zingiberaceae family. It has been used for the treatment of many diseases such as migraine, bronchitis, stomach and intestinal disorders. Cardamom contains triterpenes, resins, starch and fatty compounds. Phytosterols (stigmasterol, campesterol and β-sitosterol) are a group steroid alcohol in plants. They are used food, medicine and cosmetic industry. They are protective effects against some types of cancer too. Phytosterols are found in the vegetable oil such as the spindle, corn and soybean oil. This paper deals with the maximum oil and β-sitosterol yield were investigated by means of the supercritical CO₂ extraction of cardamom. The effect of operating parameters as temperature, pressure and CO₂ flow rate were investigated on oil yield. The amount of β-sitosterol was analyzed by Gas Chromatography-Mass Spectrometry (GC-MS) at optimized conditions. The optimized conditions were recorded as temperature of 40^oC, pressure of 200 bar and CO₂ flow rate of 4 L/min. The maximum oil yield and amount of β-sitosterol were found as 74.83 mg oil/g seed and 4.73 mg β-sitosterol/g seed cardamom under these conditions.

For decades, compounds present in foods and beverages have been implicated in the etiology of human cancers. The International Agency for Research on Cancer (IARC) continues to classify such agents regarding their potential carcinogenicity in humans based on new evidence from animal and human studies. Furfuryl alcohol and β-myrcene belong to these potential human carcinogens due to be evaluated. The major source of furfuryl alcohol in foods is thermal processing and ageing of alcoholic beverages while β-myrcene occurs naturally as a constituent of essential oils of plants such as hops, lemongrass and derived products. This study aimed to summarize the occurrence of furfuryl alcohol and β-myrcene in foods and beverages using data from own nuclear magnetic resonance (NMR) analysis and literature review. The highest content of furfuryl alcohol was found in coffee beans (>100 mg/kg) and in some fish products (about 10 mg/kg) while among beverages, wines contained between 1–10 mg/L with 8 mg/L in pineapple juice. The content of β-myrcene was highest in hops. In conclusion, the data about the occurrence of the two agents is either very old or based on single sample analysis, and currently judged as insufficient for exposure and risk assessment. The results of this study point out the food and beverage groups that may be considered for future monitoring of furfuryl alcohol and β-myrcene.

Ox Tongue (Echium amoenum) is an important medicinal plant rich in secondary metabolites, including alkaloids, quinones, and unsaturated fatty acids. The present study examined the concentration of oil, fatty acid profiles, and antioxidant activity of six different Iranian Echium accessions. The oil concentration varied across these populations, ranging from 16.20% to 22.36% in the first year and from 21.00% to 25.50% in the second year. The major fatty acids identified in the oils were oleic acid (18.35% to 19.40%), linoleic acid (23.80% to 26.20%), and α-linolenic acid (32.30% to 34.20%) during the first year. In the second year, the predominant fatty acids were oleic acid (15.82% to 19.32%), linoleic acid (21.55% to 24.70%), and α-linolenic acid (33.95% to 37.40%). Principal component analysis revealed distinct profiles for each population: Sari was notable for its high α-linolenic acid and γ-linolenic acid content, Fasa was distinguished by its high stearidonic acid levels, Roodsar had a high concentration of stearic acid, Vazneh Sar was rich in linoleic acid and palmitic acid, and Leron had the highest oleic acid content. The Sari population had the highest oil content at 25.50%, while Fasa had the highest α-linolenic acid content at 37.40% during the establishment year. Leron exhibited the highest antioxidant attributes. These findings indicate that selecting elite Echium populations with high levels of unsaturated fatty acids and potent antioxidant properties could be advantageous for the food industry, as they offer enhanced nutritional and functional qualities.

Wendan (a type of pomelo), as a popular fruit in China, is less known in other countries. Its peel is widely used in food and traditional medicine. Four different origins of Wendan pomelo were selected, and crude extracts were obtained by the Soxhlet extraction method. The composition of Wendan peel was analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) in positive ion mode. The compounds were identified by searching the Metabolite Link (METLIN), Spectral Database for Organic Compounds (SDBS) and referring to literature reports. A total of 20 compounds were identified among the samples from the four origins, of which 8 compounds were common. The majority of the compounds belonged to the flavonoid and coumarin classes, Meranzin hydrate was identified for the first time in pomelo peel. In vitro antioxidant activity experiments showed that samples from Taizhou, Zhejiang exhibited the highest antioxidant activity in the DPPH, ABTS, and FRAP assays, with values of 0.59 mg/mL, 97.06 μmol TE/g, and 60.62 μmol Fe2+/g, respectively. Samples from Zhangzhou, Fujian showed antioxidant activity second only to the samples from Taizhou, Zhejiang. The sample from Zhangzhou, Fujian Province, showed excellent inhibitory activity in the α-glucosidase inhibition assay (IC50=7.99 mg/mL).

Waxy rice is one of the most popular traditional crops served as a staple food in China. In this study, the effect of different factors including α-amylase activity, protein, and amylopectin structure on the pasting properties of four waxy rice varieties were investigated. Rice flours treated with AgNO3 solution, DL-dithiothreitol (DTT) or protease, suggested that both α-amylase activity and protein significantly decrease the pasting viscosity of waxy rice flours. Chain length distribution of amylopectin as measured by high performance ion exchange chromatography (HPAEC-PAD) showed that starch with higher ratio of short chain leading to a higher pasting viscosity. X-Ray diffractograms showed that the crystal type of all the four varieties of rice starches were characteristic A-type. Relative crystallinity of each rice starch was further calculated, and a higher crystallization resulted in a higher viscosity. Our study would provide a fundamental knowledge of the relationship between different factors and waxy starch pasting properties, as well as be a reference for controlling the quality of waxy rice starch-based food.

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

We used atomistic molecular dynamics (MD) simulations to study polyelectrolyte brushes based on anionic α-L-glutamic acid and α-L-aspartic acid grafted on cellulose in the presence of divalent CaCl2 salt at different concentrations. The motivation is the search of the ways to control properties such as sorption capacity and the structural response of the brush to multivalent salts. For this detailed understanding of the role of side chain length, chemical structure and their interplay is required. It was found that in the case of glutamic acid oligomers, the longer side chains facilitate attractive interactions with the cellulose surface, which forces the grafted chains to lie down on the surface. The additional methylene group in the side chain enables side chain rotation enhancing this effect. On the other hand, the shorter and more restricted side chains of aspartic acid oligomers prevent attractive interactions to a large degree and push the grafted chains away from the surface. The difference in side chain length also leads to differences in other properties of the brush in divalent salt solutions. At a low grafting density, the longer side chains of glutamic acid allow the adsorbed cations to be spatially distributed inside the brush resulting in a charge inversion. With an increase in grafting density, the difference in the total charge of the aspartic and glutamine brushes disappears, but new structural features appear. The longer sides allow for ion bridging between the grafted chains and the cellulose surface without a significant change in main chain conformation. This leads to the brush structure being less sensitive to changes in salt concentration.

The paper summarizes the current knowledge about the structure, species, and content differ-ences of β-D-glucans as a storage and functional component, especially of cereal grains. The pa-per also provides comprehensive information on the biosynthesis of this plant cell wall polysac-charide, genetic and non-genetic factors influencing the content variability and indicates the pos-sibilities of breeding modern varieties with a defined content of this metabolite. The final part of the text is also devoted to the influence of significant technological processes applied to cere-als containing β-D-glucans. The chapter discusses the influence of these processes on the content and structure of the polysaccharide and the resulting changes in its physicochemical properties. Part of the discussed issue are the possibilities of effective application of β-D-glucans in different food products.

Arylsulfatase and β-glucuronidase are two important enzymes in human, which play important role on dynamic equilibrium of steroidal estrogens. This work probably for the first time reported that hydrogen peroxide (H2O2), hypochlorite and peracetic acid (PAA) could effectively inhibit the activities of arylsulfatase and/or β-glucuronidase. The 50 percent of inhibitions (IC50) of H2O2, and PAA on arylsulfatase were found to be 142.90±9.00, 91.83±10.01, and 43.46±2.92 μM, respectively. The corresponding respective IC50 of hypochlorite and PAA on β-glucuronidase were 704.90±41.40 and 23.26±0.82 μM, while H2O2 showed no inhibition on β-glucuronidase. It was further revealed that the inhibition of hypochlorite on both arylsulfatase and β-glucuronidase was irreversible. On the contrary, the inhibition by H2O2 and PAA was reversible. Moreover, it was found that the inhibitions of arylsulfatase and/or β-glucuronidase by these three chemicals were pH-dependent, among which the inhibition by H2O2 was competitive and non-competitive for PAA. In general, H2O2 and hypochlorite can be endogenously produced in human, which suggested that the two compounds are potential endocrine disruption compounds (EDCs) as they can cause endocrine disruption via inhibition of arylsulfatase and β-glucuronidase. This work further indicated that any agent that can induce production of H2O2 or hypochlorite in human is potential EDC, which explains why some EDCs with very weak or no estrogenic potency can cause endocrine disruption that confirmed in epidemiological studies.

SAA is an acute phase protein that elevates under inflammatory circumstance. The serum level of SAA was associated with the progression of inflammation in numerous diseases. However, little attention was paid to the correlation between SAA and ONFH. In this study, SAA was found risen in the femoral head of osteonecrosis patients through proteomics analysis and further confirmed by ELISA. Furthermore, SAA was proven affecting bone metabolism in rBMSCs. It facilitated the proliferation of rBMSCs whereas it suppressed the osteogenic differentiation of rBMSCs and accelerated the adipogenic differentiation of rBMSCs. Thus, we deem that serum amyloid A, which is a vital acute phase protein in inflammation, affected bone metabolis and plays an imperative role in the pathophysiological process of ONFH.

Andrographis paniculata leaves have been widely used in traditional medicine due to their rich content of phenolic compounds. In this study, we evaluated the total phenolic and flavonoid content of Andrographis paniculata leaf extracts (ALE), as well as its antioxidant activities against DPPH, ABTS, and hydrogen peroxide radicals. Additionally, we conducted cell viability assays, RT-PCR, and western blot analysis to investigate the biochemical effects of ALE on UVB-induced HaCaT cells. Our results revealed that ALE exhibited a high concentration of polyphenols and flavonoids, which were associated with potent abiotic antioxidant properties. Furthermore, ALE treatment effectively abrogated the damage caused by UVB radiation on key molecules such as hyaluronan synthase 1, Aquaporin 3, and loricrin in HaCaT cells. ALE also demonstrated the ability to reduce the overactivation of mitogen-activated protein kinases (MAPKs) and the expression of pro-inflammatory cytokines, including interleukin-6 and interleukin-1β in UVB-induced HaCaT cells. Additionally, ALE positively influenced the peroxisome proliferator-activated receptor alpha in these cells. Overall, our findings highlight the antioxidant and anti-inflammatory effects of ALE, as well as its significant role in modulating skin barrier functions. These results contribute to the growing body of evidence supporting the therapeutic potential of ALE in skincare and dermatological applications.

SARS-CoV-2 was detected in China in December 2019. Myocardial injury is a crucial presentation of COVID-19, based on the association of ACE-2 and SARS-CoV-2. Down-regulating ACE-2 decreases the cardioprotective effects of angiotensin, leading to a higher TNF-α activation. TNF-α causes the inflammatory response in the myocardial damage as an apoptotic inducer. Moreover, as an inducer of necroptosis, TNF-α binds to a part of TNF receptor 1, which involves receptor-interacting protein 1 (RIP1) and causes cell death through RIP1 inhibition and NF-κB stimulation, which are also done through Tpl-2. Calcineurin controls the Tpl-2-driven NFAT stimulation. Bcl-2 or Bcl-X_L entirely blocks these pathways. Bcl-2 overexpression reduces FasL expression with a mechanism based on Bcl-2 inhibiting the NFAT. Moreover, the Fas/FasL system activates apoptosis in various cells. Bcl-XL stimulates Fas-related cell death. Additionally, TNF-α, as a part of inflammatory cytokine storms, indirectly interacts with NFAT/Bcl-2 through Tpl-2/NF-κB. Diversely, TNF-α and IL-1ẞ, the basis of inflammatory cytokine storms in COVID-19, can stimulate generating NO. Also, IL-2 is highly up-regulated in COVID-19 patients and stimulates NO generation in patients. TNF-α can provoke the generation of superoxides in neutrophils. A well-determined mechanism is the intracellular production of NO via calcium-calmodulin-dependent NO synthase (NOS). NO enhances NFAT’s calcium-dependent activity. Also, Intra/extracellular calcium exchange activates calcineurin and its related molecule, NFAT. Nitration provokes RIP1 necroptosis cascade, with respiratory complex I. Nitrites converse protection against ischemia-reperfusion injuries in the myocardium. Regulating this intrinsic molecular pathway can prevent the necroptosis of cardiomyocytes.

With the growing hope that disease-modifying treatments could target the molecular basis of neurodegenerative diseases even before the onset of symptoms, there is mounting pressure to define disease entities based on pathophysiology rather than on clinical syndromes. The Alzheimer’s disease research community has recently transitioned from diagnostic criteria based on an amnestic syndrome to a purely biomarker-based disease definition, relying on the demonstration of amyloid-beta pathology, tau pathology, and neurodegeneration. In contrast, current diagnostic criteria for Parkinson’s disease still rely on the presence of the well-described clinical syndrome of parkinsonism, with the addition of characteristic motor- and non-motor signs and symptoms. However, there is now unequivocal evidence that Parkinson’s disease starts years before the onset of parkinsonism. Furthermore, neuropathologically defined Lewy body disease is clinically heterogeneous, combining a range of motor, non-motor, dopaminergic and non-dopaminergic features. Finally, clinically defined Parkinson’s disease has diverse underlying etiologies most, but not all, associated with α-synuclein positive Lewy pathology. In light of recent scientific advances, we propose a biologically based definition for the diagnosis of Parkinson's disease, initially to be used for research purposes. The criteria use a three-component ‘G-S-N’ system. The first is documentation of defined gene variants (‘G’), which cause or strongly predispose to PD as the most upstream component. The second is α-synuclein pathology (‘S’), currently defined as pathological α-synuclein deposition in tissue or positive α-synuclein seeding assays. The third is evidence of underlying neurodegeneration (‘N’), currently defined by specific neuroimaging procedures. The associated clinical syndrome (‘C’) is defined by a single high-specificity feature or multiple lower-specificity features. Initiating this transition will enable the field to fuel both basic and clinical research and move closer to the precision medicine required to develop clinically meaningful disease-modifying therapies. We acknowledge current limitations, ethical implications, and the need for prospective validation of this approach.

Degradation of intracellular components through autophagy is a fundamental process to maintain cellular integrity and homeostasis. Recently a glycogen-selective autophagy pathway has been described, termed ‘glycophagy’. Glycogen is a primary storage depot and regulator of glucose availability, and glycophagy is emerging as a critical physiological process involved in energy metabolism. Glycophagy-mediated degradation of glycogen appears to operate in parallel with the well-described canonical pathway of glycogenolysis involving glycogen phosphorylase. Evidence suggests that starch-binding domain protein-1 (Stbd1) is a key glycogen-binding protein involved in tagging glycogen for glycophagy, and that Gabarapl1 is primarily involved as the Atg8 family protein recruiting the Stbd1-glycogen complex into the forming glycophagosome. The nuances of glycophagy protein machinery, regulation and lysosomal glucose release are yet to be fully elucidated. In this mini-review, we critically analyze the current evidence base for glycophagy as a selective-autophagy process of physiological importance and highlight areas where further investigation is warranted.

Background: Night-migratory birds sense the Earth´s magnetic field by an unknown molecular mechanism. Theoretical and experimental evidence support the hypothesis that light-induced formation of a radical-pair in European robin cryptochrome 4a, ErCry4a, is the primary signalling step in the retina of the bird. In the present work, we investigated a possible route of cryptochrome signalling involving the α-subunit of the cone specific heterotrimeric G protein from European robin. Methods: Protein-protein interaction studies include surface plasmon resonance, pulldown affinity binding and Förster resonance energy transfer. Results: Surface plasmon resonance studies showed direct interaction revealing high to moderate affinity for binding of non-myristoylated and myristoylated G protein to ErCry4a, respectively. Pulldown affinity experiments confirmed this complex formation in solution. We validated these in vitro data by monitoring the interaction between ErCry4a and G protein in a transiently transfected neuroretinal cell line using Förster resonance energy transfer. Conclusions: Our results suggest that ErCry4a and the G protein also interact in vivo and might constitute the first biochemical signalling step in radical-pair-based magnetoreception.

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuro-inflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby lipopolysaccharides may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments which may relieve the characteristic non-motor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

Background and objectives: The hepatoprotective activity of vitamin E and C is evident due to their ability of modulating the antioxidant pathway. In this study, we have evaluated the effects of α-tocopherol and ascorbic acid on paracetamol induced liver damage with offsetting various levels of drug treatment following an in vivo experimental protocol on Wistar albino male rats. Materials and Methods: The level of lipid peroxidation as well as histological examination of liver tissues were observed among 50 Wistar albino male rats to evaluate hepatoprotective effect of α-tocopherol and ascorbic acid on hepatocytes. The experiment was divided into 5 groups (10 rats in each group)- Basal control group (Group-I, with propylene glycol), Paracetamol treated control group (Group –II), α-tocopherol pretreated & paracetamol treated group (Group –III), Ascorbic acid pretreated & paracetamol treated group (Group –IV) and Ascorbic acid pretreated & paracetamol treated group (Group –IV). Results: The mean (± SD) Malondialdehyde (MDA) concentration were significantly reduced in α-tocopherol pretreated and paracetamol treated group (P<0.001), Ascorbic acid pretreated and paracetamol treated group (P≤0.05) and combined α-tocopherol with ascorbic acid pretreated & paracetamol treated group (P<0.001). Statistically significant differences in histological findings of rat liver were observed in paracetamol treated control group (P<0.001), ascorbic acid pretreated and paracetamol treated group (P<0.001). The serum alanine aminotransferase (ALT) level was also significantly higher in paracetamol treated group (P<0.001), α-tocopherol pretreated plus paracetamol treated group (P≤0.05) and in ascorbic acid pretreated plus paracetamol treated group (P<0.001). Conclusion: The combined pretreatment of α-tocopherol & ascorbic acid have better hepatoprotective effects than α-tocopherol or ascorbic acid alone against paracetamol induced liver damage. The decrement of free radicals produced by vitamin E could be a better hepatoprotective antioxidant than vitamin C in paracetamol induced toxicity.

We have drawn a few interesting conclusions while studying reaction products of Ph₂Si(OH)₂ with Al(ⁱBu)₃ and tetraisobutylalumoxane. In the first place, this is the production (at Ph₂Si(OH)₂ and Al(ⁱBu)₃ equimolar ratio) of oligomer siloxyalumoxane structure with alternating four- and six-member rings, as well as isobutyl and phenyl groups migration between aluminum and silicon due to the formation of intramolecular four-member cyclic complex [Ph₂(OH)SiO]Al(ⁱBu)₂ → [(ⁱBu)Ph(OH)SiO]Al(ⁱBu)Ph. Ph₂Si(OH)₂ interaction with Al(ⁱBu)₃ not only starts from intramolecular complex production, but the chain is terminated for the same reason, which in the case of Ph₂Si(OH)₂ reaction with tetraisobutylalumoxane results in failure of obtaining high-polymer siloxyalumoxane compounds. When Al(ⁱBu)₃ interacts with α- and γ-diols, no oligomer compounds are produced. Al(ⁱBu)₃ reaction with α, γ-diols results in monomer compounds that are likely to have cyclic structure. Notably at Al(ⁱBu)₃ interaction with α-diol only double excess of Al(ⁱBu)₃ allows full replacement of hydrogen in α-diol hydroxyl groups by aluminum alkyl residue with 1,3-bis(diisobutylalumoxymethyl)-1,1,3,3-tetramethyldisiloxane production. At equimolar ratio of initial reagents the second isobutyl radical at Al does not interact with the second hydroxyl group of α-diol, apparently due to the steric hindrance and 1-(diisobutylalumoxymethyl)-3-(hydroxymethyl)-1,1,3,3-tetramethyl-disiloxane is produced. Al(ⁱBu)₃ reactions with γ-diol also result in monomer compounds but the presence of a chain consisting of three СН₂-groups between Si and hydroxyl group facilitates interaction between the second hydroxyl group of γ-diol and the second isobutyl radical Al(ⁱBu)₃. Tetraisobutylalumoxane reaction with α- and γ-diols results in oligomer compounds.

The microbial contamination in food packaging have been a major concern that paved the way for the search for natural based new anti-microbial agents, such as modified α-mangostin. In the present work, twelve synthetic analogs were obtained via semi-synthetic modification of α-mangostin by Ritter reaction, reduction by palladium-carbon (Pd-C), alkylation, and acetylation. The evaluation of the anti-microbial potential of the synthetic analogs showed higher therapeutic value than the parent molecule. The anti-microbial studies proved that I E showed higher antibacterial activity whereas I I showed most significant antifungal activity. Due to their microbial properties, modified α-mangostin can be utilized as active anti-microbial agents in food packaging.

Plants produce specific structures constituting a barrier hindering penetration of pathogens, while they also produce substances inhibiting pathogen growth . These compounds are secondary metabolites, such as phenolics, terpenoids, sesquiterpenoids, resins, tannins and alkaloids. Bioactive compounds are secendary metabolities from trees and shrubs are used in medicine, herbal medicine and cosmetology. To date fruits and flowers of exotic trees and shrubs have been primarily used as sources of bioactive compounds. In turn, search for new sources of bioactive compounds is currently focused on native plant species due to its availability. Application of such raw material needs to be based on knowledge of their chemical composition, particularly health-promoting or therapeutic compounds. Research conducted to date on European trees and shrubs has been scarce. This paper presents results of literature studies conducted to systematise knowledge on bioactive compounds found in trees and shrubs native to central Europe. The aim of this review providing available information on the subject is to indicate gaps in the present knowledge.

Dunaliella salina is a rich source of 9-cis β-carotene, which has been identified as important in the treatment of retinal dystrophies and other diseases. We previously showed that chlorophyll absorption of red light photons in D. salina is coupled to oxygen reduction and phytoene desaturation and increases the pool size of β-carotene [1]. Here we show for the first time that growth under red light also controls conversion of extant all-trans β-carotene to 9-cis β-carotene by β-carotene isomerases. Cells illuminated with red light from a light emitting diode (LED) during cultivation contained a higher 9-cis β-carotene content compared to cells illuminated with white or blue LED light. The 9-cis/all-trans β-carotene ratio in red light treated cultures reached >2.5:1 within 48 hours and was independent of light intensity. Illumination using red light filters that eliminated blue wavelength light also increased the 9-cis/all-trans β-carotene ratio. With norflurazon, a phytoene desaturase inhibitor which blocked downstream biosynthesis of β-carotene, extant all-trans β-carotene was converted to 9-cis β-carotene during growth with red light and the 9-cis/all-trans β-carotene ratio was ~2:1. With blue light under the same conditions, 9-cis β-carotene was likely destroyed at a greater rate than all-trans β-carotene (9-cis/all-trans ratio 0.5:1). Red light perception by the red light photoreceptor, phytochrome, may increase the pool size of anti-oxidant, specifically 9-cis β-carotene, both by upregulating phytoene synthase to increase the rate of biosynthesis of β-carotene and to reduce the rate of formation of reactive oxygen species (ROS), and by upregulating β-carotene isomerases to convert extant all-trans β-carotene to 9-cis β-carotene.

The over use of pharmaceutical compounds, essentially antibiotics, led to an increase of their concentrations in aquatic ecosystems. In this study, the white-rot fungus Coriolopsis gallica (high-laccase-producing fungus) was investigated for the biodegradation of ampicillin (AMP) under different cultivation conditions. The biotransformation of the antibiotic was confirmed by means of high-performance liquid chromatography (HPLC), and the antibacterial activity was evaluated via the bacterial growth inhibition agar well diffusion method using Escherichia coli as an ampicillin-sensitive test strain. The results showed that AMP (50 mg L-1) was totally removed by C. gallica after 6 days of incubation in a liquid medium. The antibiotic removal rate was maximal with a fungal culture aged 9 days. Such a culture achieved the removal of a higher concentration of up to 500 mg L-1 of ampicillin in 3 days. This higher antibiotic removal rate was concomitant with the maximal laccase production in culture supernatant. In addition, four consecutive doses of 500 mg L-1 of ampicillin were transformed by the same fungal culture in 24 days. After that, the fungus was unable to remove the antibiotic. The measurement of ligninolytic enzyme activity showed that laccase of C. gallica might participate in the biotransformation of AMP.

The protein TRPM8, a non-selective, calcium (Ca2+) permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β–lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring C-terminal amides and diversely substituted N’-terminal monobenzyl groups, in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca2+ entry, thereby establishing critical structure-activity relationships. While the substitution of the tert-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the N’-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the TRP ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein, which come upon four main poses by the pore zone, differents from those described for other known antagonists. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin.

Forty-five male Dorper crossbred lambs (40.17 ± 0.35 kg BW) were used in order to investigate the effects of the duration of calcium propionate (CaPr) supplementation in lambs finished with zilpaterol hydrochloride (ZH) on the productive performance, carcass characteristics, and meat quality. Lambs were individually housed and fed a finishing-diet for 42 d before being slaughtered. Lambs received the following treatments: 1) No additives (CTL), 2) ZH supplementation for 28 d (with 3 d ZH withdrawal before slaughter) at a dosage of at 7.2 mg/kg diet (ZH), for treatments 3, 4, and 5, lambs received ZH and 10g CaPr/lamb/d throughout the entire phase (42 d), or during the last 28 or 14 d before slaughter. Compared to CTL, ZH lambs exhibited a similar average daily gain (ADG) but had lower dry matter intake (DMI), leading to increased feed efficiency. Supplementing with ZH alone did not affect carcass traits, visceral mass, whole cuts, or meat quality. Lambs that received both CaPr and ZH exhibited quadratic increases (p &lt; 0.05) in final BW (FBW), ADG, and dressing percentage (D%). These increases were optimal at an estimated inclusion durations of 26 d for FBW, 30 for ADG, and 39 d for D%. The ADG:DMI ratio and the longissimus muscle area (LMA) both exhibited quadratic increases (p &lt; 0.05). The optimal duration of CaPr supplementation for ADG:DMI ratio was found to be 28 d, while for LMA, it was 14 d. As the period of CaPr supplementation increased, there was a linear increase (p &lt;0.05) in hot carcass weight, leg circumference, and whole cuts of breast IMPS209 and shoulder IMPS207. Cook loss percent increased quadratically (p &lt; 0.05), being higher when CaPr was included for an estimated duration of 26 d. As the duration of CaPr supplementation increased, the purge loss percentage (PLR) also increased linearly (p &lt; 0.05). In conclusion, including CaPr in the diet for a duration of 28 d in lambs improved the response to ZH supplementation on the productive performance, carcass weight and some whole cuts. However, it can also have a negative effect on PRL%.

This study presents an innovative analytical method for the detection and quantification of 14 β-agonists in pork using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method involves the use of a solid phase microextraction (SPME) probe, consisting of a wooden tip coated with polyacrylonitrile (PAN) and molecularly imprinted polymer (MIP). This probe has been integrated into an automated extraction device, designed in our laboratory to extract the target analytes prior to LC-MS/MS analysis. Compared to the traditional solid-phase extraction (SPE) procedure, the proposed approach significantly reduces the costs related to adsorbent ma-terial and solvent consumption, and shortens purification time, thereby reducing both the tech-nical workload and associated expenses. The methodology has been carefully validated in ac-cordance with the National Standard of the People's Republic of China (GB/T 22286-2008), evalu-ating key parameters including the limit of detection (LOD), limit of quantification (LOQ), matrix effects, linearity, and both intra-day and inter-day precision. The average recovery rates for all β-agonists were observed to lie between 71.6% and 82.2%, with relative standard deviations (RSDs) consistently below 15% for both types of precision. The LOD and LOQ values were found to range from 0.09 to 0.39 μg/kg and 0.27 to 0.99 μg/kg, respectively. In terms of accurate detection of positive samples, the developed method demonstrated a closer approximation to the true value of the sample compared to the National Standard method GB/T 31658.22-2022. Overall, the proposed method exhibits substantial promise for the routine assessment of β-agonists in pork and presents a practical alternative for compliance monitoring in regulatory settings.

Alzheimer's disease (AD) is characterized by memory impairment and existence of amyloid-β (Aβ) plaques and neuroinflammation. Due to the pivotal role of oxidative damage in AD, natural antioxidative agents, such as polyphenol-rich fungi, have garnered scientific scrutiny. Here, the aqueous extract of mixed medicinal mushroom mycelia (MMMM) - Phellinus linteus, Ganoderma lucidum, and Inonotus obliquus - cultivated on a barley medium, was assessed for its anti-AD effects. A neuron-like PC12 cells, which were subjected to Zn2+, an Aβ aggregator, was employed as an in vitro AD model. The cells pretreated with or without MMMM assayed for Aβ immunofluorescence, cell viability, reactive oxygen species (ROS), apoptosis, and antioxidant enzyme activity. 5XFAD mice were administered with 30 mg/kg/day MMMM for 8 weeks and underwent memory function tests and histologic analyses. In vitro results demonstrated that the cells pretreated with MMMM exhibited attenuation in Aβ immunofluorescence, ROS accumulation, and apoptosis, and increment in cell viability and antioxidant enzyme activity. In vivo results revealed that 5XFAD mice administered with MMMM showed attenuation in memory impairment and histologic deterioration such as Aβ plaques accumulation and neuroinflammation. MMMM might mitigate AD-associated memory impairment and cerebral pathologies, including Aβ plaque accumulation, and neuroinflammation, by impeding Aβ-induced neurotoxicity.

Enzyme immobilization is known to enhance polypeptide resistance towards environmental changes, particularly in terms of their stability. The Y509E mutant of β-xylosidase from Geobacil-lus stearothermophilus (XynB2Y509E) (which also bears xylanase activity) has been immobilized in chitosan spheres through either entrapment or covalent bond formation methods. In the immo-bilization by entrapment, besides observing a total loss of xylanase activity, it was found that chitosan concentration affects the process efficiency. Additionally, the maturation time of the spheres and the alkaline pH used to precipitate the spheres affect the β-xylosidase activity of the enzyme. In covalent bond immobilization, it was found that the pH during the modification with glutaraldehyde, as well as the subsequent protein binding, were key factors in preserving the dual enzymatic activity. The activity expressed after immobilization by covalent bonding was 23% higher compared to the activity expressed following entrapment immobilization, with values of 122.3 and 99.4 U. g-1, respectively. Both biocatalysts showed increased thermal and pH stability, along with an improved storage capacity, as they retained 40% and 88% of their activi-ty after being stored at 4 C for two months. Moreover, XynB2Y509E immobilized by covalent binding also exhibited outstanding reusability, retaining a 92% of activity after ten cycles of re-use.

β-thalassemia, a congenital genetic hematological disorder characterized by decreased or absence of β-globin chains, leads to decrease in levels of Hemoglobin A. The affected individuals can be categorized into two cohorts based on transfusion dependency: transfusion dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT). Remarkably, despite the primary pathology lying in β-globin chain depletion, β-thalassemia exhibits an intriguing association with iron overload. Iron metabolism, a tightly regulated physiological process, reveals a complex interplay in these patients. Over time, both cohorts of β-thalassemic individuals develop iron overload, albeit through distinct mechanisms. Addressing the diverse complications arising due to iron overload in β-thalassemic patients, the utilization of iron chelators has gained a lot of significance. With varying efficacies, routes of administration, and modes of action, different iron chelators offer unique benefits to patients. In the Indian context, three commercialized iron chelators have emerged, showcasing a high adherence rate to the iron chelator-based treatment regimens among β-thalassemic individuals. In this review, we explore the intriguing connection between β-thalassemia and iron overload, shedding light on the intricate mechanisms at play. We delve into the intricacies of iron metabolism, unveiling the distinct pathways leading to iron accumulation in these patients. Additionally, we critically evaluate the therapeutic efficacy of different iron chelators, emphasizing their respective advantages in managing iron overload complications. Through this comprehensive analysis, we aim to deepen our understanding of β-thalassemia and iron overload, paving the way for optimized treatment strategies. Ultimately, our findings provide valuable insights into improving the care and outcomes of individuals affected by β-thalassemia.

It is believed that fetal hemoglobin (HbF) expression in adults is largely genetically regulated. The increased expression of HbF in pregnancy has been reported in a small number of articles. Different mechanisms have been proposed, but the description of HbF expression during pregnancy remains unclear. The objectives of this study were to document HbF expression during peri and postpartum periods, confirm its maternal origin, and assess clinical and biochemical parameters potentially associated with HbF modulation. In this observational prospective study, 345 pregnant women were followed. At baseline, 169 had HbF expression (≥1% of total hemoglobin) and 176 did not have HbF expression. Women were followed at the obstetric clinic during their pregnancy. Clinical and biochemical parameters were measured at each visit. Analyses were made to determine which parameters had a significant correlation to HbF expression. Results show that HbF expression of ≥ 1% during peri and postpartum periods in pregnant women without influencing comorbidities is at its highest peak during the first trimester. In all women, it was proven that HbF was of maternal origin. A significant positive correlation between HbF expression, β-HCG, and HbA1C was present. A significant negative association between HbF expression and total hemoglobin was found. HbF expression induction during pregnancy is probably associated with increase in β-HCG and HbA1C, and decrease of total hemoglobin, which could temporarily reactivate the fetal erythropoietic system.

A controllable synthesis of trisubstituted imidazoles and pyrroles has been developed through rhodium(II)-catalyzed regioselective annulation of N-sulfonyl-1,2,3-trizaoles with β-enaminones. The imidazole ring was formed through 1,1-insertion of N-H bond to α-imino rhodium carbene and subsequential intramolecular 1,4-conjugate addition when α-carbon atom of amino group bearing with methyl, whereas utilizing phenyl substituent constructed pyrrole ring via intramolecular nucleophilic addition. Features such as mild conditions, good functional groups tolerance, gram-scale synthesis, and valuable transformations of the products qualified this unique protocol as an efficient tool for the synthesis of N-heterocycles.

Iloperidone (ILO) is a second-generation antipsychotic drug and a first-line treatment approved by USFDA in May 2009. Iloperidone belongs to Biopharmaceutical Classification Systems (BCS) class II; thus, it is poorly water-soluble, highly permeable, and has pH-dependent solubility. Cyclodextrins and their derivatives have a wide range of applications in different formulations due to their complexation ability, which improves the solubility, stability, safety, and bioavailability of a drug. We have tried the complexation of iloperidone with sulfobutyl ether-β-cyclodextrin (SEβCD) to improve its solubility and dissolution. Complexation was done by the kneading method. The characterization of the SEβCD complexes with Iloperidone was done by FTIR, differential scanning calorimetry (DSC), saturation solubility, etc. A multimedia dissolution of the complex was carried out and compared with the plain drug. A significant improvement in drug release was found from SEβCD complexes in all media when compared with the drug alone.

Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wildtype (+/+) and knockout (-/-) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of PEPCK mRNA independent of genotype, while increasing CPT1 mRNA only in GPR109a -/- mice. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and -/- mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator activated receptor α (PPARα) mRNA expression. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the ketogenic state or the pharmacological benefits associated with niacin.

The transforming growth factor-β (TGF-β), in which overexpression have been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Three series of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14a–h, 15a–h, 16a–h, 22a, 22b, 22d, 23a, 23b, 23d, 24b, and 24d were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38α mitogen activated protein (MAP) kinase inhibitory activity in an enzymatic assays. Among these compounds, the most active compound 16f inhibited ALK5 phosphorylation with an IC₅₀ value of 0.28 µM, with 98% inhibition at 10 µM. Compound 16f also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound 3 (LY-2157299). Molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.

As a chronic disease, osteoarthritis (OA) leads to degradation of both cartilage and subchondral bone, of which the development is related to proinflammatory cytokines like interleukin-1β. In the present study, the anti-inflammatory effect of Specnvezhenide in osteoarthritis and mechanism of it was studied in vitro and in vivo. The results showed that Specnvezhenide decreases interleukin-1β-induced expression of matix-degrading enzymes and reduces the activation of NF-κB and wnt/β-catenin pathways in vitro. Furthermore, Specnvezhenide treatment prevents the degeneration of both cartilage and subchondral bone in rats OA model. As conclusion, to the best of our knowledge, we report firstly that Specnvezhenide decreases interleukin-1β-induced inflammation on rat chondrocytes by inhibiting activation of NF-κB and wnt/β-catenin pathways, and has therapeutic potential in OA treatment.

Environmental estrogen pollution and estrogen effects on the female reproduction system are well-recognized scientifically. Among the estrogens, 17 β-estradiol is a priority in environmental estrogen pollution, and it is also a major contributor to estrogen which regulates the female reproduction system. 17 β-estradiol is carcinogen and has a tumor promotion effect relating to breast cancer, lung cancer and others. It also affects the psychological well-being such as depression, fatigue and others. Thus, a simple method of detection of 17 β-estradiol will be important for both environmental estrogen pollution and women’s health care. This study demonstrates a simple-use, cost effective 17 β-estradiol biosensor system which can be used for both environment and women’s health care applications. The bio-recognition mechanism is based on the influence of the redox couple, K₃Fe (CN) ₆/K₄Fe (CN) ₆ by the interaction between 17 β-estradiol antigen and its α-receptor (ER- α; α-estrogen antibody). The transduction mechanism is an electrochemical analytical technique, differential pulse voltammetry (DPV). The levels of 17 β-estradiol antigen studied was between 2.25 pg/mL to 2,250 pg/mL, Phosphate buffered saline (PBS), tap water from the Cleveland regional water district, and simulate urine were used as the test media covering the potential application areas for 17 β-estradiol detection. An interference study by testosterone which has a similar chemical structure and molecular weight as those of 17 β-estradiol was carried out, and this 17 β-estradiol biosensor showed excellent specificity without any interference by similar chemicals.

To decrease oral pathogens and increase the number of beneficial bacteria, probiotics and bioactive compounds made via microbial bioconversion are recently used. In addition, the interest regarding probiotics-mediated bioconversion with popular medicinal plants is increasing. These compounds produced during the process exhibit synergistic effect and enhance a variety of biological activities including pathogen inhibition in host. Therefore, we developed bioconverted milk with high inhibitory activity against oral pathogens and α-glucosidase. Lactiplantibacillus plantarum SMFM2016-RK was chosen as the probiotic due to its beneficial characteristics such as high acid and bile tolerance, antioxidant activity, and α-glucosidase inhibition. Based on the minimal bactericidal concentration against three oral pathogens, the following appropriate concentrations of Artemisia herba-alba extract were added to milk: 5 mg/mL of A. herba-alba ethanol extract and 25 mg/mL of A. herba-alba hot-water extract. Four bioconverted milks (BM), BM1, BM2, BM3, and BM4, were produced by combining L. plantarum SMFM2016-RK alone, L. plantarum SMFM2016-RK and ethanol extract, L. plantarum SMFM2016-RK and hot-water extract, and L. plantarum SMFM2016-RK with both extracts. As a result of antimicrobial activity, BM3 inhibited the growth of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis the most, and BM4 suppressed the growth of Fusobacterium nucleatum the most. In addition, bioconverted milk containing A. herba-alba (BM2, BM3, and BM4) inhibited α-glucosidase more effectively than BM1. In conclusion, A. herba-alba-added milk bioconverted by L. plantarum SMFM2016-RK displayed the growth inhibitory effect on oral pathogens and the α-glucosidase inhibitory activity, thus it necessitates to evaluate the effects on the alleviation of oral diseases and glycemic control through future animal experiments.

Background and Objectives: Knee osteoarthritis (KOA) is a degenerative disease that is targeting continuously people of different ages, but especially the elderly population, the number of which tends to increase continuously at the global level. Apart from age, excess weight can influence the evolution of the disease, with obesity being associated with a weak inflammation stage, and an imbalance between pro-inflammatory and anti-inflammatory cytokines. The present work aimed to identify specific biomarkers alike ACRP-30, IL-10, TNF-α, and IL-6 in synovial fluid and correlate them with patients’ clinical data. Materials and Methods: 24 subjects with KOA and over 50 years of age are involved in the present study. All patients performed a supine X-ray at the target knee. Ultrasound was performed using an ESAOTE MyLab Omega (ESAOTE Spa, Italy) ultrasound device and a 6-19 MHz linear array transducer. Results: The obtained results highlighted a significant correlation between age and adiponectin level (p=0.0451, r=-0.412). Also, the IL-10 values are lower in cases where the intensity of the pain is more pronounced (p=0.0405, r=-0.421). In addition, analyzing the data by gender, it was observed that in the case of males, stiffness is more related to age (p=0.0079, r=0.7993), compared to women (p=0.0203, r=0.6223). In the case of women, the progression of the disease tends to increase more intensively total WOMAC score’s values (p=0.00031, r=0.8342), compared with men (p=0.0289, r=7013). Regarding interleukins and BMI, significant correlations were observed only in the case of men. Conclusions: A significant correlation between age and adiponectin, and adiponectin and IL-6, suggests that advanced age may contribute to adiponectin reduction. Comparing men with women, it was observed that men's age is more related to rigidity, and IL-6 and IL-10 are directly correlated to BMI and women seem to be more sensitive to pain and stiffness.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although prognosis continually improved along years, a significant proportion of patients still relapse from the disease due to leukemia resistance to therapy. Methotrexate (MTX), a folic acid antagonist, is a chemotherapy agent commonly used against ALL and a immune-system suppressant for rheumatoid arthritis, that presents multiple and complex mechanisms of action and resistance. Previous studies have shown that MTX modulates the nuclear factor kappa B (NF-κB) pathway, an important family of transcription factors involved in inflammation, immunity, cell survival, and proliferation, frequently hyperactivated in ALL. Using gene set enrichment analysis (GSEA) on publicly available gene expression data from 161 newly diagnosed pediatric ALL patients, we found “TNF-α signaling pathway” to be the most enriched Cancer Hallmark in MTX poor responder patients. Transcriptomic analysis in a panel of ALL cell lines (6 BCP-ALL and 7 T-ALL) also identified the same pathway as differentially enriched among MTX resistant cell lines, as well as in slowly dividing cells. To better understand the crosstalk between NF-κB activity and MTX resistance, we genetically modified the cell lines to express luciferase under a NF-κB biding site promoter. We observed that the fold change in NF-κB activity triggered by TNF-α (but not MTX) treatment correlated with MTX resistance and proliferation across the lines. At the individual gene level, NFKB1 expression was directly associated with a poorer clinical response to MTX, and with both an increased TNF-α-triggered NF-κB activation and MTX resistance in the cell lines. Despite these results, pharmacological inhibition (with BAY 11-7082 and parthenolide) or stimulation (with exogenous TNF-α supplementation) of the NF-κB pathway did not alter MTX resistance of the cell lines significantly, evidencing a complex interplay between MTX and NF-κB in ALL.

Hb Adana is a non-deletional α-thalassaemia variant, due to mutations in α1- or α2-globin codon 59 (αCD59) that produce unstable α-globin. Clinical appearance can range from silent carrier to blood transfusion reliance, hepatosplenomegaly, skeletal deformities, and spinal cord compression. Despite the importance of Hb Adana inheritance, this Hb variant is challenging to study since molecular tests are scarce and routine diagnosis can be missed. This study explored the distribution of Hb Adana among local high school students and evaluate the hematological parameters and haemoglobin analysis of Hb Adana in this region of Malaysia. This retrospective study included 13,721 blood samples from high school students enrolled in Malaysia's National Thalassaemia Screening Program at Hospital Raja Perempuan Zainab II (HRPZ II). Multiplex Gap PCR was used to detect deletional α-thalassaemia. Common non-deletional α-thalassaemia was detected using multiplex ARMS PCR. Evaluable data were retrieved from the HRPZ II database. Results: A total of 2327 subjects exhibited common deletional (n=1037, 44.6%) and non-deletional (n=1290, 55.4%) α-thalassaemia. Hb Constant Spring was the most frequent non-deletional α-thalassaemia. Thirty-one participants (1.33%) had αCD59α/αα and one (0.04%) had αCD59α/-α3.7. The 32 Hb Adana subjects were 87.5% Malay, and 12.5% Orang Asli. Additionally, seven cases of HbE/Hb Adana were discovered. The haemoglobin level in heterozygous Hb Adana ranged from mild anaemia to normal, 95.0 g/L to 153.0 g/L. The MCV and MCH were approximately 73 fL and 23 pg, respectively. Conclusions: We have denoted the distribution of alpha thalassaemia mutation patterns among high school students in Kelantan, Northeast Peninsular of Malaysia. Our observation showed Hb Adana was rarely uncommon in our region and the co-inheritance with an α-gene deletion generates α+-thalassaemia; with HbE, α0-thalassaemia. All heterozygous Hb Adana exhibited low MCVs and MCHs.

α-amylase inhibitors (aAIs) have been proved efficient for the management of type 2 diabetes. This study aimed to search the potential aAIs produced by microbial fermentation. Among various bacterial strains, Pseudomonas aeruginosa TUN03 was found as a potential aAI - producing strain, and shrimp heads powder (SHP) was screened as the most suitable C/N source for fermentation. P. aeruginosa TUN03 exhibited the highest aAIs productivity (3100 U/mL) in the medium containing 1.5% SHP with the initial pH of 7-7.5, and fermentation was performed at 27.5 °C in 2 days. Further, aAIs compounds were investigated for scale-up production in a 14 L – bioreactor system, and the results highlighted high yield (4200 U/mL) in much shorter fermentation time (12 h) compared to fermentation in flasks. The bioactivity-guided purification resulted in the isolation of one major target compound. This active compound was confirmed as hemi-pyocyanin (HPC), with good purity, via using high-performance liquid chromatography and gas chromatography-mass spectrometry. Notably, HPC demonstrated potent activity comparable to acarbose, a commercial antidiabetic drug; this is the first-ever report of aAI activity of HPC. The docking study indicated that HPC inhibits α-amylase via binding to amino acid Arg421 at the biding site on enzyme α-amylase with good binding energy (-9.3 kcal/mol) and creating two linkages of H-acceptor.

We present here seven new zircon (U-Th)/He (ZHe) ages and three new zircon fission track ages (ZFT) analyzed from an age-elevation profile (Machu Picchu, Peru). ZFT data present older ages in comparison with the other thermochronological data, whereas the ZHe data interestingly present similar ages than the ones obtained with apatite (U-Th)/He (AHe). It has been proposed that He retention in zircon is linked to the damage dose, with an evolution of the closure-temperature from low values associated to low α-dose (<1016 α/g), subsequently increasing before decreasing again at very high α-dose (>1018 α /g). Studies have been focused on the He diffusion behavior at high α-dose, but little is known at low dose. We propose that the ZHe closure temperature at α-dose ranging from 0.6×1015 to 4×1016 α/g is in the range of ~60-80°C. This value is lower than the one proposed in the current damage model ZRDAAM and demonstrates that the ZHe and AHe methods could have similar closure temperatures at low α-dose (i.e. similar ages). These new data strengthen our previous geological conclusions and even highlight an about twice more important cooling rate than the one deduced from AHe and apatite fission-track data alone registered at Machu Picchu.

Hematite (-Fe2O3) with uniform hexagonal flakes morphology has been successfully synthesized using a combination of gelatin as natural template with F127 via hydrothermal method. The resulting hematite was investigated as adsorbent and photocatalyst for removal of ibuprofen as pharmaceutical waste. Hexagonal flake-like hematite was obtained following calcination at 500 oC with the average size was measured at 1-3 µm. Increasing the calcination temperature to 700 oC transformed the uniform hexagonal structure into cubic shape morphology. Hematite also showed high thermal stability with increasing the calcination temperatures, however, the surface area was reduced from 47 m2/g to 9 m2/g. FTIR analysis further confirmed the formation Fe-O-Fe bonds, and the main constituent elements of Fe and O were observed in EDX analysis for all samples. Fe2O3-G samples have an average adsorption capacity of 55-25.5 mg/g at 12-22% of removal efficiency when used as adsorbent for ibuprofen. The adsorption capacity was reduced with increasing the calcination temperatures due to the reduction of available surface area of the hexagonal flakes when transformed into cube. Photocatalytic degradation of ibuprofen using hematite flakes achieved 50% of removal efficiency meanwhile combination of adsorption and photocatalytic degradation further removed 80% of ibuprofen in water/hexane mixtures.

The effects of mixing orders of tannic acid (TA), starch and α-amylase on the enzyme inhibition of TA were studied, including mixing TA with α-amylase before starch addition (order 1), mixing TA with pre-gelatinized starch before α-amylase addition (order 2) and co-gelatinizing TA with starch before α-amylase addition (order 3). It was found that the enzyme inhibition was always highest for order 1 because TA could bind with the enzyme active site thoroughly before digestion occurred. Both order 2 and 3 reduced α-amylase inhibition through decreasing binding of TA with the enzyme, which resulted from the non-covalent physical adsorption of TA with gelatinized starch. Interestingly, at low TA concentration, α-amylase inhibition for order 2 was higher than order 3, while at high TA concentration, the inhibition was shown with opposite trend, which arose from the difference in the adsorption property between the pre-gelatinized and co-gelatinized starch at the corresponding TA concentrations. Besides, both the crystalline structures and apparent morphology of starch were not significantly altered by TA addition for order 2 and 3. Conclusively, although a polyphenol may have an acceptable inhibitory activity in vitro, the actual effect may not reach the expected one when taking processing procedures into account.

In the search of potent α-amylase inhibitors, we have synthesized seventeen derivatives of 2-mercaptobenzimidazole bearing sulfonamide (1-17) and evaluated for their α-amylase inhibitory potential. All compounds display a variable degree of α-amylase activity having IC50 values ranging between 0.90 ± 0.05 to 11.20 ± 0.30 µM when compared with the standard drug acarbose having IC50 value 1.70 ± 0.10 µM. Compound 1, 2, 11, 12 and 14 having IC50 values 1.40 ± 0.10, 1.30 ± 0.05, 0.90 ± 0.05, 1.60 ± 0.05 and 1.60 ± 0.10 µM respectively were found many folds better than the standard drug acarbose. The remaining analogs showed good inhibitory potentials. All the synthesized compounds were characterized by HREI-MS, 1H and 13C-NMR. Structure activity relationship (SAR) has been recognized for all newly synthesized analogs. Through molecular docking study, binding mode of active analogs with α-amylase enzyme was confirmed.

In this article, we consider the three dimensional $\alpha$-fractional nonlinear delay differential system of the form \begin{align*} D^{\alpha}\left(u(t)\right)&=p(t)g\left(v(\sigma(t))\right),\\D^{\alpha}\left(v(t)\right)&=-q(t)h\left(w(t))\right),\\D^{\alpha}\left(w(t)\right)&=r(t)f\left(u(\tau(t))\right),~ t \geq t_0, \end{align*} where $0 < \alpha \leq 1$, $D^{\alpha}$ denotes the Katugampola fractional derivative of order $\alpha$. We have established some new oscillation criteria of solutions of differential system by using generalized Riccati transformation and inequality technique. The obtained results are illustrated with suitable examples.

We do fuzzification the concept of domination in crisp graph by using membership values of nodes, α-strong and arcs. In this paper, we introduce a new variation on the domination theme which we call vertex domination. We determine the vertex domination number γ_v for several classes of fuzzy graphs, specially complete fuzzy graph and complete bipartite fuzzy graphs. The bounds is obtained for the vertex domination number of fuzzy graphs. Also the relationship between M-strong arcs and α-strong is obtained. In fuzzy graphs, monotone decreasing property and monotone increasing property is introduced. We prove the vizing’s conjecture is monotone decreasing fuzzy graph property for vertex domination. we prove also the Grarier-Khelladi’s conjecture is monotone decreasing fuzzy graph property for it. We obtain Nordhaus-Gaddum (NG) type results for these parameters. The relationship between several classes of operations on fuzzy graphs with the vertex domination number of them is studied.

The Chinese drug Bombyx Batryticatus mori.L which also named as the white stiff silkworm is widely used in clinics, due to the significant antispasmodic and promotional blood circulation effects. In addition, its hypoglycemic effect is also recognized in recent years. From a pathological point of view, the enzymatic glycosylation and non-enzymatic glycation both have important roles in regulating properties of proteins and are associated with Diabetes. With the db/db mouse model, we examined the alterations of N-glycosylation of diabetic myocardium at primary stage and clarify the differences in glycosylation of myocardium before and after with 1-DNJ treatment. Hydrophilic chromatography solid phase extraction enrichment and LC-MS/MS identification was applied to profile the alternations in protein glycosylation. Meanwhile, N-glycan α1, 6-fucosylation alterations were profiled with LCA lectin blot and FITC-labelled lectin affinity histochemistry. Our results showed that AGES, hydroxyproline, CTGF and other serum indicators and fibrosis related cytokines expressional levels were reduced significantly by 1-DNJ in a dose-dependent manner. In order to verify this result, the well-known pathway of TGF-β/smad2/3 was picked out and α1, 6-core fucosylated TGFR-βⅡwas semi-quantified with western blot method. The result sustained the conclusion from LCA lectin affinity histochemistry and lectin blot analysis. The expressional level of α1, 6-fucosyltransferase mRNA was increased in the myocardium of db/db mice, however, the 1-DNJ administration did not show obvious inhibitory effect on FU8 expression. This unexpected result can be interpreted as 1-DNJ plays the roles by reducing the concentration of substrate rather than inhibiting α1，6-fucose glycosyltransferase expression. Meanwhile, 1-DNJ crude extract from BBm with some flavonoids accompany can also play the roles of anti-oxidant, and all the chemicals protect the diabetic myocardium from hyperglycemia damage commonly.

Fibroblast activation protein (FAP) is a membrane-tethered serine protease overexpressed in the reactive stromal fibroblasts of &gt; 90% human carcinomas, which makes it a promising target for developing radiopharmaceuticals for imaging and therapy of carcinomas. Here, we synthesized two novel (R)-pyrrolidin-2-yl-boronic acid-based FAP-targeted ligands; SB02055 (DOTA-conjugated (R)-(1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)glycyl)pyrrolidin-2-yl)boronic acid) and SB04028 (DOTA-conjugated ((R)-1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)-D-alanyl)pyrrolidin-2-yl)boronic acid). natGa- and 68Ga-complexes of both ligands were evaluated in preclinical studies and compared to previously reported natGa/68Ga-complexed PNT6555. Enzymatic assays showed that FAP binding affinities (IC50) of natGa-SB02055, natGa-SB04028 and natGa-PNT6555 were 0.41±0.06, 13.9±1.29 and 78.1±4.59 nM, respectively. PET imaging and biodistribution studies in HEK293T:hFAP tumor-bearing mice showed that while [68Ga]Ga-SB02055 presented with a nominal tumor uptake (1.08±0.37 %ID/g), [68Ga]Ga-SB04028 demonstrated clear tumor visualization with ~1.5-fold higher tumor uptake (10.1±0.42 %ID/g) compared to [68Ga]Ga-PNT6555 (6.38±0.45 %ID/g). High accumulation in the bladder indicated renal excretion of all three tracers. [68Ga]Ga-SB04028 displayed low background level uptake in most normal organs, and comparable to [68Ga]Ga-PNT6555. However, since its tumor uptake was considerably higher than [68Ga]Ga-PNT6555, the corresponding tumor-to-organ uptake ratios for [68Ga]Ga-SB04028 were also significantly greater than [68Ga]Ga-PNT6555. Our data demonstrate that (R)-(((quinoline-4-carbonyl)-D-alanyl)pyrrolidin-2-yl)boronic acid is a promising pharmacophore for the design of FAP-targeted radiopharmaceuticals for cancer imaging and radioligand therapy.

The present review is a comprehensive update of the synthesis of monocyclic β-lactams via cycloaddition reactions. According to the IUPAC definition of cycloaddition, both elementary and stepwise processes (formal cycloadditions) have been considered. The years 2019-2022 are covered by the cited literature. The focus of the review is on synthetic aspects with emphasis on the structural scope, reaction conditions, mechanistic aspects, and selectivity results. Selected significant data related to biological activities and synthetic applications are also highlighted.

With around one billion of the world's population affected, the era of Metabolic-associated fatty liver disease (MAFLD) pandemic has entered the global stage. MAFLD is a chronic progressive liver disease with accompanying metabolic disorders such as type 2 diabetes mellitus and obesity which can progress asymptomatically to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC), and for which, to date there is almost no approved pharmacologic options. Because MAFLD has a very complex etiology and it affects also extrahepatic organs, a multidisciplinary approach is required when it comes to finding an effective and safe active substance for MAFLD treatment. The optimal drug for MAFLD should diminish steatosis, fibrosis and inflammation in the liver, and the winner for MAFLD drug authorisation seems to be the one that significantly improves liver histology. Saroglitazar (Lipaglyn®) was approved for Metabolic dysfunction associated steatohepatitis (MASH) in India in 2020; however, the drug is still being investigated in other countries. Despite that a pharmaceutical industry is still lagging behind to develop an ap-proved pharmacologic therapy for MAFLD, research has been recently intensified and many molecules which are underway in the final stages of clinical trials are expected to be approved in the coming few years. Already this year, the first drug (Rezdiffra™) in the United States was ap-proved via accelerated procedure for treatment of MAFLD, i.e. of MASH in adults. This review underscores the most recent information related to the development of drugs for MAFLD treatment, focusing on the molecules that have come furthest towards approval.

This review examines the challenges faced by the pig industry, with a specific emphasis on improving the health and growth of weaned pigs. It emphasises the immediate necessity of investigating alternative approaches to managing pig nutrition and health due to restrictions on the use of antibiotics and the prohibition of zinc oxide in weaned pig diets. The weaning phase is identified as a critical stage in piglet development, characterized by stressors that affect their gastrointestinal health, immune responses, and overall physiology. The primary challenge during weaning arises from transitioning piglets from a digestible milk-based diet to a less digestible cereal-based feed, causing nutritional stress. This manifests as reduced feed intake, leading to gastrointestinal disturbances, intestinal inflammation, and adverse effects on intestinal structure and microbiota. To address these challenges and optimise piglet development, various nutritional strategies have been explored. Notably, glucans, particularly β-glucans from fungi, cereals, algae, and yeast, show promise in alleviating weaning-related issues. Furthermore, it's important to highlight the critical roles played by vitamin D and selenium in piglet nutrition. These essential nutrients can be sourced naturally from enriched mushrooms that are specifically enriched with vitamin D and selenium, providing a valuable dietary option. In conclusion, effective nutritional strategies, including glucans, vitamin D, selenium, and enriched mushrooms, are beneficial for addressing weaning-related challenges.

Chrysin, a flavonoid compound, has attracted interest as a therapeutic agent due to its anti-inflammatory, antidiabetic, antidepressant, and particularly its anticancer properties. Although studies have presented findings regarding the anticancer properties of chrysin, research on its molecular mechanisms of action remains largely insufficient. This research aimed to deeply investigate chrysin's effects on the breast cancer cell line, MDA-MB-231, in terms of proliferation, invasion, colony formation, and apoptosis. The XTT test results confirmed chrysin's cytotoxic effect on MDA-MB-231 cells, indicating a 48-hour IC50 value of 115.77 µM. Chrysin induced apoptosis in cells, as evidenced by Annexin V assay, and also reduced their colony-forming and invasion. Gene expression analyses showed elevated levels of APC, AXIN1, AXIN2, GSK3A, GSK3B, CK1α, CTNNB1, as well as apoptosis-related genes CASP3, -7, -9, and BAX. This increase was corroborated by the observed rise in protein levels of caspase 3/7 and GSK3B. Moreover, molecular docking results showed that chrysin interacted with genes in the WNT/β-catenin pathway and exhibited drug-like ADME properties. In conclusion, chrysin exhibits potential anticancer effects against MDA-MB-231 cells. It is hoped that these findings will advance preclinical and clinical studies on chrysin's potential in breast cancer treatment.

Soy isoflavones are considered important sources of bioactive compounds, but they are poorly absorbable, due to their large hydrophilic structures. Some biotransformation strategies have been used to convert the glycosidic form into aglycones, making them available for absorption. This study evaluated the potential of enzymatic and/or microbial fermentation bioprocesses in soymilk extract before and after gastrointestinal in vitro digestion. Commercial β-glucosidase and mix of commercial probiotics containing Lactobacillus acidophilus, L. casei, Lactococcus lactis, Bifidobacterium bifidum e B. lactis were used to biotransform soymilk extract. Isoflavone profile was quantified by HPLC-DAD, total phenolic content by Folin–Ciocalteu test, and antioxidant capacity by ORAC and FRAP. Soymilk enzymatically treated (ET) followed by microbial fermentation (ET+F) resulted in the conversion of glycosylated isoflavones (6-fold lower than control for daidzin and 2-fold for genistin) to aglycones (18-fold greater than control for dadzein and genistein), besides to increase the total phenolic content (3.48 for control and 4.48 mg/ml ET+F) and to improve antioxidant capacity represented by the ORAC (120 for control and 151 mg/ml ET+F) and by the FRAP (285 for control and 317 µl/ml for ET+F) before in vitro digestion. Further, the digested ET+F samples resulted a higher content of genistein (2-fold higher than control) also an increase in the total phenolic content (2.81 for control and 4.03 mg/ml for ET+F) and antioxidant capacity by ORAC were greater compared to undigested samples. In addition, the microbial fermentation process isolated also resulted in the positive effects, but de combination of ET followed by F presented a synergistic effect, suggesting the greater potential for both bioprocesses to contribute to functional and nutritional properties on fermented soy-based products.

Diabetes mellitus leads to cardiovascular complications including impaired cardiac β-adrenoceptor (β-AR) function. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin (EMPA) improve outcomes in heart failure patients and animal models thereof. Therefore, we have investigated the effects of EMPA on in vivo cardiac function (pressure-volume loop analysis) and β-AR-mediated contractile responses (papillary strips) in streptozotocin (STZ; 40 mg/kg, i.p.)-induced diabes in male Sprague Dawley rats (control, EMPA-treated control, diabetic, EMPA-treated diabetic) in a design reflecting late-onset treatment. 13-16 weeks after STZ injection treatment with a low dose of EMPA (10 mg/kg/day, daily oral gavage) or vehicle was administered for another 8 weeks. EMPA did not change cardiac function in control rats. Diabetic rats had a reduced heart rate, cardiac output, stroke work, rate of contration and rate of relaxation and increased isovolumic relaxation, whereas in vitro responses were not markedly attenuated. Treatment with EMPA showed a trend for improvement of some but not all parameters. Our results indicate that low dose EMPA treatment had limited effects on cardiac impairment despite reducing blood glucose when initiated after diabetes is manifest. Future studies with a higher dose and greater sample sizes could help to clarify the possible benefits of EMPA on the diabetic heart.

β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an an-ti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP had an anti-cancer effect against the CRC cell lines HCT116, and DLD-1, SW480 and COLO320DM with IC50 values of 7.88 nM, and 8.22 nM, 9.84 nM and 7.757 nM, respec-tively induction of DNA damage. Colonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either alone, suggesting that APP sensitizes CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

Mushrooms have been an invaluable ingredient in terms of food and medicine to humanity since time immemorial. Mushrooms have been shown to be possessing properties such as anti-tumor, antiproliferative, antioxidant, immunomodulatory, anti-diabetic. Traditional Czech republic medicine involved using Piptoporus betulinus in curing colorectal cancer; similarly, fruiting bodies of Inonotus obliquus were employed in Folk medicine in eastern Europe since the 16^th century. The oriental practice of utilizing mushrooms has witnessed an overwhelming attentiveness from the global research fraternity in exploring its wonder substances. Cancer is one of the key problems faced by researchers in finding an efficient medicine without inducing severe health complications. Mushrooms contain a plethora of bioactive compounds involved in tumor inhibition, such as hispolon, lentinan, gannoderic acid, illudin-s, and many more. The current article briefly describes various edible mushrooms with anti-tumorigenic compounds and their effect on the cancer cells of various means.