Deciphering molecular mechanisms underlying the inhibition of ß-glucuronidase by xanthones from Centaurium spicatum.

Herein, we scrutinized the inhibitory potential of five xanthones and a flavonoid, sourced from Centaurium spicatum, against ß-glucuronidase activity. The results showed that gentisin and azaleatin emerged as the most potent inhibitors, with significantly lower IC50 values of 0.96 ± 0.10 and 0.57 ± 0.04 µM, respectively. The evaluation of enzyme kinetics unveiled that the isolated xanthones manifested inhibition of ß-glucuronidase through a mixed inhibition mode, whereas azaleatin exhibited a noncompetitive inhibition mechanism. The findings from molecular docking analysis unveiled that the compounds under investigation, particularly azaleatin, displayed comparatively diminished binding affinities towards ß-glucuronidase. Furthermore, the tested drugs were shown to occupy a common binding site as the employed reference drug. Our comprehensive Molecular Dynamics (MD) simulations analysis revealed consistent trajectories for the investigated drugs, wherein azaleatin and gentisin demonstrated notable stabilization of energy levels. Analysis of various MD parameters revealed that drugs with the lowest IC50 values maintained relatively stable interactions with ß-glucuronidase. These drugs were shown to exert notable alterations in their conformation or flexibility upon complexation with the target enzyme. Conversely, the flexibility and accessibility of ß-glucuronidase was reduced upon drug binding, particularly with azaleatin and gentisin, underscoring the stability of the drug-enzyme complexes. Analysis of Coul-SR and LJ-SR interaction energies unveiled consistent and stable interactions between certain isolated drugs and ß-glucuronidase. Azaleatin notably displayed the lowest average Coul-SR interaction energy, suggesting strong electrostatic interactions with the enzyme's active site and significant conformational variability during simulation. Remarkably, LJ-SR interaction energies across different xanthones complexes were more negative than their Coul-SR counterparts, emphasizing the predominant role of van der Waals interactions, encompassing attractive dispersion and repulsive forces, in stabilizing the drug-enzyme complexes rather than electrostatic interactions.

Insight into the catalytic performances of Fe0@chitosan/cellulose green hybrid structure for enhanced photo-Fenton's oxidation of levofloxacin toxic residuals: Pathway and toxicity.

A green hybridized structure of Fe0 painted chitosan/cellulose base (Fe0@CS/CF) has been developed using cellulose extracted from sugarcane bagasse along with reduction agents sourced from Khaya senegalensis leaves. The composite was assessed as an affordable, powerful, and multifunctional catalyst for enhancing the degradation of Levofloxacin (LVX) remnants within water supplies via photo-Fenton's interactions. Using a dosage of 0.5 g/L, the Fe0@CS/CF blend demonstrated noteworthy catalytic qualities, resulting in the complete photo-Fenton's degradation of LVX at a level of 25 mg/L after 40 min. However, the complete diminution of organic carbon (TOC) occurred only after 100 min, suggesting the presence of significant intermediate residues. The identified intermediate chemicals and confirmed hydroxyl radicals as the main oxidizer suggest that the degradation pathway involves carboxylation/decarboxylation, hydroxylation, demethylation, and oxidation of quinolone rings. The toxicity properties of untreated LVX solutions and their subsequent oxidized byproducts were assessed by evaluating their inhibiting impact on Vibrio fischeri over various durations. The samples that experienced partial oxidation at initial testing demonstrated a higher level of toxicity in comparison to the parent LVX. However, the sample that was treated for 100 min demonstrated substantial biological safety and a non-toxic nature. The blend of ingredients has a synergistic impact that enhances the uptake, Fenton's, photocatalytic, and photo-Fenton's characteristics of the hosted Fe0 nanoparticles.

Esculentoside A Inhibits Proliferation, Colony Formation, Migration, and Invasion of Human Colorectal Cancer Cells.

Esculentosides include a group of plant-derived compounds with tremendous pharmacological potential. The antiproliferative effects of esculentoside A against different colorectal cancer cells were evaluated. We found that the proliferation of all the colorectal cancer cells was halted by esculentoside A. The IC50 of esculentoside A ranged from 16 to 24 µM against different colorectal cancer cells. Investigation of the underlying molecular mechanism revealed that esculentoside A caused an increase in the colorectal cancer cells at the G1 phase of the cell cycle, indicative of G0/G1 cell cycle arrest. The percentage of G1 cells increased from 22.68% in control to 54.23% at 16 µM esculentoside A. We also found that the colony formation of HT-29 cells was inhibited by 59% at 24 µM esculentoside A. Finally, effects of esculentoside A on the motility of HT-29 colorectal cancer cells were investigated, and it was found that esculentoside A caused a significant decline in HT-29 colorectal cancer cell migration and invasion. The migration and invasion of esculentoside A-treated HT-29 cells were 45% and 51% higher, respectively, than those of untreated cells. Summing up, these results suggest that esculentoside A exhibits antiproliferative effects against human colorectal cancer cells.

Anti-inflammatory and Immunomodulatory Potency of Selenium-Enriched Probiotic Mutants in Mice with Induced Ulcerative Colitis.

Selenium-enriched Lactobacillus plantarum and Bifidobacterium longum mutants were used as a protector against Piroxicam-induced ulcerative colitis (UC). In this study, 32 BALB/c male mice were distributed to four groups: the control group, the Piroxicam group which was given 0.8 mg Piroxicam, SP and SB groups which were given 0.8 mg Piroxicam, and plus Lactobacillus plantarum and Bifidobacterium longum selenium-enriched mutants, respectively. Bodyweight; serum content of IgG, IgM, TNF-α, IL-2, IL-6, and IL-10; CBC; myeloperoxidase enzyme activity; histopathological examination of colon and spleen; and expression of TNF-α, IL-2, IL-6, and IL-10 genes in colon and spleen with qRT-PCR were determined. Bodyweight was found to reduce in the Piroxicam group and then recovery in the SB group. Serum content of IgG, IL-2, and IL-10 reduced in the Piroxicam group, whereas IgG, TNF-α, and IL-6 increased in the Piroxicam group in comparison to the other groups. Myeloperoxidase activity witnessed a significant increase in the Piroxicam group compared with the other groups. No significant differences were observed between all groups in measurements of red cells, hemoglobin, neutrophil, monocyte, eosinophil, and basophil in blood. Meanwhile, the white blood cells and platelets recorded the highest and lowest value, respectively, in the Piroxicam group. The colon of the Piroxicam group showed a noticeably massive infiltration of inflammatory cells in the lamina propria. These inflammations were mildly reduced in the SP group, while the reduction in the SB group was significant. In the Piroxicam group, splenic parenchyma saw an increase in the number of melanomacrophages, while hypertrophic plasma cells were observed in the SP group. The spleen of the SB group exhibits a nearly normal form. TNF-α and IL-6 genes had significantly upregulated in the colon of the Piroxicam group compared to the control group, while they were significantly downregulated in the SB group. In contrast, IL-2 and IL-10 genes had upregulated in the colon of the SB group compared to the control groups, while they had downregulated in the Piroxicam group. The expression of these genes had not recorded significant differences between all groups in the spleen. Therefore, this study recommends Bifidobacterium longum selenium-enriched mutants as anti-inflammatory and immunomodulatory supplements.

Rosmarinic acid mitigates chlorpyrifos-induced oxidative stress, inflammation, and kidney injury in rats by modulating SIRT1 and Nrf2/HO-1 signaling.

Chlorpyrifos (CPF) is a widely used broad-spectrum pesticide with multi-organ toxic effects. Oxidative stress was found to play a role in the deleterious effects of CPF, including nephrotoxicity. This study investigated the protective effect of the antioxidant polyphenol rosmarinic acid (RA) against CPF-induced kidney injury, with an emphasis on oxidative injury, inflammation, SIRT1, and Nrf2/HO-1 signaling. Rats received 10 mg/kg CPF and 25, 50, and 100 mg/kg RA orally for 28 days, and the samples were collected for analysis. CPF increased serum urea and creatinine and kidney Kim-1 and caused several histopathological alterations. ROS, MDA, NO, NF-κB p65, TNF-α, and IL-1ß were elevated in the kidney of CPF-intoxicated rats. RA ameliorated kidney function markers, prevented tissue injury, suppressed ROS, MDA, and NO, and downregulated NF-κB p65, TNF-α, and IL-1ß in CPF-intoxicated rats in a dose-dependent manner. RA decreased Bax, caspase-3, oxidative DNA damage, and Keap1, boosted antioxidant enzymes and Bcl-2, and upregulated Nrf2, HO-1, and SIRT1 in CPF-administered rats. Molecular docking simulation revealed the binding affinity of RA toward NF-κB, Keap1, HO-1, and SIRT1. In conclusion, RA prevented CPF nephrotoxicity by attenuating oxidative stress, inflammation, and apoptosis and upregulating SIRT1 and Nrf2/HO-1 signaling.

Impact of gervital against histopathological, ultrastructural, and biochemical alterations caused by methotrexate or azathioprine in albino rat testis.

Methotrexate (MTX) and azathioprine (AZA) are chemotherapeutic, immunosuppressive, cytotoxic drugs with reported adverse effects, including oxidative damage to testis. This study aims to evaluate the potential effect of grape seed extract (GSE; gervital) to prevent testicular damage caused by MTX and AZA. Male albino rats were separated into six groups: group I, normal control group; group II, GSE (150 mg/kg/day); group III, MTX (8 mg/kg/week); group IV, AZA (15 mg/kg/day); group V, GSE (150 mg/kg/day) + MTX (8 mg/kg/week); group VI, GSE (150 mg/kg/day) + AZA (15 mg/kg/day). All rats were sacrificed, blood samples were obtained for testosterone analysis, and testis was removed for histological and ultrastructural studies and oxidation measurements. A reduction in relative body and testis weight, along with a significant decrease in testosterone levels, was observed. Histopathological and ultrastructural alterations induced by MTX or AZA included reduced spermatozoa, sloughing, marked reduction of spermatogenic cells, and pyknosis of some nuclei. Significant oxidative stress manifested as reduced glutathione (GSH) levels and catalase (CAT) and superoxide dismutase (SOD) activities, as well as increased malondialdehyde (MDA) levels. GSE administration showed an ameliorative effect on testosterone levels and histopathological and ultrastructural changes. GSE treatment also suppressed the increases in MDA levels and the decreases in GSH levels and CAT and SOD activities. In conclusion, these findings confirm that GSE is an effective antioxidant that protects testis from histopathological and ultrastructural damage induced by MTX and AZA. Therefore, GSE is a promising candidate for future use to minimize and alleviate MTX and AZA risks.

Metabolic Syndrome and Cardiometabolic Risk Factors in the Mixed Hypercholesterolemic Populations with Respect to Gender, Age, and Obesity in Asir, Saudi Arabia.

This record study aimed to investigate the prevalence of metabolic syndrome (MetS) profiles regarding sex, age, and obesity for the riskier factor of cardiovascular diseases in a general population in Saudi Arabia. Laboratory and anthropometric measurements were performed on non-specific participants with variant ages and BMI in either sex. Serobiochemical changes were measured for metabolic profiles, i.e., A1C/FSG, TC, TGC, HDLC/LDLC, Vit.D, TSH/T4, Hb, and Cr. The study was applied in a Polyclinic, Abha, Saudi Arabia in 2020 G. The general population showed variable incidences of MetS profiles, such as 69.4% diabetes, 85.5% hypothyroidism, and 92.2% obesity. Hypothyroidism showed a higher incidence in women rather than in men, but men were more dyslipidemic, with higher TGC and LDLC but low HDLC, compared to women. Men <40 Y. showed diabetes and hypothyroidism, but elders were dyslipidemic. Women <40 Y. showed anemia and hypovitaminosis-D but were suffering from hypothyroidism at all ages. Diabetes, hypothyroidism, hypovitaminosis-D, and dyslipidemia were the main MetS components in both overweight and obese participants, and an incidence of more than 50% in each profile was recorded. Diabetes with hypertension was characteristic of obese participants rather than those overweight. About 66.1% of the mixed-hypercholesterolemic cases were diabetic, but 18.9% of the mixed-diabetic participants were hypercholesterolemic. Castelli's risk factors, CRI-I and CRI-II, and atherogenic indices, AIP and AC, were measured for evaluating the cardiac risk in different populations based on the AUC-ROC and cut-off values. Insulin-resistance marker (TyG) was also measured, showing considerable cut-off values for diabetic susceptibility in the lipidemic participants with higher TGC and TC rather than HDLC or LDLC. In conclusion, MetS showed higher susceptibility to sex and age with increased incidence in women rather than men. However, the cardiac risk was more susceptible to men of higher TGC and low HDLC than women. Type 2 Diabetes mellitus (T2DM) was more prominent in both elders (≥40 Y.) than younger ages of either sex. Anemia and deficiency of Vit. D was characteristic of young women (<40 Y.). Hypothyroidism affects young men <40 Y. but was recorded in women of all ages. Both dyslipidemia and diabetes could trigger CVD, showing higher cardiac risk in mixed-hypercholesterolemic men rather than women. Our study strongly suggests that the consumption of unhealthy junk food, tobacco smoking, lack of exercise, and physical inactivity could be conclusive evidence of MetS in the Saudi population.

Candesartan Attenuates Cisplatin-Induced Lung Injury by Modulating Oxidative Stress, Inflammation, and TLR-4/NF-κB, JAK1/STAT3, and Nrf2/HO-1 Signaling.

Cisplatin (CIS) is an effective chemotherapeutic agent against different cancers. The use of CIS is associated with acute lung injury (ALI) and other adverse effects, and oxidative stress and inflammation were implicated in its toxic effects. Candesartan (CAN), an angiotensin II (Ang II) receptor blocker, showed beneficial effects against oxidative stress and inflammation. Therefore, this study investigated the potential of CAN to prevent CIS-induced oxidative stress, inflammation, and lung injury in rats, pointing to the involvement of TLR4/NF-κB, JAK1/STAT3, PPARγ, and Nrf2/HO-1 signaling. The rats received CAN (5 mg/kg) for 10 days and were challenged with a single dose of CIS (7 mg/kg) on day 7. CIS caused injury to the alveoli and the bronchial tree, increased lipid peroxidation, nitric oxide, myeloperoxidase, TLR-4, NF-κB p65, iNOS, TNF-α, IL-6, IL-1ß, and caspase-3, and decreased cellular antioxidants and IL-6 in the lungs of rats. CAN effectively prevented tissue injury, suppressed TLR-4/ NF-κB signaling, and ameliorated oxidative stress, inflammatory markers, and caspase-3 in CIS-administered rats. CAN enhanced antioxidants and IL-10, decreased Ang II, increased Ang (1-7), suppressed the phosphorylation of JAK1 and STAT3, and upregulated SOCS3 in CIS-administered rats. These effects were associated with the downregulation of Keap1 and enhanced Nrf2, GCLC, HO-1, and PPARγ. In conclusion, CAN prevented CIS-induced lung injury by attenuating oxidative stress, suppressing TLR-4/NF-κB and JAK1/STAT3 signaling, Ang II, and pro-inflammatory mediators, and upregulating PPARγ, and Nrf2/HO-1 signaling.

The Effect of Dietary Saccharomyces cerevisiae on Growth Performance, Oxidative Status, and Immune Response of Sea Bream (Sparus aurata).

The objective of this study was to evaluate the beneficial effect of Saccharomyces cerevisiae (SC) on growth, intestinal morphometric characteristics, blood indices, redox balance, expression of immune-related genes, and their involvement in disease resistance in sea bream (Sparus aurata). Three hundred healthy sea bream fingerlings were allocated into equal four groups (15 fish per hapa). The first group was served as a control and received a basal diet, while the other three groups were fed diets containing 1, 2, and 4 g/kg diet SC, respectively. At the end of week 16, the daily weight gain, specific growth rate, and feed utilization were significantly higher in the SC2 and SC4 groups than the control (p < 0.05). SC dose-dependently improved intestinal morphology, and the 4 g/kg diet significantly increased dry matter, crude fat, and crude protein percentage of body composition when compared with the control group. The 4 g/kg SC boosted innate immune response and phagocytic activity, and all SC-supplemented diets improved total protein, glucose, triglycerides, and urea concentrations, as well as intestinal digestive enzymatic activities. All estimated oxidative markers were significantly enhanced in the group that received 4 g/kg SC when compared with the control and other SC groups (p < 0.05). Feeding the fish a diet supplemented with 4 g/kg SC markedly regulated the expression of HSP70, IGF1, and IL-1ß genes. In addition, the 4 g/kg SC-supplemented diet was the most effective in protecting the fish against Vibrio parahaemolyticus challenge. In conclusion, SC-enriched diet improved growth performance, intestinal morphology, redox homeostasis, and immune response of S. aurata with the 4 g/kg concentration as the most effective.

Upregulation of Nrf2/HO-1 Signaling and Attenuation of Oxidative Stress, Inflammation, and Cell Death Mediate the Protective Effect of Apigenin against Cyclophosphamide Hepatotoxicity.

Liver injury is among the adverse effects of the chemotherapeutic agent cyclophosphamide (CP). This study investigated the protective role of the flavone apigenin (API) against CP-induced liver damage, pointing to the involvement of Nrf2/HO-1 signaling. Rats were treated with API (20 and 40 mg/kg) for 15 days and received CP (150 mg/kg) on day 16. CP caused liver damage manifested by an elevation of transaminases, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), and histological alterations, including granular vacuolation, mononuclear cell infiltration, and hydropic changes. Hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO) were increased and glutathione (GSH) and antioxidant enzymes were decreased in CP-administered rats. CP upregulated the inflammatory markers NF-κB p65, TNF-α, IL-6, and iNOS, along with the pro-apoptotic Bax and caspase-3. Pre-treatment with API ameliorated circulating transaminases, ALP, and LDH, and prevented histopathological changes in CP-intoxicated rats. API suppressed ROS, MDA, NO, NF-κB p65, iNOS, inflammatory cytokines, oxidative DNA damage, Bax, and caspase-3 in CP-intoxicated rats. In addition, API enhanced hepatic antioxidants and Bcl-2 and boosted the Nrf2 and HO-1 mRNA abundance and protein. In conclusion, API is effective in preventing CP hepatotoxicity by attenuating oxidative stress, the inflammatory response, and apoptosis. The hepatoprotective efficacy of API was associated with the upregulation of Nrf2/HO-1 signaling.