Deciphering the Molecular Mechanisms of Reactive Metabolite Formation in the Mechanism-Based Inactivation of Cytochrome p450 1B1 by 8-Methoxypsoralen and Assessing the Driving Effect of phe268.

This study provides a comprehensive computational exploration of the inhibitory activity and metabolic pathways of 8-methoxypsoralen (8-MP), a furocoumarin derivative used for treating various skin disorders, on cytochrome P450 (P450). Employing quantum chemical DFT calculations, molecular docking, and molecular dynamics (MD) simulations analyses, the biotransformation mechanisms and the active site binding profile of 8-MP in CYP1B1 were investigated. Three plausible inactivation mechanisms were minutely scrutinized. Further analysis explored the formation of reactive metabolites in subsequent P450 metabolic processes, including covalent adduct formation through nucleophilic addition to the epoxide, 8-MP epoxide hydrolysis, and non-CYP-catalyzed epoxide ring opening. Special attention was paid to the catalytic effect of residue Phe268 on the mechanism-based inactivation (MBI) of P450 by 8-MP. Energetic profiles and facilitating conditions revealed a slight preference for the C4'=C5' epoxidation pathway, while recognizing a potential kinetic competition with the 8-OMe demethylation pathway due to comparable energy demands. The formation of covalent adducts via nucleophilic addition, particularly by phenylalanine, and the generation of potentially harmful reactive metabolites through autocatalyzed ring cleavage are likely to contribute significantly to P450 metabolism of 8-MP. Our findings highlight the key role of Phe268 in retaining 8-MP within the active site of CYP1B1, thereby facilitating initial oxygen addition transition states. This research offers crucial molecular-level insights that may guide the early stages of drug discovery and risk assessment related to the use of 8-MP.

Berberine attenuates inflammation and oxidative stress and modulates lymphocyte E-NTPDase in acute hyperlipidemia.

Hyperlipidemia is a common clinically encountered health condition worldwide that promotes the development and progression of cardiovascular diseases, including atherosclerosis. Berberine (BBR) is a natural product with acknowledged anti-inflammatory, antioxidant, and metabolic effects. This study evaluated the effect of BBR on lipid alterations, oxidative stress, and inflammatory response in rats with acute hyperlipidemia induced by poloxamer-407 (P-407). Rats were pretreated with BBR (25 and 50 mg/kg) for 14 days and acute hyperlipidemia was induced by a single dose of P-407 (500 mg/kg). BBR ameliorated hypercholesterolemia, hypertriglyceridemia, and plasma lipoproteins in P-407-adminsitered rats. Plasma lipoprotein lipase (LPL) activity was decreased, and hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was enhanced in hyperlipidemic rats. The expression of low-density lipoprotein receptor (LDL-R) and ATP-binding cassette transporter 1 (ABCA1) was downregulated in hyperlipidemic rats. BBR enhanced LPL activity, upregulated LDL-R, and ABCA1, and suppressed HMG-CoA reductase in P-407-administered rats. Pretreatment with BBR ameliorated lipid peroxidation, nitric oxide (NO), pro-inflammatory mediators (interleukin [IL]-6, IL-1ß, tumor necrosis factor [TNF]-α, interferon-γ, IL-4 and IL-18) and enhanced antioxidants. In addition, BBR suppressed lymphocyte ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase (E-ADA) as well as NO and TNF-α release by macrophages isolated from normal and hyperlipidemic rats. In silico investigations revealed the binding affinity of BBR toward LPL, HMG-CoA reductase, LDL-R, PSK9, ABCA1, and E-NTPDase. In conclusion, BBR effectively prevented acute hyperlipidemia and its associated inflammatory responses by modulating LPL, cholesterolgenesis, cytokine release, and lymphocyte E-NTPDase and E-ADA. Therefore, BBR is an effective and safe natural compound that might be employed as an adjuvant against hyperlipidemia and its associated inflammation.

Multi-target action of Garcinia livingstonei extract and secondary metabolites against fatty acid synthase, α-glucosidase, and xanthine oxidase.

Garcinia livingstonei is a traditional herbal medicine that showed beneficial health effects and bioactivities. Four compounds have been isolated from the plant leaves and were elucidated as lupeol, betulin, podocarpusflavone A, and amentoflavone. The inhibitory activities of G. livingstonei extract and isolated metabolites against fatty acid synthase (FAS), α-glucosidase, and xanthine oxidase (XO) were investigated in vitro. The affinity of the compounds toward the studied enzymes was investigated in silico. The plant extract inhibited FAS, α-glucosidase, and XO with IC50 values of 26.34, 67.88, and 33.05 µg/mL, respectively. Among the isolated metabolites, betulin exhibited the most inhibitory activity against α-glucosidase and XO with IC50 values of 38.96 and 30.94 µg/mL, respectively. Podocarpusflavone A and betulin were the most potent inhibitors of FAS with IC50 values of 24.08 and 27.96 µg/mL, respectively. Computational studies corroborated these results highlighting the interactions between metabolites and the enzymes. In conclusion, G. livingstonei and its constituents possess the potential to modulate enzymes involved in metabolism and oxidative stress.

An integrated phytochemical, in silico and in vivo approach to identify the protective effect of Caroxylon salicornicum against cisplatin hepatotoxicity.

Cisplatin (CIS) is a chemotherapeutic medication for the treatment of cancer. However, hepatotoxicity is among the adverse effects limiting its use. Caroxylon salicornicum is traditionally used for treating inflammatory diseases. In this investigation, three flavonoids, four coumarins, and three sterols were detected in the petroleum ether fraction of C. salicornicum (PEFCS). The isolated phytochemicals exhibited binding affinity toward Keap1, NF-κB, and SIRT1 in silico. The hepatoprotective role of PEFCS (100, 200 and 400 mg/kg) was investigated in vivo. Rats received PEFCS for 14 days and CIS on day 15. CIS increased ALT, AST and ALP and caused tissue injury along with increased ROS, MDA, and NO. Hepatic NF-κB p65, pro-inflammatory mediators, Bax and caspase-3 were increased in CIS-treated animals while antioxidants and Bcl-2 were decreased. PEFCS mitigated hepatocyte injury, and ameliorated transaminases, ALP, oxidative stress (OS) and inflammatory markers. PEFCS downregulated pro-apoptosis markers and boosted Bcl-2 and antioxidants. In addition, PEFCS upregulated Nrf2, HO-1, and SIRT1 in CIS-administered rats. In conclusion, PEFCS is rich in beneficial phytoconstituents and conferred protection against liver injury by attenuating OS and inflammation and upregulating Nrf2 and SIRT1.

The melatonin receptor agonist agomelatine protects against acute pancreatitis induced by cadmium by attenuating inflammation and oxidative stress and modulating Nrf2/HO-1 pathway.

Pancreatitis is a serious effect of the heavy metal cadmium (Cd) and inflammation and oxidative stress (OS) are implicated in Cd-induced pancreatic injury. This study evaluated the effect of the melatonin receptor agonist agomelatine (AGM) on Cd-induced acute pancreatitis (AP), pointing to its modulatory effect on inflammation, OS, and Nrf2/HO-1 pathway. Rats were supplemented with AGM orally for 14 days and a single injection of cadmium chloride (CdCl2) on day 7. Cd increased serum amylase and lipase and caused pancreatic endocrine and exocrine tissue injury. Malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) were elevated, nuclear factor (NF)-kB p65, inducible NO synthase (iNOS), interleukin (IL)-6, tumor necrosis factor (TNF)-α and CD40 were upregulated, and antioxidants were decreased in the pancreas of Cd-administered rats. AGM ameliorated serum amylase and lipase and pancreatic OS, NF-kB p65, CD40, pro-inflammatory mediators and caspase-3, prevented tissue injury and enhanced antioxidants. AGM downregulated Keap1 and enhanced Nrf2 and HO-1 in the pancreas of Cd-administered rats. In silico findings revealed the binding affinity of AGM with Keap1, HO-1, CD40L and caspase-3. In conclusion, AGM protected against AP induced by Cd by preventing inflammation, OS and apoptosis and modulating Nrf2/HO-1 pathway.

Mechanistic aspects of reactive metabolite formation in clomethiazole catalyzed biotransformation by cytochrome P450 enzymes.

Clomethiazole (CLM), a sedative and anticonvulsant drug, is commonly employed for the treatment of alcohol withdrawal syndrome because it suppresses cytochrome P450 (P450) activity associated with the generation of free radicals and liver damage. The catalyzed biotransformation of thiazole-containing drugs by P450 is known to afford reactive metabolites. These metabolites can alter the biological functions of macromolecules and result in toxicity and adverse drug interactions. Multitargeted molecular modeling and quantum chemical DFT calculations were performed to explore the binding modes and molecular mechanisms underlying the mechanism-based inactivation (MBI) of P450 by CLM. The mechanistic details associated with reactive metabolite formation from further metabolic processes were extensively assessed. Seven possible routes were proposed for CLM-P450 biotransformation including CLM hydroxylation, sulfoxidation, N-oxidation, CN epoxidation (oxaziridine formation), and CC epoxidation. The results revealed a degree of preference for the C-N epoxidation pathway because of the low energy requirements of its rate-determining step (8.74 and 10.07 kcal mol-1 for LS and HS states, respectively). A kinetic competition for the CLM-methyl hydroxylation pathway was detected because the H-abstraction energy barrier was relatively comparable to the thermodynamically prevailing oxaziridine formation rate-determining step (12.58 and 14.52 kcal mol-1 for quartet and doublet states, respectively). Our studies assessed the mechanisms of covalent nucleophilic epoxide adduct formation through nucleophilic addition, hydrolysis of epoxidation products, and nonenzymatic degradation. CLM was shown to display P450-inhibitory activity by forming covalent adducts rather than further metabolization to reactive metabolites. The outcomes of molecular docking allowed assessing the binding profile of CLM with three human P450 isozymes, namely, CYP2E1, CYP3A4, and CYP2D6.

A flavonoid-rich fraction of Euphorbia peplus attenuates hyperglycemia, insulin resistance, and oxidative stress in a type 2 diabetes rat model.

Background: Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR) and hyperglycemia. Plants are valuable sources of therapeutic agents for the management of T2D. Euphorbia peplus has been widely used as a traditional medicine for the treatment of various diseases, but its beneficial role in T2D has not been fully explored. Methods: The anti-diabetic efficacy of E. peplus extract (EPE) was studied using rats with T2D induced by high-fat diet (HFD) and streptozotocin (STZ). The diabetic rats received 100, 200, and 400 mg/kg EPE for 4 weeks. Results: Phytochemical fractionation of the aerial parts of E. peplus led to the isolation of seven known flavonoids. Rats with T2D exhibited IR, impaired glucose tolerance, decreased liver hexokinase and glycogen, and upregulated glycogen phosphorylase, glucose-6-phosphatase (G-6-Pase), and fructose-1,6-bisphosphatase (F-1,6-BPase). Treatment with 100, 200, and 400 mg/kg EPE for 4 weeks ameliorated hyperglycemia, IR, liver glycogen, and the activities of carbohydrate-metabolizing enzymes. EPE attenuated dyslipidemia, serum transaminases, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and liver lipid accumulation, nuclear factor (NF)-κB p65, and lipid peroxidation, nitric oxide and enhanced antioxidants. All EPE doses upregulated serum adiponectin and liver peroxisome proliferator-activated receptor γ (PPARγ) in HFD/STZ-induced rats. The isolated flavonoids showed in silico binding affinity toward hexokinase, NF-κB, and PPARγ. Conclusion: E. peplus is rich in flavonoids, and its extract ameliorated IR, hyperglycemia, dyslipidemia, inflammation and redox imbalance, and upregulated adiponectin and PPARγ in rats with T2D.

Multitargeted molecular modelling of alginic acid modified with 4-aminophenol dopped with silver nanoparticles as a potent cytotoxic agent.

The activity of alginic acid as a cytotoxic agent was improved by structure modification using 4-aminophenol (4-AP) through condensation and polymerization processes. Then, silver nanoparticles were employed through doping to further enhance the cytotoxic activity of the modified polymer. The structure of the prepared materials was characterized by FT-IR, 1HNMR, UV spectroscopy, X-ray diffraction, and electron microscopy, and the thermal behavior of all synthesized materials was intensively studied. The cytotoxicity of the prepared compounds against cell lines of human hepatocellular (HepG-2) and lung (A-549) carcinomas was investigated. Alginic acid modified with 4-AP (Alg-4-AP3) showed the highest activity against HepG-2 and A-549 among all tested materials with IC50 values of 3.0 ± 0.19 µg/mL and 3.63 ± 0.23 µg/mL, respectively. Multitargeted molecular docking was employed to explore the binding modes of our compounds with the receptors EGFR, HER2, and VEGFR 2. The results revealed the inhibitory activity of our tested compounds against the proposed protein receptors, findings coincided with the in vitro results. In conclusion, the modification of alginic acid with 4-AP improved its cytotoxic activity against HepG-2 and A-549 cancer cells. In addition, doping the new materials with silver nanoparticles (AgNPs) further enhanced the cytotoxic activity.

Wood as a green and sustainable alternative for environmentally friendly & flexible electronic devices.

Electronic are usually constructed from non-renewable, non-biodegradable, and hazardous materials. Due to the frequent upgrading or discarding of electronic devices, which contributes significantly to environmental pollution, there is a high demand for electronics made from renewable and biodegradable materials with less harmful components. To this end, due to their flexibility, strong mechanical, and optical properties, wood-based electronics have become very appealing as substrates especially for flexible electronics and optoelectronics. However, incorporating numerous features including high conductivity and transparency, flexibility, and mechanical robustness into an environmentally friendly electronic device remains very challenging. Herein, authors have provided the techniques used to fabricate sustainable wood based flexible electronics coupled with their chemical, mechanical, optical, thermal, thermomechanical, and surface properties for various applications. Additionally, the synthesis of a conductive ink based on lignin and the development of translucent wood as a substrate are covered. Future developments and broader applications of wood-based flexible materials are discussed in the final section of the study, with an emphasis on their potential in fields including wearable electronics, renewable energy, and biomedical devices. This research improves upon prior efforts by demonstrating new ways to simultaneously attain better mechanical and optical qualities and environmental sustainability.

The protective effect of 7-hydroxycoumarin against cisplatin-induced liver injury is mediated via attenuation of oxidative stress and inflammation and upregulation of Nrf2/HO-1 pathway.

Cisplatin (CIS) is an effective chemotherapy against different solid cancers. However, the adverse effects, including hepatotoxicity, limit its clinical use. 7-hydroxycoumarin (7-HC) possesses antioxidant and hepatoprotective activities, but its protective effect against CIS hepatotoxicity has not been investigated. This study evaluated the effect of 7-HC on liver injury, oxidative stress (OS), and inflammation provoked by CIS. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 2 weeks followed by intraperitoneal injection of CIS (7 mg/kg) at day 15. CIS increased serum transaminases, alkaline phosphatase (ALP), and bilirubin and provoked tissue injury accompanied by elevated reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO). Liver nuclear factor (NF)-κB p65, inducible NO synthase (iNOS), pro-inflammatory cytokines, Bax, and caspase-3 were upregulated, and antioxidant defenses and Bcl-2 were decreased in CIS-treated rats, while 7-HC prevented liver injury and ameliorated OS, inflammatory and apoptosis markers. In addition, 7-HC enhanced nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase (HO)-1 in CIS-administered rats and in silico studies revealed its binding affinity toward HO-1. In conclusion, 7-HC protected against CIS hepatotoxicity by mitigating OS and inflammatory response and modulating Nrf2/HO-1 pathway.

Betulin prevents high fat diet-induced non-alcoholic fatty liver disease by mitigating oxidative stress and upregulating Nrf2 and SIRT1 in rats.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic hepatic disorder characterized by hepatic lipid accumulation. This study explored the effect of betulin (BE), a terpenoid with promising antioxidant, anti-inflammatory and insulin sensitizing effects, on NAFLD induced by high fat diet (HFD). Rats received HFD and BE (15 and 30 mg/kg) for 12 weeks and blood and liver samples were collected for analyses. HFD caused hyperlipidemia, cholesterol and triglycerides accumulation in the liver, hepatocellular ballooning, fibrosis, insulin resistance (IR), lipid peroxidation (LPO), and NF-kB p65 upregulation. BE ameliorated serum and liver lipids, blood glucose and insulin, liver LPO, prevented steatosis and fibrosis, suppressed NF-kB p65 and enhanced antioxidants in HFD-fed rats. BE downregulated acetyl-CoA carboxylase (ACC1) and fatty acid synthase (FAS), and upregulated Nrf2, HO-1 and SIRT1 in the liver of HFD-fed rats. In silico investigations revealed the binding affinity of BE towards FAS, NF-kB, Keap1, HO-1 and SIRT1. In conclusion, BE attenuated HFD-induced NAFLD by ameliorating hyperlipidemia, IR, lipogenesis, liver lipid accumulation, and oxidative stress. The protective effect of BE was associated with enhanced Nrf2/HO-1 signaling and SIRT1.

Molecular modeling and DFT studies on the antioxidant activity of Centaurea scoparia flavonoids and molecular dynamics simulation of their interaction with ß-lactoglobulin.

Plants of the genus Centaurea have been widely used as natural therapeutics in different countries. This study investigated the antioxidant-structure activity relationship of eight flavonoids isolated from Centaurea scoparia using DFT studies and in vitro radical scavenging and xanthine oxidase (XO) inhibition assays, and to correlate the theoretical values with the experimental findings. Docking analysis was carried out to explore the binding modes of the isolated phytochemicals with XO and bovine ß-lactoglobulin (BLG). Interactions of the isolated compounds with BLG were studied using molecular dynamics (MD) simulations which revealed the involvement of hydrogen bonding. The root-mean-square deviation (RMSD) of BLG and BLG-flavonoid complexes reached equilibrium and fluctuated during the 10 ns MD simulations. The radius of gyration (Rg) and solvent accessible surface area (SASA) revealed that various systems were stabilized at approximately 2500 ps. In addition, the RMS fluctuations profile indicated that the ligand's active site exerted rigidity behavior during the simulation. The hydrogen atom transfer (HAT) and the energies of hydrogen abstractions were estimated by calculating the bond dissociation enthalpy (BDE) of O-H in gas phase and water. The isolated compounds showed radical scavenging and XO inhibitory activities along with binding affinity with XO as revealed in silico. The BDE was linked to the radical scavenging processes occurring in polar solvents. These processes are single electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). Our calculations indicated the agreement between the calculated results and the experimentally measured antioxidant activity of the flavonoids isolated from C. scoparia.

Arbutin ameliorates hyperglycemia, dyslipidemia and oxidative stress and modulates adipocytokines and PPARγ in high-fat diet/streptozotocin-induced diabetic rats.

Arbutin is a glycosylated hydroquinone with antioxidant and anti-hyperglycemia effects. However, its beneficial effects in type 2 diabetes (T2D) were not clarified. This study evaluated the effect of arbutin on hyperglycemia, dyslipidemia, insulin resistance, oxidative stress, and inflammatory response in T2D. Rats induced by high fat diet and streptozotocin were treated with arbutin (25 and 50 mg/kg) for 4 weeks. Diabetic rats exhibited glucose intolerance, elevated HbA1c%, reduced insulin, and high HOMA-IR. Liver glycogen and hexokinase activity were decreased in T2D rats while glucose-6-phosphatase (G6Pase), fructose-1,6- biphosphatase (FBPase), and glycogen phosphorylase were upregulated. Circulating and hepatic cholesterol and triglycerides and serum transaminases were elevated in T2D rats. Arbutin ameliorated hyperglycemia, dyslipidemia, insulin deficiency and resistance, and liver glycogen and alleviated the activity of carbohydrate-metabolizing enzymes. Both doses of arbutin decreased serum transaminases and resistin, and liver lipids, TNF-α, IL-6, malondialdehyde and nitric oxide, downregulated liver resistin and fatty acid synthase, and increased serum and liver adiponectin, and liver reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). These effects were associated with the upregulation of hepatic PPARγ. Arbutin inhibited α-glucosidase in vitro and in silico investigations revealed the ability of arbutin to bind PPARγ, hexokinase, and α-glucosidase. In conclusion, arbutin effectively ameliorated glucose intolerance, insulin resistance, dyslipidemia, inflammation, and oxidative stress, and modulated carbohydrate-metabolizing enzymes, antioxidants, adipokines and PPARγ in T2D in rats.

Flavonoids of Haloxylon salicornicum (Rimth) prevent cisplatin-induced acute kidney injury by modulating oxidative stress, inflammation, Nrf2, and SIRT1.

Cisplatin (CIS) is an effective chemotherapeutic drug used for the treatment of many types of cancers, but its use is associated with adverse effects. Nephrotoxicity is a serious side effect of CIS and limits its therapeutic utility. Haloxylon salicornicum is a desert shrub used traditionally in the treatment of inflammatory disorders, but neither its flavonoid content nor its protective efficacy against CIS nephrotoxicity has been investigated. In this study, seven flavonoids were isolated from H. salicornicum methanolic extract (HSE) and showed in silico binding affinity with NF-κB, Keap1, and SIRT1. The protective effect of HSE against CIS nephrotoxicity was investigated. Rats received HSE (100, 200, and 400 mg/kg) for 14 days followed by a single injection of CIS. The drug increased Kim-1, BUN, and creatinine and caused multiple histopathological changes. CIS-administered rats showed an increase in renal ROS, MDA, NO, TNF-α, IL-1ß, and NF-κB p65. HSE prevented tissue injury, and diminished ROS, NF-κB, and inflammatory mediators. HSE enhanced antioxidants and Bcl-2 and downregulated pro-apoptosis markers. These effects were associated with downregulation of Keap1 and microRNA-34a, and upregulation of SIRT1 and Nrf2/HO-1 signaling. In conclusion, H. salicornicum is rich in flavonoids, and its extract prevented oxidative stress, inflammation, and kidney injury, and modulated Nrf2/HO-1 and SIRT1 signaling in CIS-treated rats.

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.

7-hydroxycoumarin modulates Nrf2/HO-1 and microRNA-34a/SIRT1 signaling and prevents cisplatin-induced oxidative stress, inflammation, and kidney injury in rats.

The kidneys are vulnerable to toxicity and acute kidney injury (AKI) is the main adverse effect associated with the clinical use of the chemotherapeutic agent cisplatin (CIS). Oxidative stress and inflammation are implicated in CIS nephrotoxicity. In this study, the effect of the antioxidant 7-hydroxycoumarin (7-HC) against CIS-induced renal intoxication was evaluated. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 14 days and CIS (7 mg/kg) at day 15, and samples were collected 3 days after CIS administration. CIS increased serum urea, creatinine and kidney injury molecule (Kim)-1, caused multiple histopathological changes and increased renal reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), NF-κB p65, iNOS, and pro-inflammatory cytokines. 7-HC dose-dependently prevented kidney dysfunction and tissue injury and suppressed ROS and inflammatory mediators. 7-HC boosted renal antioxidants and Bcl-2 while decreased Bax and caspase-3 expression in CIS-administered rats. In addition, 7-HC downregulated Keap-1 and microRNA-34a and upregulated Nrf2, NQO-1, HO-1, and SIRT1. Molecular docking revealed the binding affinity of 7-HC towards NF-κB, Keap-1, and SIRT1. In Conclusion, 7-HC prevented CIS nephrotoxicity by attenuating tissue injury, oxidative stress, inflammation, and apoptotic cell death. The protective efficacy of 7-HC was associated with inhibiting NF-κB and Keap-1, and modulating Nrf2/HO-1 and microRNA34a/Sirt1 signaling.

Eco-friendly and biodegradable sodium alginate/quaternized chitosan hydrogel for controlled release of urea and its antimicrobial activity.

Hydrogels could be employed in agriculture for efficient management of water and controlled-release urea (CRU). This study aimed to synthesize a superabsorbent hydrogel for CRU by cross-linking sodium alginate (Alg) and N-(2-hydroxy-3-trimethyl ammonium) propyl chitosan chloride (HTACC). The hydrogel structure was characterized by various techniques, and the urea loading and releasing behaviors of the synthetic hydrogels were investigated. The results revealed that the maximum urea loading ranged between 107 and 200%, and that the urea loading kinetics fitted with Langmuir model followed by the Freundlich model. The urea release behavior reached equilibrium after 30 days and urea releasing kinetics fitted with the zero-order and Higuchi models. The synthesized hydrogels exerted significant antimicrobial activities and molecular docking showed their binding affinity toward glucosamine-6-phosphate synthase, ß-lactamase II, TraR binding site and nucleoside diphosphate kinase. In conclusion, these Alg/HTACC hydrogels showed swelling, urea release, and antimicrobial properties suitable to meet the plant requirements and produce economic and environmental benefits.

A flavonoid-rich fraction of Monolluma quadrangula inhibits xanthine oxidase and ameliorates potassium oxonate-induced hyperuricemia in rats.

Hyperuricemia represents a risk factor for the progression of chronic kidney disease. Oxidative stress and inflammation are implicated in the mechanisms underlying hyperuricemia-mediated kidney injury. Monolluma quadrangula possesses several beneficial effects; however, its effect on hyperuricemia has not been investigated. This study evaluated the renoprotective and xanthine oxidase (XO) inhibitory activity of M. quadrangula in hyperuricemic rats. Phytochemical investigation revealed the presence of six known flavonoid isolated for the first time from this species. The rats received M. quadrangula extract (MQE) and potassium oxonate (PO) for 7 days. In vitro assays showed the radical scavenging and XO inhibitory activities of MQE, and in silico molecular docking revealed the inhibitory activity of the isolated flavonoids towards XO. Hyperuricemic rats showed elevated serum uric acid, creatinine, urea, and XO activity, and renal pro-inflammatory cytokines, MDA and NO, and decreased GSH, SOD, and catalase. MQE ameliorated serum uric acid, urea, creatinine, and XO activity, and renal pro-inflammatory cytokines. In addition, MQE attenuated renal oxidative stress, enhanced antioxidants, downregulated URAT-1, and GLUT-9 and upregulated OAT-1 in PO-induced rats. In conclusion, M. quadrangula attenuated hyperuricemia and kidney impairment by suppressing XO activity, oxidative stress and inflammation, and modulating urate transporters.

Telmisartan attenuates diabetic nephropathy by mitigating oxidative stress and inflammation, and upregulating Nrf2/HO-1 signaling in diabetic rats.

Diabetic nephropathy (DN) is a serious complication of diabetes and can lead to renal failure. Telmisartan (TEL) is an approved angiotensin II type 1 receptor blocker for the treatment of hypertension and possesses nephroprotective efficacy. The study investigated the beneficial effect of TEL on renal oxidative stress, inflammatory response, and apoptosis in type 1 diabetic rats, pointing to the possible role of Nrf2/HO-1 signaling. Diabetes was induced by streptozotocin (STZ), and TEL (5 and 10 mg/kg) was supplement for 8 weeks. TEL ameliorated hyperglycemia, prevented body weight loss and kidney hypertrophy, decreased serum creatinine and urea, and prevented histopathological alterations in diabetic rats. Malondialdehyde (MDA), nitric oxide (NO), NF-κB p65 and TNF-α were increased, whereas GSH, SOD and Bcl-2 were decreased in the kidney of diabetic rats. Treatment with TEL ameliorated oxidative stress, suppressed NF-κB p65 and TNF-α, and boosted cellular antioxidant defenses and Bcl-2. TEL upregulated Nrf2 and HO-1 in the kidney of both normal and diabetic rats. In addition, TEL downregulated VEGF and MMP-9 in the kidney of diabetic rats. In silico molecular docking simulations revealed the potent binding affinity of TEL to NF-κB, MMP-9, Keap1 and HO-1. In conclusion, TEL attenuates DN by ameliorating hyperglycemia, oxidative stress, inflammation, apoptosis and angiogenesis and upregulation of Nrf2/HO-1 signaling.

Xanthine Oxidase Inhibitory Activity of Euphorbia peplus L. Phenolics.

BACKGROUND: Various phenolics show inhibitory activity towards xanthine oxidase (XO), an enzyme that generates reactive oxygen species which cause oxidative damage. OBJECTIVE: This study investigated the XO inhibitory activity of Euphorbia peplus phenolics. METHODS: The dried powdered aerial parts of E. peplus were extracted, fractioned and phenolics were isolated and identified. The XO inhibitory activity of E. peplus extract (EPE) and the isolated phenolics was investigated in vitro and in vivo. RESULTS: Three phenolics were isolated from the ethyl acetate fraction of E. peplus. All isolated compounds and the EPE showed inhibitory activity towards XO in vitro. In hyperuricemic rats, EPE and the isolated phenolics decreased uric acid and XO activity. Molecular docking showed the binding modes of isolated phenolics with XO, depicting significant interactions with the active site amino acid residues. Molecular dynamics simulation trajectories confirmed the interaction of isolated phenolics with XO by forming hydrogen bonds with the active site residues. Also, the root mean square (RMS) deviations of XO and phenolics-XO complexes achieved equilibrium and fluctuated during the 10 ns MD simulations. The radius of gyration and solvent accessible surface area investigations showed that different systems were stabilized at ≈ 2500 ps. The RMS fluctuations profile depicted that the drug binding site exhibited a rigidity behavior during the simulation. CONCLUSION: In vitro, in vivo and computational investigations showed the XO inhibitory activity of E. peplus phenolics. These phenolics might represent promising candidates for the development of XO inhibitors.