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.

Cadmium-induced lung injury is associated with oxidative stress, apoptosis, and altered SIRT1 and Nrf2/HO-1 signaling; protective role of the melatonin agonist agomelatine.

Cadmium (Cd) is a hazardous heavy metal extensively employed in manufacturing polyvinyl chloride, batteries, and other industries. Acute lung injury has been directly connected to Cd exposure. Agomelatine (AGM), a melatonin analog, is a drug licensed for treating severe depression. This study evaluated the effect of AGM against Cd-induced lung injury in rats. AGM was administered in a dose of 25 mg/kg/day orally, while cadmium chloride (CdCl2) was injected intraperitoneally in a dose of 1.2 mg/kg to induce lung injury. Pre-treatment with AGM remarkably ameliorated Cd-induced lung histopathological abrasions. AGM decreased reactive oxygen species (ROS) production, lipid peroxidation, suppressed NDAPH oxidase, and boosted the antioxidants. AGM increased Nrf2, GCLC, HO-1, and TNXRD1 mRNA, as well as HO-1 activity and downregulated Keap1. AGM downregulated Bax and caspase-3 and upregulated Bcl-2, SIRT1, and FOXO3 expression levels in the lung. In conclusion, AGM has a protective effect against Cd-induced lung injury via its antioxidant and anti-apoptotic effects mediated via regulating Nrf2/HO-1 and SIRT1/FOXO3 signaling.

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.

Cadmium cardiotoxicity is associated with oxidative stress and upregulated TLR-4/NF-kB pathway in rats; protective role of agomelatine.

Cardiotoxicity is one of the hazardous effects of the exposure to the heavy metal cadmium (Cd). Inflammation and oxidative injury are implicated in the cardiotoxic mechanism of Cd. The melatonin receptor agonist agomelatine (AGM) showed promising effects against oxidative and inflammatory responses. This study evaluated the effect of AGM on Cd-induced cardiotoxicity in rats, pointing to its modulatory effect on TLR-4/NF-kB pathway and HSP70. Rats received AGM for 14 days and a single dose of Cd on day 7 and blood and heart samples were collected for analyses. Cd increased serum CK-MB, AST and LDH and caused cardiac tissue injury. Cardiac malondialdehyde (MDA), nitric oxide (NO) and MPO were elevated and GSH, SOD and GST decreased in Cd-administered rats. AGM ameliorated serum CK-MB, AST and LDH and cardiac MDA, NO and MPO, prevented tissue injury and enhanced antioxidants. AGM downregulated serum CRP and cardiac TLR-4, NF-kB, iNOS, IL-6, TNF-α and COX-2 in Cd-administered rats. HSP70 was upregulated in the heart of Cd-challenged rats treated with AGM. In silico findings revealed the binding affinity of AGM with TLR-4 and NF-kB. In conclusion, AGM protected against Cd cardiotoxicity by preventing myocardial injury and oxidative stress and modulating HSP70 and TLR-4/NF-kB pathway.

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.

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.

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.

Protective effect of arbutin against cyclophosphamide-induced oxidative stress, inflammation, and hepatotoxicity via Nrf2/HO-1 pathway in rats.

Cyclophosphamide (CP) is a potent anticancer drug widely employed in chemotherapy against various types of cancer. However, CP leads to toxicity to non-targeted organs, including the liver and this limits its clinical use. This study explored the role of arbutin (ARB) against CP-mediated oxidative and inflammatory reactions and hepatotoxicity. Rats were administered ARB (25 and 50 mg/kg) for 14 days and CP (150 mg/kg). CP triggered liver tissue injury with marked increase in serum AST, ALT, ALP, and bilirubin, and hepatic malondialdehyde (MDA) and nitric oxide (NO) coupled with diminution of GSH, SOD, catalase, and GPx. Liver NF-kB p65, NOS, IL-6, TNF-α, Bax and caspase-3 were upregulated by CP injection and IL-10 and Bcl-2 were decreased. ARB prevented liver injury, suppressed MDA, NO, NF-kB p65, inflammatory markers, Bax and caspase-3 in CP-treated rats. ARB restored antioxidants, IL-10 and Bcl-2, and enhanced Nrf2 and hemeoxygenase-1 (HO) both gene and protein in the liver of rats. In conclusion, these results pinpointed the protective role of ARB on oxidative and inflammatory reactions, apoptosis, and hepatotoxicity in rats. This hepatoprotective activity was linked to the ability of ARB to modulate Nrf2/HO-1 pathway.

Betulinic acid protects against cardiotoxicity of the organophosphorus pesticide chlorpyrifos by suppressing oxidative stress, inflammation, and apoptosis in rats.

The widespread application of organophosphorus (OP) pesticides can affect the environment as well as the animal and human health. Chlorpyrifos (CPF) is a broad-spectrum OP pesticide used in agriculture and can cause several toxic effects in which oxidative stresses and inflammation play a key role. This study aimed to evaluate the protective activity of betulinic acid (BA), an antioxidant and anti-inflammatory pentacyclic triterpene, against CPF cardiotoxicity in rats. The rats were divided into four groups. CPF (10 mg/kg) and BA (25 mg/kg) were orally administered for 28 days, and blood and heart samples were collected. CPF-administered rats showed an increase in serum cardiac troponin I (cTnI), creatine kinase (CK)-MB, and lactate dehydrogenase (LDH), accompanied with multiple myocardial tissue alterations. Lipid peroxidation (LPO), nitric oxide (NO), nuclear factor-kappaB (NF-κB), interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α were increased, and antioxidant were decrease in CPF-administered rats. BA ameliorated cardiac function markers and tissue injury, decreased LPO, NO, NF-κB, and proinflammatory cytokines, and increased antioxidants. In addition, BA decreased proapoptosis markers, and increased B-cell lymphoma (Bcl)-2, IL-10, Nrf2, and HO-1 in the heart of CPF-treated rats. In conclusion, BA protected against cardiotoxicity in CPF-administered rats by mitigating oxidative stress, inflammation, and apoptosis, and enhanced Nrf2 and antioxidants.

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.

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.