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Oxidative tissue injury and inflammatory responses play major roles in cardiovascular diseases and heart failure. Visnagin (VIS) is a natural bioactive component of Ammi visnaga, with promising radical scavenging and anti‐inflammatory activities. This study explored the protective effect of VIS against isoproterenol (ISO)‐induced acute myocardial injury and oxidative stress in rats. VIS was supplemented for 14 days, and the rats received ISO (100 mg/kg) twice at an interval of 24 h. ISO‐induced myocardial injury was characterized by elevated serum CK‐MB, LDH, and troponin‐I associated with increased heart weight and several histopathological changes. ISO increased reactive oxygen species (ROS), malondialdehyde (MDA), NF‐κB p65, TNF‐α, IL‐6, and decreased glutathione and antioxidant enzymes in rats' hearts. VIS prevented myocardial injury and ameliorated the cardiac function markers, ROS, MDA, NF‐κB p65, and pro‐inflammatory cytokines in ISO‐intoxicated rats. In addition, VIS decreased Bax mRNA and caspases, and upregulated Nrf2, HO‐1, Bcl‐2, and PPARγ. Molecular docking simulations revealed the binding method of VIS to NF‐κB, Keap1, and PPARγ. In conclusion, VIS protects against ISO‐induced acute myocardial injury by attenuating oxidative tissue injury and reducing key inflammatory and apoptosis markers. In vivo and in silico results showed that activation of Nrf2/HO‐1 signaling and PPARγ mediates the cardioprotective effect of VIS.

Methotrexate (MTX) is an efficient chemotherapeutic and immunosuppressant drug, but the hepatotoxicity of MTX limits its clinical use. Naringin (Nar) is a flavonoid derived from Citrus paradise, and has been shown to possess several pharmacological activities, including free-radical scavenging and antioxidant properties. In the present study, we first tested the possible protective effects of multiple doses of Nar against MTX-induced acute hepatotoxicity in rats, and then we investigated the growth inhibition and apoptotic effects of MTX and/or Nar against the HepG2 hepatocarcinoma cell line. Our in vivo results showed that Nar significantly reduced MTX-induced increases in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin levels. Nar also reduced MTX-induced oxidative stress by significantly reducing liver malondialdehyde (MDA) and nitric oxide (NO) content and increasing superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH). In addition, Nar significantly counteracted MTX-induced increases in hepatic interleukin-6 and tumor necrosis factor-α (TNF-α). Further, Nar greatly protected hepatocyte ultrastructure against MTX-induced injury. In contrast, in vitro MTX and/or Nar treatment of HepG2 cells for 48 h exhibited a cytotoxic effect and induced apoptosis in a dose-dependent manner mediated by a significant increase in the Bax/Bcl-2 protein expression ratio. Noticeably, Nar potentiated the MTX effect on the Bax/Bcl-2 ratio. In conclusion, Nar decreased MTX-induced functional and ultrastructural liver damage in a tumor-free animal model. Also, our data introduce MTX and Nar as promising antiproliferative agents with a distinctive mode of action, inducing apoptosis in HepG2 tumor cells through activation of Bax and down-regulation of Bcl-2 protein expression.

Gentamicin (GEN) is a bactericidal aminoglycoside known to cause nephrotoxicity. Formononetin (FN) is a potent flavonoid that exhibits numerous promising pharmacological activities. In this study, we have assessed the nephroprotective efficacy of FN against GEN-induced renal injury in rats. Rats were orally administered with FN (60 mg/kg/day, for 2 weeks) and were co-treated with intraperitoneal (i.p.) injection of GEN (100 mg/kg/day) during the days 8–14. GEN-treated rats demonstrated increased urea and creatinine levels in serum associated with marked histopathological changes in the kidney. Malondialdehyde (MDA) and protein carbonyl contents were elevated, whereas glutathione concentration and catalase and superoxide dismutase activities were lowered in GEN-administered rats. The FN largely prevented tissue damage, attenuated renal function, reduced MDA and protein carbonyl, and enhanced antioxidant capacity in the kidney of GEN-administrated animals. The kidney of GEN-treated rats demonstrated elevated Bax and caspase-3 protein expression, accompanied by lowered Bcl-2 protein expression, an effect that FN attenuated. Moreover, FN treatment caused upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) expression in renal tissue of GEN-intoxicated animals. Collectively, FN protects against GEN-caused renal damage via exhibiting antioxidant, anti-inflammatory, and antiapoptotic activities and augmenting Nrf2 signaling, suggesting FN as a promising agent for preventing drug-induced organ damage.

The aim of the present study was to investigate the ameliorative potential of parsley (Petroselinum crispum) leaf essential oil (PO) against the detrimental effects of carbon tetrachloride (CCl4) on the thyroid gland and testes of mice. Twenty-four adult male mice were divided into four groups and treated for 4 weeks. The 1st control group received 3 mL/kg olive oil intraperitoneally, twice a week followed by 0.5 mL/kg saline intragastrically daily. The 2nd CCl4 group received CCl4 (3 mL/kg intraperitoneally, twice a week). The 3rd PO group received PO (0.5 mL/kg intragastrically daily), while the 4th CCl4+PO group received CCl4 coadministrated with PO at the aforementioned doses. CCl4 group recorded significant ( p < 0.05 ) reduction in the activities of antioxidant enzyme catalase (CAT) and superoxide dismutase (SOD) and significant ( p < 0.05 ) increase in the lipid peroxidation end product’s level malondialdehyde (MDA) in the testes and thyroid glands. Meanwhile, serum levels of testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid hormones (thyroid-stimulating hormone (TSH), total triiodothyronine (T3), free triiodothyronine (fT3), total thyroxine (T4), and free thyroxine (fT4)) significantly decreased. Also, histopathologically, the testicular tissue showed hypospermatogenesis within irregular-shaped seminiferous tubules with prominent edema in the interstitial spaces confirming the aforementioned biochemical alterations. Treatment with PO significantly reduced the testicular and thyroid oxidative stress ( p < 0.05 ) and elevated the testosterone (73.47%), FSH (92.11%), LH (33.33%), T3 (23.47%), fT3 (39.13%), T4 (27.91%), and fT4 (75%) as compared to that of CCl4-treated group corresponding values. The PO GC/MS analysis indicated bioactive monoterpenes (major component is 1,3,8-mentha triene 34.48%) and phenylpropenes (major component is myristicin 21.04%). Results suggested the ameliorative effect of PO against CCl4-induced hypogonadism in mice by suppressing oxidative stress and maintaining thyroid gland function.

Cadmium (Cd) is an inessential trace metal that accumulates in the kidney and may lead to renal toxicity by mediating oxidative stress (OS), inflammatory reactions, and apoptosis. The main objective of this experiment was to inspect the protecting potential of taxifolin (TA) on Cd-induced renal toxicity. Adult male mice were allocated into equal five groups as follows: control, TA-treated (50 mg/kg, oral), CdCl2-treated (4 mg/kg body weight (BW), p.o.), pretreated with TA (25 mg/kg) 1 h before CdCl2 injection (4 mg/kg BW, p.o.), and pretreated with TA (50 mg/kg) 1 h before CdCl2 injection (4 mg/kg BW, p.o.) for 14 days. Cd-intoxicated mice revealed higher serum urea and creatinine levels and notable histopathological alterations in the renal tissues. Malondialdehyde (MDA), nitric oxide (NO), nuclear factor-kappa B (NF-κB) p65, tumor necrosis factor-α (TNF-α), and IL-1β were increased. In contrast, glutathione levels, catalase and superoxide dismutase activities, and IL-10 levels were decreased under Cd-administered effects. Conversely, the TA pre-treatment highly protected tissues from Cd-toxicity, improved renal function, decreased MDA and NO levels, attenuated inflammation, and improved redox status in the renal tissues of Cd-intoxicated mice. The TA pre-treatment of Cd-intoxicated mice showed down-regulation of both Bax and caspase-3 protein and up-regulation of Bcl-2 protein expression in the kidney. Furthermore, TA pre-treatment induced higher upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) expression in kidney cells of Cd-intoxicated mice. Therefore, TA can protect renal tissues against Cd-induced nephrotoxicity via improving redox status, modulating inflammation, diminishing cell apoptosis, and activating the Nrf2/HO-1 signaling pathway.

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.

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