Oxidative stress and inflammation are key components in cardiovascular diseases and heart dysfunction. Herein, we evaluated the protective effects of (+)-taxifolin (TAX), a potent flavonoid with significant antioxidant and anti-inflammatory actions, on myocardial oxidative tissue injury, inflammation, and cell death, using a mouse model of isoproterenol (ISO)-induced acute myocardial injury. Mice were given TAX (25 and 50 mg/kg, orally) for 14 days before receiving two subsequent injections of ISO (100 mg/kg, s.c.) at an interval of 24 h on the 15th and 16th days. The ISO-induced cardiac tissue injury was evidenced by increased serum creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH), along with several histopathological changes. The ISO also induced increased malondialdehyde (MDA) with concomitant declined myocardial glutathione level and antioxidant enzymes activities. Moreover, ISO-induced heart injury was accompained with elevated cardiac NF-κB p65, TNF-α, IL-1β, Bax, and caspase-3, as well as decreased Bcl-2, Nrf2, and HO-1. Remarkably, TAX reduced the severity of cardiac injury, oxidative stress, inflammation, and cell death, while enhancing antioxidants, Bcl-2, and Nrf2/HO-1 signaling in ISO-injected mice. In conclusion, TAX protects against ISO-induced acute myocardial injury via activating the Nrf2/HO-1 signaling pathway and attenuating the oxidative tissue injury and key regulators of inflammatory response and apoptosis. Thus, our findings imply that TAX may constitute a new cardioprotective therapy against acute MI, which undoubtedly deserves further exploration in upcoming human trials.

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.

Despite its effectiveness in treating inflammatory diseases and various malignancies, methotrexate (MTX) is well known to cause hepatotoxicity, which involves increased oxidative stress and inflammation, limiting its clinical use. Herein, we looked into the effect of punicalagin (PU), a polyphenolic molecule having a variety of health-promoting attributes, on MTX-induced hepatotoxicity in mice. PU (25 and 50 mg/kg/day) was given orally to the mice for 10 days, while a single dose of MTX (20 mg/kg) was injected intraperitoneally (i.p.) at day 7. The MTX-induced liver damage was demonstrated by remarkably higher transaminases (ALT and AST), ALP, and LDH, as well as significant histological alterations in hepatic tissues. MTX-injected mice also demonstrated increases in hepatic oxidative stress markers, including malondialdehyde (MDA) and nitric oxide (NO), with a concordant drop in glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities. PU significantly attenuated the MTX-induced serum transaminases, ALP and LDH elevations, and hepatic oxidative stress measures and boosted antioxidant defenses in the liver. Moreover, the liver of MTX-treated mice showed increases in NF-κB p65 expression, pro-inflammatory cytokine (IL-6 and TNF-α) levels, and pro-apoptotic protein (caspase-3 and Bax) expression, whereas Bcl-2 and Nrf2 expressions were reduced, which were all attenuated by PU treatment. Collectively, PU inhibits oxidative damage, inflammation, and apoptosis and upregulates Nrf2 in the liver of MTX-induced mice. Thus, these findings suggest that PU may have great therapeutic potential for the prevention of MTX-induced hepatotoxicity, pending further exploration in upcoming studies.

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.

Diabetes mellitus (DM) is recognized as a major contributor to impaired testicular function and compromised male fertility. In the present study, the protective effects of the natural flavonoid diosmin (Dios) against diabetes-induced testicular injury were investigated using a rat model of streptozotocin (STZ)-induced diabetes. Diabetes was induced in rats via a single intraperitoneal injection of STZ at a dose of 50 mg/kg body weight. Dios was administered at doses of 25 and 50 mg/kg body weight for eight weeks. Diabetic rats displayed marked testicular dysfunction, evidenced by reduced serum testosterone levels, deteriorated sperm parameters, and pronounced histopathological alterations in testicular tissues. Biochemical analysis revealed elevated levels of oxidative stress markers, including malondialdehyde and protein carbonyls, along with decreased levels of reduced glutathione and diminished activities of catalase and superoxide dismutase in the testicular tissues. Furthermore, diabetes exacerbated testicular inflammation, as indicated by increased immunoexpression of NF-κB p65 and levels of pro-inflammatory cytokines. Likewise, diabetes induced testicular apoptosis, demonstrated by increased Bax and caspase-3 levels and decreased Bcl-2 levels. Treatment of diabetic rats with Dios significantly attenuated sperm parameters and testicular architecture and mitigated oxidative stress, inflammatory responses, and apoptotic cell death. Additionally, Dios enhanced antioxidant defense mechanisms and restored the Sirt1/Nrf2/HO-1 signaling pathway in the testicular tissues of diabetic rats. These results suggest that Dios may serve as an adjuvant therapeutic agent for diabetes-associated testicular dysfunction.

The liver has a tremendous regeneration potential, yet chronic liver injury poses a life-threatening condition if not managed appropriately. Apocynin, an N