The reproductive system of males is adversely impacted by lead (Pb), a toxic heavy metal. The present study examined arbutin, a promising hydroquinone glycoside, for its potential ameliorative impact against Pb-induced testicular impairment in rats. The testicular injury was induced by the intraperitoneal administration of Pb acetate (20 mg/kg/day) for 10 consecutive days. Thirty-six rats were divided into six experimental groups (n = 6 per group): control, control treated with oral arbutin (250 mg/kg), control treated with intraperitoneal arbutin (75 mg/kg), untreated Pb, Pb treated with oral arbutin, and Pb treated with intraperitoneal arbutin. The treatments were administered daily for 10 days. Arbutin was administered by the oral and intraperitoneal routes to compare the efficacy of both routes in mitigating Pb acetate-induced testicular dysfunction. The current data revealed that both oral and intraperitoneal administration of arbutin significantly enhanced serum testosterone and sperm count/motility, indicating the amelioration of testicular dysfunction. In tandem, both routes lowered testicular histopathological aberrations and Johnsen’s damage scores. These favorable outcomes were driven by dampening testicular oxidative stress, evidenced by lowered lipid peroxidation and increased glutathione and catalase antioxidants. Moreover, arbutin lowered testicular p-JAK2 and p-STAT3 levels, confirming the inhibition of the JAK2/STAT3 pro-inflammatory pathway. In tandem, arbutin suppressed the testicular NLRP3/caspase-1/NF-B axis and augmented the cytoprotective PK2/PKR2 pathway. Notably, intraperitoneal arbutin at a lower dose prompted a more pronounced mitigation of Pb-induced testicular dysfunction compared to oral administration. In conclusion, arbutin ameliorates Pb-evoked testicular damage by stimulating testicular antioxidants and the PK2/PKR2 pathway and inhibiting the JAK2/STAT3 and NLRP3/caspase-1 pro-inflammatory pathways. Hence, arbutin may be used as an adjunct agent for mitigating Pb-induced testicular impairment.

Cadmium, a ubiquitous environmental toxicant, disrupts testicular function and fertility. The dipeptidyl peptidase-4 inhibitor linagliptin has shown pronounced anti-inflammatory and anti-apoptotic features; however, its effects against cadmium-evoked testicular impairment have not been examined. Herein, the present study investigated targeting inflammation, apoptosis, and autophagy by linagliptin for potential modulation of cadmium-induced testicular dysfunction in rats. After 60 days of cadmium chloride administration (5 mg/kg/day, by gavage), testes, epididymis, and blood were collected for analysis. The present findings revealed that linagliptin improved the histopathological lesions, including spermatogenesis impairment and germ cell loss. Moreover, it improved sperm count/motility and serum testosterone. The favorable effects of linagliptin were mediated by curbing testicular inflammation seen by dampening of HMGB1/TLR4 pathway and associated lowering of nuclear NF-κBp65. In tandem, linagliptin suppressed the activation of NLRP3 inflammasome/caspase 1 axis with consequent lowering of the pro-inflammatory IL-1β and IL-18. Jointly, linagliptin attenuated testicular apoptotic responses seen by Bax downregulation, Bcl-2 upregulation, and suppressed caspase 3 activity. With respect to autophagy, linagliptin enhanced the testicular autophagy flux seen by lowered accumulation of p62 SQSTM1 alongside upregulation of Beclin 1. The observed autophagy stimulation was associated with elevated AMPK (Ser487) phosphorylation and lowered mTOR (Ser2448) phosphorylation, indicating AMPK/mTOR pathway activation. In conclusion, inhibition of testicular HMGB1/TLR4/NLRP3 pro-inflammatory axis and apoptosis alongside stimulation of autophagy were implicated in the favorable actions of linagliptin against cadmium-triggered testicular impairment.

Despite being an effective chemotherapeutic agent, the clinical use of doxorubicin (DOX) is limited by several organ toxicities including hepatic injury. Pentoxifylline (PTX) is a methylxanthine derivative with marked anti-inflammatory and anti-apoptotic features. It is unknown, however, whether PTX can mitigate DOX-evoked hepatotoxicity. This study aims to explore the potential hepatoprotective impact of PTX in DOX-induced hepatic injury and the underlying molecular mechanisms. Histopathology, immunohistochemistry, and ELISA were used to examine liver tissues. The current findings revealed that PTX administration to DOX-intoxicated rats mitigated the pathological manifestations of hepatic injury, reduced microscopical damage scores, and improved serum ALT and AST markers, revealing restored hepatic cellular integrity. These favorable effects were attributed to PTX’s ability to mitigate inflammation by reducing hepatic IL-1β and TNF-α levels and suppressing the pro-inflammatory HMGB1/TLR4/NF-κB axis. Moreover, PTX curtailed the hepatic apoptotic abnormalities by suppressing caspase 3 activity and lowering the Bax/Bcl-2 ratio. In tandem, PTX improved the defective autophagy events by lowering hepatic SQSTM-1/p62 accumulation and enhancing the AMPK/mTOR pathway, favoring autophagy and hepatic cell preservation. Together, for the first time, our findings demonstrate the ameliorative effect of PTX against DOX-evoked hepatotoxicity by dampening the hepatic HMGB1/TLR4/NF-κB pro-inflammatory axis and augmenting hepatic AMPK/mTOR-driven autophagy. Thus, PTX could be utilized as an adjunct agent with DOX regimens to mitigate DOX-induced hepatic injury.

Drug- induced kidney injury is considered as a dangerous condition caused morbidity and mortality and most notably Vancomycin induced nephrotoxicity via oxidative stress, inflammatory insult and apoptosis. our investigation was applied to assess the potential ameliorative effect of Carvacrol against vancomycin- triggered nephrotoxicity. Male Sprague-Dawley rats were allocated into 5 groups: Normal control group, DMSO; a vehicle for carvacrol group, Group of animals given carvacrol 50 mg/kg/day orally, Group of rats challenged with intraperitoneal vancomycin 200mg/kg/day and group co-treated with carvacrol and vancomycin as previously mentioned and all treatments were applied for 7 continuous days.Vancomycin caused nephrotoxicity which revealed as elevated levels of Urea, Creatinine, kidney injury molecule.1 (KIM1) and Cystatin C and confirmed histologically by degenerative changes in renal histo-architecture. Vancomycin enhanced protein expression of some inflammatory markers as tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and nuclear factor kappa B (NF-κB) along with down-regulation of protein expression of nuclear factor kappa B inhibitory protein (IKBβ). Likewise, it caused oxidative stress via down-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), heamoxygenase-1(HO-1) and glutathione (GSH) but increased Malondialdehyde (MDA) and Myeloperoxidase (MPO) levels. Also vancomycin caused apoptosis by increasing Bax gene expression together with decreasing Bcl2 gene expression. On contras, Carvacrol mitigated vancomycin induced kidney injury by restoration of kidney architecture and modulation of the inflammation, oxidative stress and apoptosis. This study discloses that carvacrol suppresses vancomycin-induced nephrotoxicity through its anti-inflammatory, anti-oxidative stress and anti-apoptotic actions via Nrf2/HO-1, IKBβ/ NF-κB and Bax -Bcl2 pathways.

Cadmium (Cd), an environmental health hazard, is a causative agent of many pathological conditions especially liver diseases. The possible ameliorative role of L. Carnitine on cadmium- provoked liver injury was discussed in this study. Twenty-four male rats were daily challenged for 30 days with CdCl2 (cadmium chloride) 5mg/kg/day and/or L. Carnitine 100 mg/kg/day. L. Carnitine administration halted the alteration of liver function biomarkers induced by cadmium which appeared as decreased AST, ALT and ALP levels . L. Carnitine prohibited CdCl2-generated oxidative stress via Nrf2/HO.1 pathway by increasing TAC and decreasing MDA and NO. L. Carnitine also restrained inflammatory insult created by CdCl2 by suppressing TLR4/NFκB pathway through reducing the inflammatory mediators including TNF-α, IL-1β and IL-18. Finally, our biochemical data were confirmed by the improvement of the liver histology by L. Carnitine . These results revealed that TLR4/NFκB axis implicated in L. Carnitine protection against CdCl2-triggered hepatotoxicity accompanied by inhibition of oxidative stress and this may provide new ideas in order to treat cadmium-related diseases