TL;DR
Man could be considered as a potential protective agent against HgCl2-induced liver injury through controlling oxidative stress, inflammation, and apoptosis.
Mercuric chloride (HgCl2) is a common environmental toxicant that causes excessive oxidative stress and inflammation in pulmonary tissue. The present work was designed to evaluate the protective impact of lapachol nanoparticles (LaP-NPs) on HgCl2-induced lung toxicity in mice. LaP-NPs were prepared by nanoprecipitation and characterised for particle size, morphology, and stability. Adult albino mice were divided into six groups: untreated controls; LaP-NPs alone; HgCl2 alone; HgCl2 plus LaP-NPs at two doses (21.5 and 53.75 mg/kg); and HgCl2 plus dexamethasone. All treatments were administered orally for 30 days. Markers of pulmonary oxidative stress (reduced glutathione [GSH], superoxide dismutase [SOD], glutathione peroxidase [GPx], and malondialdehyde [MDA]) and inflammatory cytokines were measured. The gene expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and protein 39 (P39) were evaluated, and histopathological changes were assessed. Molecular docking was conducted to investigate possible interactions between lapachol and the Nrf2 and P39 protein targets. HgCl2 exposure led to significant oxidative stress, as demonstrated by a significant decline in GSH, SOD and GPx activities along with increased MDA. This was accompanied by strong upregulation of IL-1β (+134.7% in plasma), iNOS (+405%), and MIP-1α (+4248%), as well as robust upregulation of Nrf2 (+570.6%) and P39 (+468.6%) (p < 0.001). High-dose LaPNPs treatment (53.75 mg/kg) significantly reversed the activity of antioxidant enzymes, decreased MDA accumulation, and normalised Nrf2 and P39 expression. Several inflammatory mediators were also significantly suppressed to normal control levels. Histopathological analyses confirmed the biochemical observations, demonstrating preservation of lung architecture. Also, docking simulations showed that lapachol had high predicted binding affinities for both Nrf2 (-8.25 kcal/mol) and P39 (-8.06 kcal/mol). LaP-NPs revealed excellent antioxidant and anti-inflammatory properties, which were superior to those of native lapachol and comparable to dexamethasone. The nanoformulation improved the bioavailability and multiple targeting of lapachol, suggesting a potential protective strategy for heavy-metal-induced lung injury. Limitations are that only one toxicity model was employed. LaP-NPs efficiently prevent HgClⁿ-induced lung injury by inhibiting oxidative stress, modulating stress-related genes, and reducing inflammatory pathways. These findings suggest that LaP-NPs could serve as a nanotherapeutic for heavy metal-induced pulmonary toxicity.
Nicotinamide riboside exerts protective effects against cisplatin-induced hepatorenal toxicity that are mechanistically linked to activation of the Nrf2/NQO1 antioxidant pathway and restoration of hepatic NAD+ homeostasis.
Drug-induced liver injury is an increasingly serious health problem, with a relatively high prevalence in China. Excessive acetaminophen (APAP) intake is a common cause of acute liver injury. Mechanistically, the toxic APAP metabolite N -acetyl- p -benzoquinone imine (NAPQI) depletes hepatic glutathione (GSH), thereby triggering oxidative stress. Yindan Pinggan Capsules (YDPG), a traditional Chinese medicine prescription, is used for clearing heat and promoting diuresis. However, their protective effects against APAP-induced liver injury (AILI) and the underlying molecular mechanisms remain unclear. This study aimed to evaluate the protective effect of YDPG against AILI and to elucidate the underlying mechanisms. Adult male mice were administered YDPG by oral gavage once daily for 7 days. One hour after the final YDPG administration, APAP at 300 mg/kg was injected intraperitoneally to establish a mouse model of AILI. Histopathological examination confirmed that YDPG significantly ameliorated APAP-induced hepatic necrosis and inflammation. To explore the molecular mechanisms underlying these effects, Gene Expression Omnibus data analysis, network pharmacology, and proteomics were employed. Western blot was utilized to detect the hepatic protein levels of solute carrier family 7 member 11, solute carrier family 3 member 2, glutathione peroxidase 4 (GPX4), ceruloplasmin, solute carrier family 39 member 14, acyl-CoA synthetase long-chain family member 4 (ACSL4), and lysophosphatidylcholine acyltransferase 3 (LPCAT3). YDPG significantly downregulated the overproduction of interleukin-6 and interleukin-1β in serum. Furthermore, YDPG effectively attenuated the APAP-induced elevation of serum alanine aminotransferase and aspartate aminotransferase levels. Comprehensive proteomics analysis revealed that YDPG specifically modulated the ferroptosis pathway. Western blot and immunohistochemistry confirmed the regulatory effects of YDPG on key proteins involved in ferroptosis. The findings of this study demonstrate that YDPG can alleviate hepatic injury and inhibit the progression of AILI in mice. These protective effects are attributed to YDPG’s ability to suppress the system Xc − /GSH/GPX4 axis and modulate the LPCAT3–ACSL4 pathway. Consequently, this research highlights the potential of YDPG as a therapeutic option for AILI.
Despite cisplatin (CISP) is broadly employed in cancer therapy, its adverse effects, involving hepatotoxicity, restrict its clinical usage. Thus, this study was designed to explore the prospect of repurposing rupatadine (RUPA), a dual antagonist of histamine and platelet‐activating factor (PAF), against CISP‐evoked hepatotoxicity in rats. Rats were i.p. injected with CISP (6 mg/kg) for the induction of hepatotoxicity on the 8th day of the study in the presence and absence of RUPA in two dosages (3, 6 mg/kg) orally for 14 days. Different biochemical parameters and histopathological assessments, along with the mechanistic characterizations of the possible protective impact of the RUPA were conducted. Administration of CISP evoked hepatic histopathological modifications and raised serum liver enzyme levels and hepatic MDA content, PAF, and histamine levels, along with diminishing the serum albumin level, hepatic SOD activity, and GSH level. Moreover, CISP remarkably augmented the levels of HMGB1, TLR4, p‐NF‐κB p65, IL‐6, TNF‐α, IL‐18, IL‐1β, NLRP3, and cleaved caspase‐1 proteins with an evident decline in the level of IL‐10. On the contrary, pretreatment with either RUPA.3 or RUPA.6 dramatically ameliorated these alterations triggered by CISP injection. RUPA counteracts hepatotoxicity evoked by CISP in rats via its anti‐oxidative as well as anti‐inflammatory properties via repression of hepatic HMGB1/TLR4/NF‐κB and thus restricts the activation of NLRP3/caspase‐1 signaling cascade.
Overall, chrysin demonstrates potent protective potential against PFOA-induced liver injury and may serve as a promising therapeutic candidate for environmental toxin-associated hepatotoxicity.
