Journal of Biochemical and Molecular Toxicology最新文献

Colistin (CST) is an effective antibiotic that decreases the mortality rates accompanying nosocomial infection with multidrug-resistant resistant bacteria. However, its use is limited because of the high potential of inducing severe nephrotoxicity. Celastrol (CELA) is a medicinally promising triterpenoid and the most abundant bioactive constituent of the root pulps of the widely used Chinese herb, Tripterygium wilfordii. CELA confers cellular protection because of its antioxidant, anti-inflammatory, and antiapoptotic activities. The current study aimed to investigate the potential nephroprotective effects of CELA against CST-induced nephrotoxicity. Rats were divided into five groups, and treated as follows: Group One received vehicles only; Group Two received CELA only; Group Three received CST only and Groups Four and Five received CST and CELA (0.5 or 1 mg/kg). Microscopical examination of H&E-stained kidney sections indicated that CST-only-treated animals exhibited distortion in the renal histological features; Also, Masson's trichrome, Picrosirius Red, and Periodic acid–Schiff staining highlighted fibrotic changes. This was associated with increased kidney serum markers (urea, creatinine, and cystatin C), induced oxidative stress (increased levels of MDA, decreased activities of SOD and CAT, and reduced the protein levels of Nrf-2 and HO-1), increased the immunoreactivity of the inflammatory markers (COX-2, iNOS, TNF-α, and NF-κB), and stimulated apoptosis (increased the transcription of Bax and CASP3 and decreased that of Bcl-2). In contrast, pretreatment with CELA significantly reduced the histopathological changes, oxidative stress, inflammation, and apoptosis. Therefore, CELA showed significant renal protection against CST-induced kidney injury.

Drug-induced nephrotoxicity is a significant clinical complication associated with several chemotherapeutic agents, including 5-fluorouracil (5-FU). This study was aimed to investigate the nephroprotective potential of boldine, an aporphine alkaloid, against 5-FU-induced renal toxicity using in vitro (HEK293 cells) and in vivo (Wistar rats) models. In vitro cytotoxicity was evaluated using the MTT assay, AO/EB and DAPI staining was performed to identify apoptotic alterations. The expression of apoptotic and antioxidant genes was analyzed by quantitative and semi-quantitative PCR. For the in vivo study, rats were divided into five groups. One group received a single intraperitoneal dose of 5-FU (150 mg/kg) to induce nephrotoxicity. In the remaining groups, 5-FU was administered followed by oral treatment with boldine (10 or 20 mg/kg) or silymarin (100 mg/kg) for 7 days. Biochemical markers including creatinine, urea, blood urea nitrogen, uric acid in serum and oxidative stress indicators in kidney tissue were analyzed. MAPK pathway-related gene expression and histopathological changes were assessed. Treatment of HEK cells with 5-FU markedly reduced cell viability and induced apoptosis, while co-treatment with boldine restored viability and normal cell morphology. Boldine modulated the 5-FU-induced downregulation of SOD, CAT, GPx, and Bcl-2 and upregulation of Bax and caspase-3. In vivo, boldine treatment normalized elevated nephrotoxic markers in serum, enhanced antioxidant enzyme activities, and inhibited activation of ASK1, ERK1, c-Jun, and NF-κB1. Histopathological findings further confirmed that boldine preserved renal tissue integrity and prevented tubular and glomerular damage. Overall, boldine significantly protected against 5-FU-induced renal injury via anti-apoptotic, antioxidant, and anti-inflammatory mechanisms.

Transient receptor potential vanilloid-1 (TRPV1) channels have been shown to be present in many tissues, including the kidney. Previous studies have reported that TRPV1 activation has anti-inflammatory and renoprotective effects. In this study, we investigated the effects of TRPV1 agonist capsaicin on acute kidney injury (AKI) in a rat sepsis model induced by cecal ligation and puncture (CLP). Rats were divided into control, CLP and treatment groups in which 3 different doses of capsaicin (2, 6 and 30 mg/kg) were administered with CLP administration. Kidney tissues and sera from animals 24 h after CLP were analyzed. Histopathological examinations have shown that kidney damage occurs due to sepsis. TLR4/NF-κB activity, proinflammatory cytokines (IL-1β, IL-6, and TNF-α), caspase-3, caspase-8 and malondialdehyde levels increased in renal tissue due to sepsis. Serum levels of IL-1β, TNF-α and renal damage biomarkers (BUN, CRE, IL-18 and NGAL) increased due to sepsis. Capsaicin administration dose-dependently reversed sepsis-induced pathological changes in the kidney and serum. Our findings suggest that the TRPV1 agonist capsaicin has renoprotective effects in sepsis-induced AKI by reducing inflammation, oxidative damage and apoptosis. TRPV1 activation may be a promising therapeutic strategy to ameliorate sepsis-induced kidney and other organ damage.

Glutamate (Glu) possesses functional significance concerning neurological disorders by producing neurotoxicity as a major excitatory amino acid neurotransmitter. Sestrin2 (SESN2) has been affirmed to elicit wide neuroprotective properties as a highly conserved stress-responsive protein. Therefore, this project sets out to ascertain the impacts of SESN2 on Glu neurotoxicity and the concealed operating mechanism. Cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay kit, and Western blot estimated cell viability, cytotoxicity, and SESN2 expression. Commercial kits and fluorescence probes were employed to assess the degree of oxidative stress. The apoptotic changes were evaluated by terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) and Western blot. Mitochondrial function was measured by 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolocarbocyanine iodide (JC-1) staining, MitoSOX staining, and Western blot analysis of mitophagy-related proteins and immunofluorescence. Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2–related factor 2 (Nrf2) pathway–related proteins were also examined with Western blot. SESN2 expression was elevated in HT-22 cells upon stimulation with Glu. SESN2 upregulation reduced the viability loss, LDH release, oxidative stress, and apoptosis in HT-22 cells imposed by the Glu challenge, while a contrary trend was observed when SESN2 was downregulated. Moreover, hyperexpressed SESN2 activated the Keap1-Nrf2 pathway to promote mitophagy in Glu-exposed HT-22 cells. Deletion of Nrf2 partly abolished the effects of SESN2 elevation on the mitophagy, and mitophagy blocker Mdivi-1 partly reverted the influences of SESN2 overexpression on the viability, LDH release, oxidative stress, and apoptosis in Glu-stimulated HT-22 cells. SESN2 might mediate mitophagy via the Keap1-Nrf2 pathway to confer neuroprotection toward Glu-provoked toxicity.

Carotid atherosclerosis (CAS) is a significant factor in cerebrovascular disease; however, the lack of novel and reliable biomarkers hinders the current assessment of this condition. This study focuses on integrins in CAS to offer fresh ways for knowing about the disease. qRT-PCR was implemented to quantify the expression levels of intergrins in CAS. Subsequently, we used STRING and Friend analyses to identify integrin molecules from the differentially expressed genes and analyzed the correlation of these integrin molecules with immune. Finally, we examined immune subgroups of CAS and explored the roles of immune and integrin molecules in different subgroups. Immune analysis enunciation, macrophage was the predominant immune cell types in CAS plaques. Additionally, most immune checkpoint molecules possessed higher expression levels in CAS than in control group. Two subtypes, namely, C1 immune subtype and C2 nonimmune subtype, were classified across carotid atherosclerotic plaques. Through STRING and Friend analyses, ITGAX, ITGAM, and ITGB7 were intended to be pivotal molecules of CAS, and these integrin molecules were more highly expressed in the C1 subgroup. Furthermore, these integrin molecules were interrelated with the soakage of immunological cells and the immune regulatory molecules in CAS. Our findings identify several promising genes related to CAS and immune subtypes, offering new therapeutic targets for immunotherapy in CAS.

Resveratrol (RES) has been shown to be a promising protective agent against asthma. However, its role in the steroid-resistant asthma is unknown. Studies showed RES displayed hormetic action, protecting the cells at a lower dose while inducing cytotoxicity at higher doses, which limits its clinical application. In this study, we determined the efficacy of different doses of RES in a steroid-resistant asthma model. A toluene diisocyanate (TDI)-induced steroid-resistant murine asthma model was established. The effects of different doses of RES were tested both in vitro and in vivo. We observed low-doses RES (1, 10 mg kg⁻¹) ameliorated TDI-induced airway hyperresponsiveness, airway neutrophil accumulation, mucus production and collogen deposition as well as the release of Th2 and Th17-related cytokines. Yet, the high-dose RES (100 mg kg⁻¹) had no protective effects. As a SIRT1 activator, RES expectedly increased pulmonary SIRT1 expression at doses of 1,10 and 100 mg kg⁻¹, but only low-dose RES (1, 10 mg kg⁻¹ in mice and 10 μM in vitro) decreased TDI-induced bronchial epithelial HMGB1 acetylation, nucleocytoplasmic translocation and release. Further, we found pulmonary p300, a nuclear histone deacetyltransferase, significantly upregulated by TDI was suppressed by only low-doses RES (1, 10 mg·kg⁻¹). In addition, low-dose rather than high-dose RES attenuated TDI-induced bronchial epithelial DNA damage and mitochondrial oxidative stress. Our data suggested that low-dose RES inhibits HMGB1 acetylation and release and maintains SIRT1-p300 balance, which ameliorates airway inflammation in TDI-induced steroid-resistant asthma.

Lipid metabolic disorders, driven by oxidative stress, lipid peroxidation, and chronic inflammation, are key contributors to toxicological damage underlying Nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and metabolic syndrome. The nuclear factor erythroid 2–related factor 2 (NRF2) pathway, a master regulator of antioxidant and detoxification responses, plays a critical role in mitigating cellular toxicity and maintaining lipid homeostasis. A multidisciplinary approach was applied to uncover the molecular toxicology of NRF2 in lipid metabolism. Transcriptomic meta-analysis of GEO datasets identified differentially expressed NRF2-regulated genes in lipid-associated chronic liver diseases (CLD). Clinical meta-analysis synthesized evidence on NRF2 activators and their effects on lipid-related toxic endpoints. Network pharmacology was used to map overlapping targets between NRF2 activation and lipid toxicity, while molecular docking assessed the binding potential of NRF2 activators with KEAP1, a negative regulator of NRF2. Transcriptomic analysis revealed widespread dysregulation of NRF2-dependent antioxidant genes such as GPX4, HMOX1, and NQO2, with 3178 DEGs significantly associated with oxidative stress, ferroptosis, and glutathione metabolism. Clinical meta-analysis demonstrated that NRF2 activators reduced toxic lipid parameters, including triglycerides (↓ 21.81%), LDL (↓ 18.36%), and total cholesterol (↓ 14.15%). Network pharmacology identified 985 overlapping genes linking NRF2 activation to oxidative stress, lipid peroxidation, and fatty acid metabolism. Sixteen natural and synthetic NRF2 activators were highlighted, with molecular docking showing strong KEAP1 binding by quercetin (–9.2 kcal/mol) and luteolin (–9.2 kcal/mol), consistent with disruption of KEAP1–NRF2 interactions and detoxification pathway activation. This integrative molecular toxicology study establishes NRF2 as a central regulator at the interface of oxidative stress and lipid metabolism. Both natural and synthetic NRF2 activators mitigate toxic lipid accumulation and oxidative injury, supporting NRF2 modulation as a promising strategy for preventing and treating lipid metabolic disorders such as NAFLD, atherosclerosis, and metabolic syndrome.

Obesity and its associated metabolic disorders pose a significant global health challenge. The gut microbiota, influenced by dietary factors, plays a crucial role in regulating lipid metabolism and glucose homeostasis. This review explores the potential of curcumin, a polyphenol derived from turmeric, as an epigenetic modulator in obesity management. Curcumin exhibits diverse biological activities, including the ability to modulate gut microbiota composition, enhance intestinal barrier integrity, and regulate long non-coding RNA (lncRNA) expression. By influencing these pathways, curcumin effectively mitigates obesity-related inflammation, improves insulin sensitivity, and reduces hepatic steatosis. Clinical and preclinical studies demonstrate that curcumin supplementation can significantly improve obesity-related markers, particularly in bioavailability-enhanced formulations. We highlight key mechanistic gaps and propose targeted in vitro, in vivo, and clinical studies to validate curcumin–SNHG9 interactions as a novel epigenetic therapy for obesity.