Journal of Biochemical and Molecular Toxicology最新文献

Cyclophosphamide (CYP) is a widely-used chemotherapeutic drug known to induce ovarian damage and infertility in women. The present study evaluated the potential protective roles of zofenopril, a sulfhydryl-containing angiotensin-converting enzyme inhibitor, and thymoquinone (ThQ), alone and in combination, against CYP-induced ovarian damage in rats. Thirty adult female rats were divided into five groups: a control group that received normal saline; a CYP-Induced group given a single intraperitoneal (IP) dose of 200 mg/kg CYP on day 17 of the experiment; and three groups pre-treated with zofenopril, ThQ, or Zofenopril+ThQ for 17 days before CYP-administration, and continuing for 2 days after CYP exposure. Animals were euthanized, and blood and ovarian tissues were collected 48 h after CYP administration. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), and estradiol (E2) levels were measured, as well as the apoptotic biomarker caspase-3, total antioxidant capacity (TAOC), and tumor necrosis factor (TNF‑α). Ovarian histomorphometry was also assessed. CYP injection induced ovarian injury, characterized by reduced serum AMH and E2 levels, increased FSH and LH levels, oxidative stress, and increased levels of inflammatory and apoptotic markers. In addition, severe ovarian atrophy, regression and degradation of ovarian follicles, and atrophic follicles were observed. Zofenopril and ThQ administration significantly mitigated these CYP-mediated effects, restoring hormone levels, reducing oxidative stress and inflammation, and improving ovarian histology compared with the CYP-Induced group. Based on the present study, zofenopril and ThQ have protective effects against CYP-induced ovarian injury; while co-administration of zofenopril+ThQ was more effective at inhibiting CYP-induced effects on TAOC, TNF‑α, and caspase-3 levels.

Colitis-associated colorectal neoplasia is the third most life-threatening consequence of prolonged ulcerative colitis. In the present investigation, we evaluated the efficacy of PARP-1 inhibitors, 3-aminobenzamide and Olaparib, in a rodent model of colitis-associated colorectal cancer (CACC) induced by azoxymethane (AOM) and Dextran sulphate sodium (DSS). For model induction, male BALB/c mice were provided DSS (3% w/v) in three cycles within drinking water following an injection of AOM (10 mg/kg, intraperitoneally). A week after the DSS treatment, 3-aminobenzamide (5, 10 and 20 mg/kg; i.p.) and Olaparib (10 mg/kg; orally) were given until sacrifice. PARP inhibitors reduced tumour progression by down-regulating mRNA expression for inflammatory markers, PARP-1, NLRP3, ASC, Caspase-1, and TNF-α. Immunoblotting showed modulation of beclin-1 expression, while transmission electron microscopy results revealed an increase in autophagosome numbers within tumour tissues. Immunofluorescence for Ki67 and immunoblotting of PCNA indicated elevated cell proliferation in the AOM/DSS group, mitigated by the treatment with 3-aminobenzamide (20 mg/kg) and Olaparib (10 mg/kg). Finally, DNA damage was also reduced by the intervention of 3-aminobenzamide and Olaparib as indicated by decrease γH2AX expression. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and β-catenin expression suggested decrease apoptosis within tumour tissue. Both 3-aminobenzamide (20 mg/kg; i.p.) and Olaparib (10 mg/kg; orally) exhibited coloprotective effects by modulating PARP-1-NLRP3 inflammasome and autophagy pathways in a model of colitis-associated colorectal cancer.

Endometrial cancer (EC) poses a great threat to women's health worldwide. Splicing factor 3B, subunit 1 (SF3B1) and the methyltransferase Wilms tumor 1-associated protein (WTAP) have been confirmed to be involved in the progression of EC, but the relationship between them and whether they jointly regulate EC is still unclear. The mRNA and protein levels of SF3B1 and WTAP were analyzed by qRT-PCR and western blot. Then, cell proliferation, apoptosis, migration, and invasion behaviors were assessed by EdU, flow cytometry, wound healing, and Transwell assays. Bioinformatics tools were applied to predict the binding sites of WTAP on SF3B1 mRNA and the correlation between WTAP and SF3B1. The binding of the two and the m6A methylation level of SF3B1 were verified by RIP and MeRIP. Finally, the effect of WTAP/SF3B1 on EC tumors in vivo was determined by a xenograft tumor model. SF3B1 was highly expressed in EC and its knockdown inhibited the proliferation, expedited apoptosis, repressed migration and invasion, and promoted ferroptosis of EC cells. Besides, WTAP bound to SF3B1-bound mRNA and induced its m6A methylation modification. Overexpression of WTAP accelerated the malignant progression of EC cells and restrained ferroptosis. Interestingly, overexpression of SF3B1 completely abolished the tumor suppressive effect induced by WTAP knockdown. WTAP stimulated tumor growth in vivo and suppressed ferroptosis by stabilizing SF3B1 expression. In conclusion, WTAP effectively suppressed ferroptosis in EC cells by modulating SF3B1 via m6A methylation, thereby aggravating EC.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder posing major global health challenges due to its complex pathophysiology and increasing prevalence among the elderly. In the present work, the molecular hybridization technique was utilized to design and synthesize nicotinic hydrazide-1,3,5-triazine hybrids. Accordingly, this study aimed to design, perform in silico screening, synthesize, and evaluate the in vitro and in vivo anti-AD potential of the proposed compounds. Docking studies revealed that the compounds displayed key interactions with catalytic site and peripheral anionic site residues. Based on binding affinity, ten compounds were synthesized and characterized using different spectroscopic techniques. In vitro AChE and BChE inhibitory assays revealed that the compound 4A36 showed the highest inhibitory ability with log IC₅₀ values of 5.97 μM against AChE and 4.57 μM against BChE. In addition, cytotoxicity screening revealed that 4A36 was non-toxic in SH-SY5Y neuroblastoma cells in the concentration range of 15.625−250 µg/mL. Acute oral toxicity evaluation of the compound revealed no adverse effects up to 175 mg/kg b.w. Further, in vivo studies using the scopolamine-induced model further validated the therapeutic promise of the compound. At a dose of 30 mg/kg b.w., the compound demonstrated significant improvements in learning and memory, reduced MDA levels with concurrent elevation of antioxidant enzymes SOD and Catalase, and reduced AChE activity in hippocampal tissue. Histopathological observations revealed that treatment groups, especially at higher dose (30 mg/kg b.w.), preserved the granular layer of the dentate gyrus and improved neuronal integrity compared to the disease control. These findings indicate that 4A36 at a dose of 30 mg/kg b.w. may be considered as a promising lead compound in AD.

Chronic kidney injury is a cosmopolitan concern of health as it is related to high morbidity and mortality. The current study was a preclinical investigation that used a rat model to study the renal protective effect of sodium molybdate (SM) against folic acid (FA)-induced nephropathy. Chronic kidney disease (CKD) was induced in rats by a single intraperitoneal (i.p.) injection of 250 mg/kg FA. SM orally administered at doses of 0.1 and 0.2 g/kg/day for 35 days. SM attenuated FA-induced chronic kidney injury that demonstrated by a significant decrease in urine total proteins/24 h, serum creatinine, urea concentrations, and LDH activity, and renal MDA concentration and elevation in renal TAC and GSH content. Furthermore, renal TNF-α, NF-κB, caspase-3, α-SMA, and hydroxyproline contents significantly reduced, meanwhile renal Bcl2 significantly increased. FA-induced histopathological alterations were mitigated. SM's renoprotective effect against FA-induced renal injury might be attributed to its free radical scavenger, anti-inflammatory, antiapoptotic, and/or antifibrotic mechanisms.

We investigated first time in the literature the effects of tartrazine, a common industrial dye, and quercetin, a possible protective, on the kidneys. The rats were randomly assigned to the control, tartrazine, quercetin, and tartrazine + quercetin groups, with each group consisting of eight Wistar albino rats. The trials lasted for 1 month, after which kidney tissues and blood samples were collected. In the tartrazine group, increases were observed in malondialdehyde (MDA), superoxide dismutase (SOD), total oxidant status (TOS), oxidative stress index (OSI), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), glomerular diameter and damage, histopathological damage score, glomerular and tubular caspase-3 immunoreactivity H-score, as well as serum urea, uric acid, and creatinine levels in the kidney tissue. Additionally, kidney tissue histopathology and apoptotic deteriorated in the same group. The deteriorated biochemical and histopathological parameters improved with quercetin administration. Tartrazine led to nephrotoxicity in rats, as indicated by kidney tissue oxidant capacity, inflammation, apoptosis, increased kidney function tests, and deterioration in histopathology. Quercetin exhibited strong antioxidant, antiapoptotic, and anti-inflammation activity and can be used as a protective agent against tartrazine-induced nephrotoxicity.

Neurodegenerative disorders are characterized by progressive neuronal dysfunction, cholinergic impairment, and disruption of cellular homeostasis. Ionic balance and metabolic stability are increasingly recognized as critical contributors to neuronal resilience under injurious conditions. The present study aimed to evaluate the potential protective effects of selected sodium (Na⁺) and potassium (K⁺) salts in differentiated SH-SY5Y neuronal cells subjected to hydrogen peroxide (H₂O₂; 100 µM), a widely used model of neuronal injury. Following H₂O₂ exposure, cells were treated with non-toxic concentrations of the following salts: Sodium citrate tribasic dihydrate (Na₃C₆H₅O₇·2H₂O), Sodium hydrogen carbonate (NaHCO₃), Disodium hydrogen phosphate (Na₂HPO₄), Potassium sodium tartrate tetrahydrate (KNaC₄H₄O₆·4H₂O). Salt treatments ameliorated the decline in cell viability and partially reversed changes in total antioxidant status (TAS), total oxidant status (TOS), and acetylcholinesterase (AChE) activity induced by H₂O₂. To further explore potential mechanistic interactions, molecular docking and molecular dynamics (MD) simulations were conducted on human AChE. The salts were found to interact primarily with peripheral residues surrounding the active-site gorge, suggesting a possible allosteric influence rather than direct engagement with the catalytic triad. Among the tested compounds, disodium hydrogen phosphate (Na₂HPO₄) exhibited the most stable binding profile over 100 ns MD simulations. Overall, these findings provide preliminary evidence that selected Na⁺- and K⁺-based salts may attenuate neuronal injury and support cellular function under stress conditions. Given their established safety profiles and accessibility, these compounds warrant further investigation as potential adjunctive agents for mitigating processes relevant to neurodegeneration.

Skeletal muscle is highly susceptible to hypobaric hypoxia linked muscle protein loss due to disturbed proteostasis and redox homeostasis. Carnosine, an endogenous dipeptide possesses antioxidant, anti-inflammatory, anti-glycation and pH buffering properties. The present study investigated the beneficial efficacy of carnosine in amelioration of muscle protein loss during chronic hypobaric hypoxia exposure in rats. Further, probable molecular mechanism for it's protective efficacy was also established via molecular docking study along with support of in-vivo study. Male Sprague-Dawley rats were divided into three groups: Control (unexposed rats), HH (07d hypobaric hypoxia exposed rats), HH + CAR (Carnosine supplement rats with 07d hypobaric hypoxia exposure 50 mg/kg supplemented). Carnosine administration downregulated myostatin expression levels while IGF-1 level was upregulated and this was accompanied with an increase in total protein content. The expression levels of FOXO, MAFbx, MuRF1, markers of muscle atrophy were also declined on carnosine supplementation. Further, myogenesis markers, myoG, and mTOR were found increased in carnosine supplemented rats. Along with these activities, carnosine also managed excessive reactive oxygen species (ROS) production, protein oxidation and damage. Ergo, molecular docking study supported the fact that carnosine has the ability to bind with IGFBP and myostatin, a negative regulator of muscle atrophy. Carnosine attenuates muscle protein loss via enhancing myogenesis, managing redox, and protein homeostasis. All these activities together enhances protein concentration and ameliorates hypobaric hypoxia induced muscle protein loss. Therefore, carnosine supplementation can be an effective therapeutic strategy in combating skeletal muscle protein loss linked with high altitude induced hypobaric hypoxia.