Journal of Biochemical and Molecular Toxicology最新文献

Diabetic neuropathy (DN), one of the most common microvascular complications of diabetes, is a condition involving complex pathophysiological mechanisms such as oxidative stress, inflammation, apoptosis, primarily resulting from chronic hyperglycemia. This study aimed to evaluate potential effects of Saxagliptin (Sax), a DPP-4 enzyme inhibitor, on in vitro and in vivo models of DN. Dorsal root ganglion neurons isolated from 1 to 2-day-old Wistar Albino rats were exposed to a high-glucose environment for 24 h to induce in vitro DN model. In this model, effects of Sax on cell viability and associated intracellular signaling pathways were investigated. In the in vivo model, streptozotocin-induced diabetic mice were divided into four groups: control, DN, DN+Sax-2, DN+Sax-10 (n = 10). For 15 days, DN group received 0.9% isotonic sodium chloride, while DN+Sax-2 and DN+Sax-10 groups were administered Sax orally via gavage at doses of 2 and 10 mg/kg, respectively, with concurrent nociceptive behavioral testing. At end of experiment, animals were decapitated, biochemical and histological analyses were performed on collected blood and pancreatic tissues. Sax, significantly increased cell viability via phosphoinositide 3-kinase pathway (p < 0.05). Compared to DN group, Sax-treated groups showed improvements in mechanical allodynia and thermal hyperalgesia; increased levels of superoxide dismutase, catalase, glutathione, total antioxidant status, interleukin-10; decreased levels of malondialdehyde, interleukin-1β, interleukin-6 (p < 0.05). Additionally, caspase-3 expression in pancreatic tissue was suppressed, and histopathological damage was markedly reduced (p < 0.0001). These findings suggest that Sax suppresses inflammation, inhibits oxidative damage and apoptosis, thereby reducing hyperalgesia, and may have therapeutic effects against DN.

This study explores the design, synthesis, characterization, and pharmacological evaluation of chalcone-derived C-Mannich base compounds, which exhibit significant pharmacological potential in medicinal chemistry. A series of compounds 6(a–j) was designed and investigated for the physicochemical properties, drug-likeness, toxicity profile, and molecular interactions through in silico methods. Computational tools, including SwissADME online server and ProTox II web tool were utilized to assess their pharmacokinetics, druggability, and toxicity, while molecular docking investigations were performed with the ADT tools, AutoDock 4.2 software to ascertain the binding interactions of query molecules with critical protein targets, such as ESR1, ERBB2, PIK3CA, PIK3R1, EGFR, SRC, STAT3 and IGF1R. The selected compounds 6(a, c, e, i, and j) were synthesized via a modified Mannich reaction utilizing dehydrozingerone (DHZ) along with 3-hydroxy benzaldehyde and various secondary amines. The synthesized derivatives were characterized using the spectral and CHN elemental analysis. The in vitro antiproliferative potential of selected derivatives 6(a, c, e, i, and j) was evaluated against the MCF-7 (breast adenocarcinoma), A549 (Small cell lung carcinoma), HeLa (Cervical cancer), HeP2 (Colon cancer), HepG2 (Liver carcinoma) and NHDF (Normal Human Dermal Fibroplasts) the MTT assay using doxorubicin as standard. The study demonstrates that DHZ-derived C-Mannich base compounds possess significant anticancer efficacy, positioning them as promising candidates for subsequent therapeutic development.

A new series of thiazolyl–pyrimidine hybrids (5a–g, 7, and 10a–e) was synthesized via the condensation of bromoacetyl dihydropyrimidinone with various thiosemicarbazones. The identity of the synthesized compounds was established using elemental analysis along with IR, ¹H NMR, ¹³C NMR, and mass spectrometry. Their antiproliferative potential was subsequently assessed against MCF-7 (breast) and HepG-2 (liver) cancer cell lines, with doxorubicin employed as the standard reference. Several derivatives showed potent cytotoxicity; notably, 5g, 5b, 5f, and 10e exhibited IC₅₀ values of 3–5 μM, comparable to doxorubicin. Structure–activity relationship (SAR) studies indicated that electron-donating para-substituents and heteroaryl/coumarinyl moieties enhanced activity, while bulky fused rings and halogen groups reduced it. Given the persistent burden of breast and liver cancers, and the critical role of epidermal growth factor receptor (EGFR) in tumor progression, selected hybrids (5a, 5b, 5f, 5g, 10d, and 10e) were further investigated in silico. Molecular docking revealed strong binding to the cancer receptor, supporting their potential as anticancer leads. ADMET predictions suggested favorable pharmacokinetic and safety profiles. Collectively, these findings identify thiazolyl–pyrimidine hybrids as promising scaffolds and apoptosis inducers for future breast and liver cancer therapy.

Distal-less homeobox genes (DLX) comprise a family of cell-type-specific transcription factors crucial for the differentiation of various cell types. Despite reports of their dysregulated expression in cancer, the functional roles of DLX6 in carcinogenesis remain poorly understood. This study investigated the role and underlying mechanisms of DLX6 in Lung adenocarcinoma (LUAD). Analysis of data from The Cancer Genome Atlas (TCGA) and Tissue Microarray (TMA) demonstrated that elevated DLX6 expression was associated with poor prognosis in LUAD patients. Both in vitro and in vivo experiments confirmed that DLX6 promoted LUAD growth. Mechanistically, DLX6 transcriptionally inhibited cyclin-dependent kinase inhibitor 1B (CDKN1B), leading to activation of the p27^Kip1/CDK2-CyclinE signaling axis and promoting the G1-to-S phase transition in the cell cycle. Functional rescue experiments confirmed that CDKN1B knockdown attenuated DLX6-mediated tumor growth. Furthermore, DLX6 was identified as a novel downstream target of miR-145, a tumor-suppressive microRNA. MiR-145 directly bound to DLX6, reducing its mRNA and protein levels and effectively counteracting DLX6's oncogenic effects. Collectively, these findings uncovered a previously uncharacterized role of DLX6 in LUAD development and proposed the miR-145/DLX6/p27^Kip1/CDK2-CyclinE signal axis as a potential therapeutic target for LUAD management.

To explore the key risk genes involved in developing NAFLD into HCC. Four datasets-related NAFLD progression (NAFLD, NASH, Hepatofibrosis, Cirrhotic, and Tumor) were obtained from the GEO database. GO and KEGG analyses were performed to identify the biological functions, pathways, and cellular processes associated with the genes. GSVA analyses were performed to assess the variation in pathway activity across different samples based on gene expression profiles. We performed ordinal logistic regression analysis, collinearity analysis, importance analysis of influence factors (LASSO, XGBoost, and RandomForest), and Venn analysis to identify the hub genes within disease progression. The SHAP model and K-M survival analysis screened out risk genes-related development of NAFLD into HCC. The mRNAsi_score analysis evaluates the correlation of NENF expression and tumor stemness. A vector expressing NENF transfection was used to increase its expression. CCK8, cell spheroid formation assay, colony formation, transwell, western blot, and RT-PCR assays were used to detect cell viability, tumor stemness, and gene and protein expression. NENF high expression was associated with NAFLD progression NENF was identified as the risk gene and positively associated with mRNAsi_score. Its expressions gradually increased with the progress of NAFLD to HCC. NENF promoted cells' lipid accumulation. NENF enhanced the induction of L02 cells into stem cells and augmented the tumor-like stem cell properties of L02 cells. NENF, as an important biomarker, promoted the development of NAFLD devolved to HCC by enhancing the tumor-like stem cell properties of normal cells.

Polybrominated diphenyl ethers (PBDEs) have emerged as a major environmental pollutant and are widely employed in different industrial and consumer products. The 4-bromodipehnyl ether (BDE-3) is the most common and fundamental mono-BDE which is being used as a flame retardant in different products. The present investigation was conducted to evaluate the neurotoxicological effects of BDE-3 via. DNA damage, oxidative stress biomarkers, apoptotic, histopathological and ATR-FTIR analysis in brain of adult zebrafish. The 96 h LC₅₀ was determined for zebrafish adult and further zebrafish were exposed to sublethal concentrations that is 0.48 mg/L (¼ LC₅₀) and 0.97 mg/L (½ LC₅₀) of BDE-3 for 96 h. The DNA damage in terms of tail length (TL), tail intensity (TI), tail moment (TM) and olive tail moment (OTM) was found to be significantly elevated in a concentration and duration dependant manner. A significantly increased MDA content, GST and AChE activity was reported in the brain tissue after BDE-3 exposure whereas a depleted SOD activity was observed. The histological analysis revealed the different types of alterations in brain tissue. The viable cell frequency was found to be decreased whereas apoptotic and necrotic cell frequency were found to be significantly increased in BDE-3 exposed groups. The structural alterations in different biomolecules were assessed via ATR-FTIR in brain tissue. The results of the present study inflict the accelerated lipid peroxidation, altered enzymatic activity, enhanced DNA damage, disrupted histology, cell viability and biomolecular alterations in brain of zebrafish even at sub-lethal concentrations, indicating the neurotoxic nature of BDE-3.

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.