Journal of Biochemical and Molecular Toxicology最新文献

Drug-induced nephrotoxicity poses a significant clinical challenge that limits the therapeutic application of various critical medications, such as antibiotics, chemotherapeutic agents, and nonsteroidal anti-inflammatory drugs. It accounts for 19%–26% of Acute Kidney Injury cases and may advance to chronic kidney disease if not promptly addressed. The kidneys are particularly vulnerable to injury caused by xenobiotics due to their role in drug metabolism and excretion. The mechanisms of nephrotoxicity include oxidative stress, mitochondrial dysfunction, apoptosis, inflammation, crystal nephropathy, and vascular injury, all of which impair renal structure and function. Contemporary therapeutic approaches are primarily confined to supportive care and depend on traditional renal biomarkers, including serum creatinine and blood urea nitrogen, which exhibit insufficient sensitivity for early detection. Thus, there is an increasing demand for efficacious nephroprotective measures and dependable diagnostic indicators. Phytochemicals have garnered considerable interest due to their renoprotective capabilities, which are attributed to their antioxidant, anti-inflammatory, and anti-apoptotic properties. Compounds like quercetin, silymarin, resveratrol, and curcumin have shown encouraging results in experimental models of nephrotoxicity. Furthermore, innovative biomarkers such as NGAL, KIM-1, IL-18, and cystatin C enhance diagnostic accuracy for early renal injury. This narrative review examines nephroprotective phytochemicals, novel biomarkers, and nanotechnology-based delivery methods to improve therapeutic efficacy.

As a pollutant, Fine particulate matter (PM2.5) directly deposits in alveoli to induce lung inflammation, yet its pathogenic mechanism remains unclear. PM2.5-induced pulmonary inflammation will trigger the activation of Caspase-1 (Casp1). We seek to elucidate the role of pyroptosis in PM2.5-induced lung inflammation by employing Casp1 knock-out (KO) mice and a specific pyroptosis inhibitor (Disulfiram, DSF). We found the typical pathological changes were comparatively alleviated in the Casp1 KO mice. Notably, in Casp1 KO mice, there was a significant downregulation of gasdermin D (GSDMD) and GSDMD-N at the protein levels. The Casp1 KO mice exhibited a decrease in the numbers of pyroptotic neutrophils. After administrating with DSF, we observed the downregulation of GSDMD and GSDMD-N, along with a decreased number of pyroptotic neutrophils. These findings suggest that neutrophils contribute to PM2.5-induced lung inflammation depending on Caspase-1/pyroptosis signaling pathway. These results demonstrate that PM2.5 triggers lung inflammation via the neutrophil Caspase-1/pyroptosis pathway, revealing a novel mechanism of PM2.5-mediated inflammation and suggesting DSF as a potential therapeutic agent for PM2.5-induced pneumonia.

The present study has been conducted to investigate the inhibitory effects and antioxidant capacities of two pyrimidine derivatives, 4,6-Dichloro-2-(methylthio) pyrimidine-5-carbonyl chloride (p1) and 4,6-Dichloro-2-(methylthio) pyrimidine-5-carboxyamide (p2), against the glutathione S-transferase (GST) enzyme for exploring their potential as therapeutic agents in conditions related to oxidative stress and drug resistance mediated through GST. The data are compared with that of ethacrynic acid (EA), a well-documented GST inhibitor. The IC₅₀ values for molecules p1, p2, and EA were computed to be 38.5 nM, 46.2 nM, and 5.82 nM, respectively. During the second part of the inhibition study, Ki values calculated from IC₅₀ plots became 57.61 nM for molecule p1, 43.75 nM for molecule p2, and 4.43 nM for EA. Molecules p1 and p2 depicted non-competitive mechanisms, while EA followed competitive inhibition. Moreover, antioxidant capacities of molecules were tested by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay method. Using the DPPH method scavenging activity in both p1 and p2 was comparable to that of the reference standard, ascorbic acid (AA). Other than this, biological activities of GST enzyme complexes were further validated using molecular docking, molecular dynamics, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses. These complementary studies gave further insight into binding affinities, dynamic stability, and pharmacokinetic properties, reinforcing the impact of p1 and p2 complexation on GST structural and functional characteristics.

Exosomes derived from hepatitis B virus (HBV)-infected hepatocytes (HBV-Exo) promote liver fibrosis. Emerging evidence implicates METTL3 and P2RX7 as critical drivers of liver fibrosis. However, the molecular mechanisms by which HBV-Exo drive hepatic fibrosis remain poorly understood. This study investigated the mechanistic involvement of METTL3 and P2RX7 in this fibrotic process. Exosomes from pHBV1.3-transfected, HBV-replicating THLE-2 hepatocytes (HBV-THLE-2-Exo) were isolated and used to incubate LX-2 hepatic stellate cells (HSCs). Impacts on LX-2 cells were evaluated by detecting cell viability, proliferation, invasion, migration, and fibrosis marker expression. MeRIP, RIP, RNA pull-down, and mRNA stability assays were used to assess the METTL3/P2RX7 mRNA interaction. A CCl₄-induced mouse model of liver fibrosis was generated to elucidate the role in vivo. HBV-THLE-2-Exo elevated METTL3 levels in recipient LX-2 HSCs. HBV-THLE-2-Exo enhanced the proliferation, invasion, migration, and fibrosis marker expression in LX-2 HSCs in vitro. Moreover, METTL3-depleted exosomes (si-METTL3-HBV-THLE-2-Exo) attenuated LX-2 cell proliferation, invasion, migration, and expression of fibrotic markers compared to HBV-THLE-2-Exo. Mechanistically, METTL3 stabilized P2RX7 in an IGF2BP1-m6A-dependent manner. P2RX7 overexpression reversed si-METTL3-HBV-THLE-2-Exo-mediated alterations in LX-2 cell proliferation, invasion, migration, and fibrosis marker expression in vitro. Additionally, HBV-THLE-2-Exo exacerbated liver fibrosis in CCl₄-induced mice. Our findings unveil a novel METTL3/P2RX7 axis by which HBV-Exo drive HSC activation and liver fibrosis. These findings elucidate a novel exosome-mediated regulatory axis in liver fibrosis, suggesting the therapeutic potential of targeting METTL3/P2RX7 axis.

Doxorubicin (DOX) is a widely used anticancer agent, but its clinical utility is limited by significant cardiotoxicity. Parthenolide (PTL), a sesquiterpene lactone, has garnered significant attention due to its broad pharmacological potential. This study aimed to investigate the potential cardioprotective effects of PTL against DOX-induced cardiotoxicity in rats, focusing on its impact on Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and ferroptosis. Male Sprague-Dawley rats were divided into a control group, a DOX group, and DOX + PTL (10 mg/kg, 25 mg/kg, or 50 mg/kg) groups. DOX (4 mg/kg) was administered via intraperitoneal injection once weekly for 4 weeks. Cardiac function was assessed using echocardiography, and histopathological changes were examined through hematoxylin and eosin and Masson trichrome staining. Oxidative stress markers, inflammatory cytokines, and ferroptosis-related proteins—including acyl-CoA synthetase long-chain family member 4 (ACSL4), NADPH oxidase 4 (Nox4), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11)—were measured by ELISA and Western blotting. Additionally, Nrf2 and its downstream targets were analyzed to elucidate the molecular mechanisms underlying PTL's effects. PTL treatment significantly improved DOX-induced cardiac dysfunction, as evidenced by improved echocardiographic parameters and reduced histopathological damage. PTL also markedly decreased oxidative stress and inflammatory cytokines, while upregulating Nrf2 signaling and downregulating ferroptosis-related protein expression. These results suggested that the cardioprotective effects of PTL might be associated with the activation of Nrf2 signaling and suppression of ferroptosis. PTL demonstrated significant cardioprotective effects against DOX-induced cardiotoxicity, likely through Nrf2 activation and ferroptosis inhibition. PTL is a promising therapeutic agent for mitigating DOX-induced cardiac dysfunction.

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.