Journal of Biochemical and Molecular Toxicology最新文献

Acetaminophen (APAP)-induced liver injury (AILI) remains a critical clinical challenge with limited therapeutic options. This research elucidates the mechanisms through which the natural flavonoid isobavachin (ISO) confers protection against APAP-induced liver injury. In vivo experiments demonstrated that ISO treatment significantly attenuated histopathological parameters, oxidative stress and inflammation, as indicated by serum ALT/AST, MDA, SOD/GSH, TNF-α/IL-1β levels. Mechanistically, ISO inhibited CYP2E1 expression and promoted NRF2 activation. Furthermore, integrated network pharmacology, transcriptomics, and molecular docking simulations revealed the PI3K/AKT signaling pathway as a potential targets of ISO, demonstrating high-affinity confirmed between ISO and PI3K (-8.6 kcal/mol) or AKT (-6.4 kcal/mol) respectively. western blotting assay confirmed that ISO activated PI3K/AKT signaling and upregulated downstream anti-apoptotic- protein BCL2. These findings collectively suggest that ISO alleviates AILI through multi-mechanisms: inhibiting CYP2E1-mediated APAP bioactivation, modulating of the NRF2/PI3K/AKT signaling, ISO attenuates oxidative damage, suppresses inflammatory activation, and inhibits apoptosis. The results suggest that ISO represents a potential therapeutic agent for managing APAP-induced hepatotoxicity.

Mercuric chloride (HgCl₂) is an environmental pollutant with neurotoxicity. The blood–brain barrier (BBB) serves as a critical protective interface, shielding the brain from exposure to heavy metals and maintaining neurological homeostasis. Ferroptosis, a programmed cell death initiated by iron-dependent lipid peroxidation, was recently reported to be associated with various neurological disorders. Nevertheless, the relationship between HgCl₂-induced neurotoxicity, BBB dysfunction, and ferroptosis remains unclear. This study investigated the effects of embryonic exposure to HgCl₂ (35, 50, and 65 μg/kg) on brain tissue and the underlying mechanisms. These results demonstrated that HgCl₂ exposure induced brain injury by compromising BBB integrity. Intriguingly, we identified ferroptosis as a central mechanism contributing to this damage, supported by the observation of mitochondrial abnormalities. Moreover, HgCl₂ exposure induced oxidative stress, characterized by a decrease in antioxidant capacity and an increase in lipid peroxidation. Further studies revealed increased total iron level and dysregulation of iron metabolism-related proteins. It can be concluded that HgCl₂ exposure disrupted BBB integrity, promoted iron overload-mediated oxidative stress, initiated ferroptosis, and ultimately exacerbated brain injury in embryos. These findings highlight the critical role of ferroptosis in HgCl₂-induced neurotoxicity and offer novel mechanistic insights that may inform future strategies for preventing or treating heavy metal-related neurological disorders.

The CD40 pathway has become one of the most promising immunologic axes in oncology. As a central intermediary between innate and adaptive immunity, CD40 activation engages dendritic cells (DCs), amplifies antigen presentation, and stimulates potent cytotoxic T-cell (CTL) activity. Therapeutic CD40 agonists have been studied in a broad range of cancers over the past decade to reconfigure the tumor's immune microenvironment (TIME) and overcome immune refractoriness to standard immunotherapies. Clinical development has been most significant in pancreatic cancer, an exemplar cold tumor resistant to immune checkpoint blockade. Here, CD40 agonists have demonstrated efficacy to repolarize immune-desert phenotypes to a more inflamed and treatable phenotype, particularly in combination with chemotherapy or programmed cell death protein 1 (PD-1) inhibitors. Clinical evidence has also been gained in melanoma and non-small cell lung cancer, where CD40-targeted strategies are examined in combination with current checkpoint inhibitors to accelerate T-cell priming. In hematologic malignancies and B-cell lymphomas, in particular, CD40 agonists exploit the natural activity of the B-cell activating receptor, providing a strong biological rationale for their clinical efficacy. Exploratory studies have gone on to extend into bladder, prostate, mesothelioma, and head and neck cancers, demonstrating the broad translational relevance of this pathway. Hopes fostered by preliminary signs of activity remain to be qualified in light of the difficulties. Systemic immune activation-associated toxicities, such as cytokine release syndrome, have justified cautious dosing schedules and exploration of local routes of drug administration. Additionally, heterogeneity between tumors in response underscores an urgent need for predictive biomarkers to enable the selection of patients and to tailor optimal clinical effects. In the future, drug development will be reliant on prudent combinations and novel delivery methods. Conjugation to vaccines, bispecific antibodies, radiotherapy, and oncolytic viruses is an attractive route to achieve their fullest immunostimulatory capabilities. Through a flexible approach to reeducate the immune microenvironment within tumors, CD40 agonist therapy can extend the use of immunotherapy to traditionally immune-refractory malignancies. This review intends to present a cross-cancer approach to CD40 agonist therapy, compiling existing clinical evidence while highlighting common issues and prospects for harnessing this pathway across various tumor settings.

The aim of this study was to investigate the effects of oxyresveratrol (OXY) on CIS-induced nephrotoxicity through endoplasmic reticulum stress (ERS)-mediated NLRP3 inflammasome activity. A total of 36 rats were randomly divided into six groups (n = 6). Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of CIS (10 mg/kg) on day 1 in the experimental groups. OXY was administered orally at doses of 5, 10, and 20 mg/kg for three consecutive days in the treatment groups. Kidney function tests, oxidative stress markers, and molecular parameters were evaluated. Molecular analysis revealed a significant upregulation of mRNA expression of ER stress-mediated markers associated with increased NLRP3 inflammasome activity in renal tissue following CIS induced toxicity. Furthermore, oxidative stress was determined with significantly decreased SOD activity and GSH levels and increased MDA levels with cisplatin administration. It has been shown that OXY administration at increasing doses causes a decrease in serum urea and creatinine levels and changes in oxidative stress parameters, and also it was shown to cause a decrease in molecular parameters of ER stress. New findings have revealed that ER stress-mediated NLRP3 activation is induced in the kidneys due to cisplatin toxicity and that OXY, a potent antioxidant, may be effective through the pathways that are specified in cisplatin nephrotoxicity.

Lung adenocarcinoma (LUAD) is the predominant subtype of non-small cell lung cancer (NSCLC) with high mortality and treatment resistance. While the natural compound daucosterol (DS) shows anti-tumor potential, its role and mechanism in LUAD are unclear. Network pharmacology identified potential DS targets in LUAD, with binding affinity confirmed by molecular docking and dynamics simulations. In vitro, cell counting kit 8 (CCK-8), flow cytometry, and transwell assays were used to assess LUAD cell proliferation, apoptosis, migration, and invasion. Western blot and glycometabolism assays were employed to measure protein expression and glycolysis (glucose consumption and lactate production). In vivo anti-tumor efficacy of DS was validated in a xenograft mouse model using immunohistochemistry (IHC) and western blot. DS dose-dependently inhibited LUAD cell viability, migration, and invasion while inducing apoptosis. Network pharmacology identified Erb-B2 receptor tyrosine kinase 2 (ERBB2) as a key target for DS, supported by strong DS-ERBB2 binding affinity and complex stability. ERBB2 overexpression reversed DS-induced suppression of malignant phenotypes. Mechanistically, DS reduced ERBB2 expression to inhibit phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling, down-regulating hexokinase 2 (HK2) and lactate dehydrogenase (LDHA), and reducing glucose consumption and lactate production. In vivo, DS inhibited xenograft tumor growth and decreased Ki67, ERBB2, p-PI3K/PI3K, p-AKT/AKT, HK2, and LDHA expression in tumor tissues, which were reversible upon ERBB2 overexpression. DS exerts anti-tumor effects in LUAD by directly regulating ERBB2 expression, inhibiting PI3K/AKT signaling, and disrupting glycolysis. These findings support DS as a promising therapeutic candidate for LUAD.

Drug-induced liver injury (DILI) represents a critical pharmacotherapeutic challenge requiring novel interventions. The hepatoprotective mechanisms of Gypenoside XLIX (GYP XLIX) against liver injury remain underexplored. This study establishes GYP XLIX as a hepatoprotective agent against diclofenac (DF)-induced liver injury through integrated experimental approaches. Male Wistar rats were used in this investigation and grouped randomly into four groups: the control group, the DF group (50 mg/kg), the GYP XLIX group (30 mg/kg), the DF + XLIX group, and the DF + silymarin group for 7 days. Human liver cell line L02 was used for further study. The analytical methods used included network pharmacology analysis, molecular docking, H&E staining, qPCR, enzyme activity assay, and Western blot. GYP XLIX significantly ameliorated DF-induced hepatic damage, as evidenced by reduced serum ALT, AST, and ALP levels, attenuated histopathological abnormalities, enhanced antioxidant capacity (elevated SOD and GSH, decreased MDA), and suppressed pro-inflammatory cytokine release. Mechanistically, GYP XLIX targeted the AKT/NLRP3 pathway, promoting AKT phosphorylation and inhibiting NLRP3 inflammasome activation, confirming its role in alleviating hepatotoxicity through antioxidative and anti-inflammatory mechanisms. In L02 cells, GYP XLIX exerts a protective effect against DF-induced liver injury through the AKT/NLRP3 axis, and this mechanism has been further confirmed. This work supports GYP XLIX as a promising multi-target therapeutic candidate for chemical hepatotoxicity, providing new insights for clinical prevention and treatment of DILI.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. Although advanced progress has been made in recent years, the prognosis remains unsatisfactory, and new biomarkers are urgently needed for improved diagnosis and treatment. In this work, the Gene Expression Omnibus (GEO) database was screened to identify the novel circular RNA circMCM7, and its expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Actinomycin D treatment and RNase R assay were performed to examine the stability of circMCM7. CCK-8 assay and 5-ethynyl-2’-deoxyuridine (EdU) staining were used to detect the proliferation of HCC cells following sh-circMCM7 transfection. Annexin V-fluorescein isothiocyanate (FITC) staining was performed to determine the apoptosis rate. Transwell assay was employed to evaluate the invasion rate. Finally, the anti-tumor effect was verified through in vivo experiments, with proliferation and apoptosis assessed by immunohistochemistry (IHC) staining for Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively. Our results demonstrated that circMCM7 was highly expressed in HCC tumor tissues, and elevated circMCM7 expression was correlated with poor clinical outcomes in HCC patients. The closed-loop structure of circMCM7 conferred greater stability compared to linear GAPDH mRNA. Knockdown of circMCM7 significantly suppressed HCC cell proliferation and invasion while promoting apoptosis. Minichromosome maintenance complex component 7 (MCM7), a DNA replication marker, was also upregulated in HCC. Notably, overexpression of MCM7 partially rescued the inhibitory effects on proliferation and invasion, as well as the pro-apoptotic effects induced by circMCM7 knockdown. This study elucidates the oncogenic function of circMCM7 in hepatocellular carcinoma and confirms its regulatory roles in HCC cell proliferation, invasion, and apoptosis through modulation of MCM7 expression, suggesting circMCM7 as a potential therapeutic target for HCC treatment.

Atherosclerosis (AS), driven by endothelial dysfunction, is exacerbated by environmental cadmium (Cd²⁺). This study elucidates the molecular mechanism by which Cd²⁺ promotes AS, focusing on the role of growth arrest and DNA damage-inducible 45 gamma (GADD45G). Clinical correlation between plaque Cd²⁺ levels and plaque burden was assessed in human samples. In vivo studies utilized apolipoprotein E-deficient (ApoE^−⁄−) mice fed a high-fat diet (HFD) with varying cadmium chloride (CdCl₂) doses. In vitro analyses employed human umbilical vein endothelial cells (HUVECs) treated with CdCl₂, combined with siRNA knockdown, MEKK4 overexpression plasmids, and pharmacological agonists. GADD45G^−/− zebrafish were generated and exposed to HFD and CdCl₂. Functional assays included cell viability, apoptosis, migration, tube formation, inflammation, lipid deposition (Oil Red O), and molecular analyses. Cd²⁺ concentration positively correlated with plaque area in humans and dose-dependently increased plaque burden in ApoE^−⁄− mice. CdCl₂ upregulated GADD45G expression and activated the MEKK4–p38MAPK pathway in HUVECs. GADD45G knockdown attenuated CdCl₂-induced endothelial apoptosis, impaired migration and angiogenesis, and reduced inflammation and MAPK pathway activation. These protective effects were reversed by the p38MAPK agonist anisomycin or by MEKK4 overexpression. In zebrafish, CdCl₂ exacerbated HFD-induced vascular lipid deposition and inflammatory gene expression. GADD45G knockout mitigated these effects induced by HFD, which were reversed by CdCl₂ co-exposure. Cd²⁺ exacerbates AS by inducing endothelial dysfunction via GADD45G-mediated activation of the MEKK4–p38MAPK signaling axis. Thus, the GADD45G–MEKK4–p38MAPK axis represents a novel therapeutic target for mitigating Cd²⁺-associated cardiovascular risk.

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) characterized by damage and destruction of neurons. Although its precise cause remains unclear, growing evidence points to oxidative stress as a key contributor to MS onset and progression. Excessive production of reactive nitrogen species (RNS) and reactive oxygen species (ROS) can impair cellular components, accelerating demyelination and axonal loss. This process involves both the central and peripheral nervous systems, with various cells such as microglia, astrocytes, and T cells playing significant roles in mediating the damage. In contrast, neurosteroids—steroids synthesized within the CNS—have gained attention for their neuroprotective and anti-inflammatory properties. These compounds regulate neural excitability, synaptic function, and immune responses. Disruptions in the production or function of neurosteroids may contribute to the pathogenesis of neurological disorders, including MS. Although both oxidative stress and neurosteroid dysregulation have been individually implicated in MS pathology, their interplay remains poorly understood. Investigating how these two pathways interact could provide deeper insights into MS mechanisms and highlight novel therapeutic avenues aimed at restoring neurosteroid balance to reduce disease-related damage.