Journal of Biochemical and Molecular Toxicology最新文献

{"title":"Nrf2–Keap1 Axis Modulation by Phytofabricated Metal Oxide Nanoparticles in Mesenchymal Stem Cell Lineage Bias","authors":"Muhammad Irfan,&nbsp;Muhammad Taha,&nbsp;Syed Muhammad Faizan Asghar,&nbsp;Muhammad Raza","doi":"10.1002/jbt.71091","DOIUrl":"10.1002/jbt.71091","url":null,"abstract":"<p>Mesenchymal stem cells (MSCs) hold considerable therapeutic promise in regenerative medicine, yet precise control over lineage fate remains critical for reproducible clinical outcomes. This review examines the Nrf2–Keap1 (nuclear factor erythroid 2–related factor 2–Kelch-like ECH-associated protein 1) signaling axis as a redox-sensitive rheostat governing the balance between osteogenic and adipogenic differentiation. Physiological reactive oxygen species (ROS) support osteogenesis in a dose- and context-dependent manner, whereas sustained oxidative stress drives cellular senescence and adipogenic bias; emerging evidence also indicates that Nrf2 hyperactivation can itself impair osteogenic differentiation, pointing to an optimal activation window rather than a simple “more is better” relationship. Conventional plant-derived Nrf2 activators are limited by poor bioavailability and metabolic stability. Phytofabricated metal oxide nanoparticles (MONPs), synthesized using plant extracts as capping and stabilizing agents, offer a biocompatible, “green” delivery alternative. We propose that these hybrid systems may act through a dual-stimulus mechanism — phytochemical-mediated electrophilic modification of Keap1 cysteines alongside metal-oxide-core-derived, sub-cytotoxic ROS consistent with mitohormetic signaling — that together could promote Nrf2 nuclear translocation, ARE-driven antioxidant gene expression, and downstream epigenetic reinforcement of osteogenic commitment. This dual-stimulus framework, however, remains a mechanistic hypothesis: no study to date has directly demonstrated Keap1 modification, Nrf2 activation, and resulting lineage bias by phytofabricated MONPs within MSCs. Preclinical studies support the efficacy of phytofabricated MONPs in bone defect models and suggest potential for restoring function in senescent MSCs, but direct mechanistic validation in MSC systems remains an essential next step before these insights can guide rational nanoplatform design for bone regeneration.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of Genotoxic, Oxidative Stress and Histopathological Effects of Azo Dye Acid Red 119 on Blood and Gill of Freshwater Fish Channa punctata","authors":"Harpal Kaur,&nbsp;Divya Saini,&nbsp;Aditi Khanna,&nbsp;Pooja Chadha","doi":"10.1002/jbt.71092","DOIUrl":"10.1002/jbt.71092","url":null,"abstract":"<p>The unregulated release of azo dyes from textile industry effluents into freshwater systems constitutes a serious environmental and toxicological concern. The current investigation was undertaken to elucidate the acute toxicological impact of Acid Red 119 (AR 119) in the blood and gill of freshwater fish <i>Channa punctata</i>, using a multi-tiered biomarker approach encompassing genotoxic, biochemical, and histopathological endpoints. Experimental exposures involved two sub-lethal concentrations of AR 119−15.90 and 31.81 mg/L-administered over a 96 h period. The results revealed a dose-dependent and statistically significant increase in frequencies of micronucleated cells, nuclear and cellular abnormalities, and DNA damage, evidenced by elevated values of comet assay parameters such as tail length and %tail intensity, tail moment, and olive tail moment. Biochemical analysis demonstrated a significant elevation in MDA content, indicating increased lipid peroxidation, along with alterations in SOD and GST activities in blood and gill tissues. The effects were more pronounced at the higher concentration (31.81 mg/L), especially after 96 h of exposure. Histopathological analysis further showed gill tissue damage, including aneurism, epithelial lifting, vacuolization, and fusion of secondary lamellae. Taken together, these findings demonstrated that AR 119 exerts marked genotoxic and oxidative stress in <i>C. punctata</i>, underscoring the urgent need for stricter effluent regulation and sustainable treatment strategies in textile industries.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13511308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148828413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quinoline and Phthalimide Substituted Silicon Phthalocyanines as Multi-Target Inhibitors of Cholinesterases and Carbonic Anhydrases","authors":"Seda Ünlü,&nbsp;Zeynep Köksal,&nbsp;Kevser Kübra Kırboğa,&nbsp;Fikriye Tuncel Elmalı","doi":"10.1002/jbt.71090","DOIUrl":"10.1002/jbt.71090","url":null,"abstract":"<p>Two novel axially substituted silicon phthalocyanines bearing 5,7-dichloro-8-hydroxy-2-methylquinoline (<b>1a</b>) and N-(hydroxymethyl)phthalimide (<b>2a</b>) moieties were synthesized and characterized by UV-Vis, FT-IR, ¹H NMR, and mass spectrometry techniques. The biological potential of the synthesized compounds was evaluated through in vitro inhibition studies against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase isoenzymes I and II (hCA I and hCA II). IC₅₀ values were determined as 91.28 ± 25.21, 43.31 ± 20.35, 8.50 ± 2.80 and 23.35 ± 12.98 µM, for compound <b>1a</b>, and 2.78 ± 1.05, 4.88 ± 1.50, 0.94 ± 1.06 and 4.15 ± 3.01 µM for compound <b>2a</b> against AChE, BChE, hCA I, and hCA II enzymes respectively. Compound <b>2a</b> exhibited remarkable inhibitory activity. Molecular docking results supported the experimental findings, indicating that compound <b>2a</b> exhibited significantly higher inhibitory potency than compound <b>1a</b>. Structure-activity relationship analysis demonstrated that compound <b>2a</b> exhibits improved enzyme inhibition. The combined experimental and computational findings showed that compound <b>2a</b> is a promising multifunctional enzyme inhibitor. Compound <b>2a</b> exhibited remarkable inhibitory activity across all targets. Molecular docking supported the experimental findings, with compound <b>2a</b> showing more favorable Vinardo binding affinities (−8.11, −3.94, −7.39, and −7.15 kcal/mol against AChE, BChE, hCA I, and hCA II, respectively) than compound <b>1a</b>, primarily through additional hydrogen-bonding interactions provided by its phthalimide groups. The docking protocol was validated by redocking the co-crystallized ligands, which reproduced the crystallographic poses with RMSD values below 2.0 Å for all targets. DFT calculations revealed narrow HOMO-LUMO energy gaps (0.666 eV for <b>1a</b> and 0.881 eV for <b>2a</b>), consistent with the high reactivity of the phthalocyanine core, while in silico ADMET analysis indicated favorable toxicity profiles for both compounds. The combined experimental and computational findings identify compound <b>2a</b> as a promising multifunctional enzyme inhibitor.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13512772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148828494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carvacrol Mitigates TNF-α-Driven Oxidative and Bioenergetic Impairment in L6 Rat Myoblasts","authors":"Ali M. Albarrati,&nbsp;Rakan I. Nazer","doi":"10.1002/jbt.71087","DOIUrl":"10.1002/jbt.71087","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 &lt;p&gt;Tumor necrosis factor-alpha (TNF-α) mediates inflammatory cytotoxicity in skeletal muscle, causing mitochondrial dysfunction, bioenergetic collapse, and ATPase-dependent ion homeostasis disruption implicated in aging, cachexia, and inflammatory myopathy. Carvacrol (5-isopropyl-2-methylphenol), a monoterpenoid from &lt;i&gt;Origanum vulgare&lt;/i&gt; and &lt;i&gt;Thymus vulgaris&lt;/i&gt;, has antioxidant, anti-inflammatory, and membrane-stabilizing properties, but its modulation of TNF-α-induced toxicity, ROS, ATPase activities, Δψm, antioxidant enzymes, and stress-responsive gene expression remains uncharacterized. This study aimed to examine the effect of carvacrol on TNF-α-induced oxidative and bioenergetic damage in L6 rat myoblasts. L6 rat myoblasts were exposed to TNF-α (10 ng/mL, 1 h) to establish a validated model of inflammatory cytotoxicity, followed by carvacrol treatment (6.25 µg/mL, 24 h). Cytotoxicity was evaluated by MTT assay and lactate dehydrogenase (LDH) release. Intracellular ROS were quantified fluorimetrically using DCFH-DA. Oxidative stress markers included catalase and superoxide dismutase (SOD) activities, with Δψm assessed by flow cytometry (Muse MitoPotential kit). Ion-dependent ATPase activities (Na&lt;sup&gt;+&lt;/sup&gt;/K&lt;sup&gt;+&lt;/sup&gt;-, Ca&lt;sup&gt;2+&lt;/sup&gt;-, Mg&lt;sup&gt;2+&lt;/sup&gt;-dependent) were determined by inorganic phosphate release. SIRT1 and AMPK mRNA expression was quantified by RT-qPCR (&lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;mrow&gt;\u0000 \u0000 &lt;mrow&gt;\u0000 &lt;msup&gt;\u0000 &lt;mn&gt;2&lt;/mn&gt;\u0000 \u0000 &lt;mrow&gt;\u0000 &lt;mo&gt;-&lt;/mo&gt;\u0000 \u0000 &lt;mi&gt;ΔΔ&lt;/mi&gt;\u0000 \u0000 &lt;msub&gt;\u0000 &lt;mi&gt;C&lt;/mi&gt;\u0000 \u0000 &lt;mi&gt;t&lt;/mi&gt;\u0000 &lt;/msub&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;/msup&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;annotation&gt; ${2}^{ mbox{-} mathrm{Delta Delta }{C}_{{rm{t}}}}$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; method, GAPDH-normalized). TNF-α exposure induced significant cytotoxicity, membrane damage, ROS accumulation, mitochondrial depolarization, suppression of ion-dependent ATPase activities, and dysregulation of catalase and SOD. Post-exposure carvacrol treatment significantly attenuated these effects: LDH release decreased from ~340 to ~73 U/mL, ROS generation was reduced, Δψm was partially restored, and ATPase activities and antioxidant enzyme activities were recovered toward control levels. Carvacrol significantly upregulated SIRT1 mR","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13512785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148828545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acrylamide-Induced Developmental and Molecular Toxicity in Drosophila melanogaster: The Role of Vanillic Acid in CncC/Keap1 Modulation","authors":"Fahriye Zemheri-Navruz,&nbsp;Sinan Ince,&nbsp;Gamze Ataman","doi":"10.1002/jbt.71088","DOIUrl":"10.1002/jbt.71088","url":null,"abstract":"<p>Acrylamide, a chemical used in industrial applications, has been classified as an environmental toxin owing to its widespread contamination of drinking water and groundwater resources. Vanillic acid (VA) is a phenolic compound naturally occurring in numerous dietary sources and medicinal plants. VA exhibits a wide range of pharmacological properties, including antioxidant, anti-inflammatory, and neuroprotective activities. This study investigated the protective effects of VA against acrylamide-induced oxidative stress in <i>Drosophila melanogaster</i> at developmental, biochemical, and molecular levels. <i>D. melanogaster</i> were exposed to acrylamide (2 mM) alone or with VA at three doses (0.1, 0.5, and 1 mg/L). Acrylamide exposure elevated reactive oxygen species and lipid peroxidation, decreased antioxidant enzyme activities (SOD, CAT) and glutathione (GSH) levels, increased DNA damage by the Comet assay, upregulated mRNA expression of stress-related genes (<i>SOD</i>, <i>CAT</i>, <i>gclc</i> and <i>hsp70</i>) and detoxification-pathway components (<i>Keap1</i> and <i>CncC/Nrf2</i>), and adversely affected developmental parameters (larval toxicity, crawling, climbing, survival, food intake, body weight and length). Co-administration of VA dose-dependently reduced lipid peroxidation and ameliorated antioxidant enzyme activities and DNA damage. VA also modulated the impaired developmental parameters of acrylamide-exposed larvae. These findings indicate that VA possesses considerable protective potential against acrylamide toxicity, with important implications for environmental and human health.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13512777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148828243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atmospheric Aerosol Neurotoxicity and Parkinson's Disease: Mechanisms and Perspectives","authors":"Yitian Gao,&nbsp;Minxiang Dong,&nbsp;Chenyang Duan,&nbsp;Xiaohan Zheng,&nbsp;Liming Qu","doi":"10.1002/jbt.71089","DOIUrl":"10.1002/jbt.71089","url":null,"abstract":"<p>Parkinson's disease (PD) is a common neurodegenerative disease threatening the health of the middle-aged and elderly population, triggered by the combined effects of genetic susceptibility, environmental exposure and nervous system aging, among which atmospheric aerosol exposure is a key risk factor for sporadic PD. As a complex heterogeneous mixture, atmospheric aerosols contain neurotoxic components such as metal particles, persistent organic pollutants (POPs), and nano/ultrafine particles, which appear to target midbrain substantia nigra dopaminergic neurons through pathways including direct entry into the brain via the olfactory pathway, penetration across the lung-blood-brain barrier, and inflammation-mediated alterations in barrier permeability. The core molecular mechanisms that have been proposed to link aerosol exposure to sporadic PD include oxidative stress and mitochondrial dysfunction, neuroinflammation and aberrant microglial activation, disrupted protein homeostasis and abnormal aggregation of α-synuclein (α-syn), as well as altered epigenetic regulation. Moreover, neurotoxic effects may be amplified via the positive feedback loop of oxidative stress-neuroinflammation, the vicious cycle of mitophagy defects and protein aggregation, and the “multiple-hit hypothesis”. This review summarizes the toxic components of aerosols, their brain-entry routes and pathogenic mechanisms, outlines the application status of emerging technologies such as in vitro cell models and in vivo animal models, and sorts out intervention strategies including pharmacological therapy and epigenetic regulation. It also analyzes the current challenges in research on mechanisms, models, population studies and intervention strategies, and points out that future research should focus on dissecting the synergistic mechanisms of multiple components and optimizing research models, so as to provide theoretical support for exploring potential strategies for precise prevention, control and treatment of PD.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbt.71089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148828364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autocrine Control of CD276 by SPARC in Liver Cancer and Its Contribution to Immune Escape and Resistance to Immunotherapy","authors":"Mengying Tang,&nbsp;Jing Liu","doi":"10.1002/jbt.71086","DOIUrl":"10.1002/jbt.71086","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) frequently demonstrates resistance to immunotherapeutic interventions, a phenomenon largely linked to mechanisms of immune escape. Among the modulators of the tumor microenvironment, SPARC (Secreted Protein Acidic and Rich in Cysteine), a matricellular glycoprotein, has been associated with diverse oncogenic processes in multiple cancer types. However, the contribution of SPARC to immune regulation through CD276 signaling remains insufficiently characterized. To clarify this mechanism, we employed the murine Hepa1-6 hepatoma cell line established from C57BL/6 mice. Functional studies were carried out by genetically altering the expression of SPARC and CD276, followed by comprehensive assessments including Western blot analysis, polymerase chain reaction, flow cytometry, and in vivo tumorigenicity assays. Overexpression of SPARC in HCC cells led to increased CD276 levels through activation of the p65/c-Myc axis, which also promoted cancer cell stemness. This upregulation impaired the response to immune checkpoint blockade (ICB) therapy, as evidenced by reduced infiltration and activation of CD8 + T cells within the tumor microenvironment. Additionally, increased SPARC-induced CD276 expression diminished T-cell activation and proliferation, marked by decreased IFN-γ production and reduced phosphorylation of ZAP70, a key T-cell signaling molecule. Our findings underscore the critical role of SPARC in upregulating CD276 in HCC, which contributes to immune suppression and resistance to ICB therapy.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13512768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148828379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Icariside II in Neurological Disorders: Mechanistic Insights Into Alzheimer's Disease, Cerebral Ischemia and Parkinson's Disease","authors":"Ashutosh Solanki,&nbsp;Khushi Sharma,&nbsp;Jagrati Jain,&nbsp;Niraj Kumar Singh,&nbsp;Praveen T. Krishnamurthy","doi":"10.1002/jbt.71093","DOIUrl":"10.1002/jbt.71093","url":null,"abstract":"<p>Icariside II (ICS II), a PDE5 inhibitor, is a flavonoid glycoside and primary metabolite of <i>icariin</i>, derived from the herb <i>Herba epimedii</i>, and exhibits promising neuroprotective potential in various pre-clinical studies. The current review provides evidence that ICS II shows neuroprotective potential against various neurological disorders, mainly including Alzheimer's disease, Parkinson's disease and Cerebral ischemia through modulating neuroinflammation, oxidative stress, neural apoptosis, neurogenesis, mitochondrial and cognitive dysfunction. It regulates multiple signalling pathways including PI3K/Akt, Keap1/Nrf2, TLR4/MyD88/NF-κB, cGMP/PKG/CREB, TGFB1/Smad, Wnt/β-catenin signaling and BDNF/TrkB/CREB. The pre-clinical evidence suggests that ICS II attenuates oxidative stress through increasing antioxidant enzymes SOD, GSH, catalase, and HO-1, with decreasing MDA and lipid peroxidation. Neuroinflammation is suppressed by inhibition of pro-inflammatory cytokines and down-regulation of IL-1β, IL-6, TNF-α, COX-2, iNOS levels and up-regulation of tight-junction proteins like occludin, claudin-5, ZO-1. Apoptosis is regulated via altering PARP, Bcl-2, Bax/Bcl-2 ratio and reducing caspase-3 activation. Mitochondrial dysfunction is ameliorated by restoring Complex I activity and increasing mitofusin-1/2 expression and reducing mitochondrial fission factors. Collectively, these molecular mechanisms show promise for ICS II as a potential candidate in different in vivo and in vitro studies of neurological disorders.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of the KLF9/TXNRD2 Axis Leads to Mitochondrial DNA Oxidation and NLRP3 Inflammasome Activation in Ulcerative Colitis","authors":"Yijia Fan,&nbsp;Lingling Dai,&nbsp;Feng Zhu,&nbsp;Mingfang Ping,&nbsp;Xiaofeng Zhu,&nbsp;Junguo Chen","doi":"10.1002/jbt.71074","DOIUrl":"10.1002/jbt.71074","url":null,"abstract":"<p>This study investigated the roles and mechanism of the transcription factor KLF9 and its downstream target gene TXNRD2 in ulcerative colitis (UC). An in vitro inflammatory model was established by stimulating human normal colonic mucosal epithelial cells (NCM460) with LPS and ATP. KLF9 or TXNRD2 expression was knocked down using RNA interference, and rescue experiments were performed using the NLRP3-specific agonist nigericin or by co-transfection with si-TXNRD2. A 3% DSS-induced UC model was established in C57BL/6 mice. Interventions were performed by tail vein injection of sh-KLF9 adeno-associated virus and/or intraperitoneal injection of nigericin. In DSS-induced UC mouse colon tissues and LPS/ATP-stimulated NCM460 cells, KLF9 was upregulated. KLF9 directly bound to the TXNRD2 promoter. Silencing KLF9 restored TXNRD2 expression, alleviated LPS/ATP-induced oxidative stress, decreased the accumulation of cytoplasmic ox-mtDNA and mtDNA, and inhibited NLRP3 inflammasome activation, as well as reduced pyroptosis, LDH release, and pro-inflammatory cytokine secretion. si-TXNRD2 or nigericin partially reversed the protective effects of KLF9 silencing. Colon-specific KLF9 knockdown improved DSS-induced weight loss, colonic shortening, disease activity index, and histopathological damage in mice, while simultaneously upregulating TXNRD2, inhibiting the NLRP3 pathway, and reducing oxidative stress and cytoplasmic mtDNA accumulation. Nigericin intervention partially offset the protective effects of KLF9 knockdown. KLF9 suppresses TXNRD2 transcription, leading to increased mitochondrial oxidative stress and the release of ox-mtDNA in intestinal epithelial cells, which in turn triggers NLRP3 inflammasome activation, driving pyroptosis and intestinal inflammation.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Anti-Tumorigenic Effects of Curcumin and Baicalein in 7,12-Dimethylbenz[a] Anthracene-Induced Mammary Gland Tumorigenesis in Wistar Rats","authors":"Priyanka Syal,&nbsp;Nittin Dev Singh,&nbsp;Geeta Devi Leishangthem,&nbsp;Harmanjit Singh Banga","doi":"10.1002/jbt.71065","DOIUrl":"10.1002/jbt.71065","url":null,"abstract":"<div>\u0000 \u0000 <p>Mammary tumor is one of the most common neoplasms in females and remains a major therapeutic challenge due to the high cost and adverse effects of conventional chemotherapy. Therefore, herbal products such as curcumin, baicalein and their combination are used which have anti-inflammatory effects and various other pharmacological effects. The present study evaluated the effects of curcumin and baicalein against mammary tumor induced by 7,12-dimethylbenz[a]anthracene (DMBA) in Wistar rats. Thirty-eight virgin female rats were divided into five groups: Group I (SHAM), Group II (DMBA @ 80 mg/kg BW orally single dose), Group III (DMBA @ 80 mg/kg BW orally + curcumin @ 100 mg/kg BW orally), Group IV (DMBA @ 80 mg/kg BW orally + baicalein @10 mg/kg BW i.p.), and Group V (DMBA @80 mg/kg + curcumin @100 mg/kg BW + baicalein @10 mg/kg BW). Curcumin and baicalein treatment demonstrated significant efficacy. Only small palpable growths were observed in treated groups and mild early neoplastic alterations were detected histologically, with the lowest incidence in the combination group. Curcumin and baicalein supplementation significantly ameliorated the DMBA induced changes in the body weight, hematological parameters (Hb, PCV, TEC, TLC, DLC), biochemical parameters (AST, ALT, ALKP, Total protein, glucose, BUN, Creatinine), oxidative stress parameters (NO, LPO, SOD, and Catalase), and pro-inflammatory cytokines (IL-I, IL-6, TNF-α). Moreover, immunohistochemistry and RT-PCR of epithelial–mesenchymal transition markers (e-cadherin, vimentin, α-smooth muscle actin) confirmed the ameliorative effect of curcumin and baicalein, most pronounced in the combination group. These findings suggest that curcumin and baicalein may exert synergistic beneficial effects, supporting their potential as chemopreventive agents.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}