Journal of Biochemical and Molecular Toxicology最新文献

{"title":"USP1 Promotes Malignant Progression of Cervical Cancer Cells by Deubiquitinating and Stabilizing ATG13 to Enhance Autophagic Activity.","authors":"Chunyan Liu, Zhitong Liu, Changyan Dong, Xiaona Jiang, Xiao Chen","doi":"10.1002/jbt.71060","DOIUrl":"10.1002/jbt.71060","url":null,"abstract":"<p><p>Autophagy is an evolutionarily conserved lysosomal degradation pathway that exerts context-dependent regulatory effects on tumorigenesis and development. Ubiquitin-specific protease 1 (USP1) has been identified as an oncogenic driver in multiple malignant tumors, yet its specific biological function in cervical cancer, especially its regulatory crosstalk with autophagy, remains largely unexplored. Immunohistochemistry, qRT-PCR, and Western blotting were used to examine USP1 expression in cervical cancer tissues and cell lines. A series of biological assays including CCK-8, colony formation, Transwell, and flow cytometry were conducted to explore the impacts of USP1 silencing on cell proliferation, migration, invasion, and apoptosis. Autophagic flux was monitored by LC3 immunofluorescence staining and Western blotting of autophagy-related markers. Co-immunoprecipitation and in vitro ubiquitination assays were used to clarify the interaction between USP1 and ATG13 and the deubiquitination effect of USP1 on ATG13. Rescue experiments with ATG13 overexpression combined with or without the USP1 inhibitor ML323 were performed to verify the functional regulatory axis of USP1-ATG13-autophagy. In addition, a xenograft mouse model was established by subcutaneously injecting SiHa cells stably expressing sh-USP1 and/or ATG13-overexpressing lentivirus into nude mice; tumor volume and weight were assessed 4 weeks post-injection. USP1 exhibited markedly elevated expression in both cervical cancer tissues and cell lines, and its overexpression was strongly associated with high pathological grades of cervical cancer. Functional assays revealed that silencing USP1 observably suppressed the proliferation, migration, and invasion of C33A and SiHa cells, and simultaneously promoted cellular apoptosis. Mechanistically, USP1 could directly bind to ATG13 and mediate its deubiquitination, thereby enhancing the protein stability of ATG13 and promoting the autophagic flux of cervical cancer cells. Notably, overexpression of ATG13 could reverse the inhibition of autophagy and the suppression of malignant phenotypes induced by USP1 knockdown, and this rescue effect was completely abrogated by ML323 treatment. In vivo xenograft experiments confirmed that USP1 knockdown significantly inhibited cervical cancer tumor growth, while ATG13 overexpression markedly rescued the tumor-suppressive effect induced by USP1 silencing. Our study reveals a novel molecular mechanism by which USP1 promotes the malignant progression of cervical cancer through stabilizing ATG13 and subsequently enhancing autophagic activity. USP1 may serve as a promising therapeutic target for cervical cancer, and modulation of autophagy holds clinical potential in cervical cancer intervention.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 8","pages":"e71060"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700466","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":"Barbaloin Attenuates Cisplatin-Induced Hippocampal Neurotoxicity by Suppressing Oxidative Stress, Neuroinflammation, and Apoptosis: In Vivo and In Silico Evidence.","authors":"Rahamat Unissa Syed, Rihab Akasha, Nancy Mohammad Elafandy, Sally Hassan Abobaker, Afrah Nashmi Al-Shammari, Lama Abdullah Altwalah, Rawabi Mohammed Menwer Aldafeeri, Amira Ibrahim Mohammed Ahmed Alfaki, Mohd Sajjad Ahmad Khan, Ashgan A Ahmed","doi":"10.1002/jbt.71063","DOIUrl":"10.1002/jbt.71063","url":null,"abstract":"<p><p>The neurotoxicity of cisplatin (CIS) in the hippocampal leads to cognitive effects caused by oxidative stress, neuroinflammation, apoptosis, and dysfunction of neurotransmitters. The major bioactive phytonutrient in Aloe vera is barbaloin (BLN), which has been shown to have antioxidant and anti-inflammatory effects, but its neuroprotective ability against CIS-induced neurotoxicity has not been investigated. To assess the neuroprotective action of BLN in CIS-induced hippocampal neurotoxicity in rats and to understand the molecular interactions between BLN and major neuroinflammatory and apoptotic proteins. A total of 24 male Wistar rats were split into 4 groups (n = 6): control, CIS (5 mg/kg), CIS + BLN 25 mg/kg, and CIS + BLN 50 mg/kg over 21 days. Cognitive ability (Morris water maze), oxidative stress indicators (MDA, GSH, SOD, CAT), neuroinflammatory cytokines (TNF-α, IL-1β, IL-6, NF-κB, TGF-β1), caspase-3, neurotransmitters, and hippocampal histopathology were measured. Molecular docking and 100-ns molecular dynamics simulations (MDS) with MM-GBSA analysis were done with TNF-α, TGF-β1, NF-κBp65, and caspase-3. BLN significantly reduced cognitive impairment, oxidative stress, neuroinflammation, and apoptosis, and restored neurotransmitter homeostasis and hippocampal cytoarchitecture (all p < 0.0001). Molecular docking demonstrated positive binding energies (- 7.226 to -8.566 kcal/mol), and MDS revealed the presence of stable BLN-protein complexes (ΔG_bind = -56.07 kcal/mol for TGF-β1). BLN exhibits considerable neuroprotective properties against CIS-induced neurotoxicity in the hippocampus, suggesting its potential as a natural dietary phytonutrient supplement to ameliorate chemotherapy-induced cognitive impairment.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 8","pages":"e71063"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13443480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678817","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":"MiR-138-5p Suppresses Glucose Metabolism to Inhibit the Progression of Nasopharyngeal Carcinoma by Targeting the CENPN/PI3K/Akt/mTOR Signaling.","authors":"Hongxia Guan, Yang Jiang, Hui Li","doi":"10.1002/jbt.70943","DOIUrl":"10.1002/jbt.70943","url":null,"abstract":"<p><p>Nasopharyngeal cancer (NPC) is a malignant tumor that originates from mucosal epithelial cells of the nasopharynx. As an emerging cancer-associated microRNA, miR-138-5p has been shown to modulate various malignant cell malignancies. However, its precise biological function and regulatory mechanism in NPC remain to be further elucidated. Human NPC cell lines (HK-1 and C666-1) were used for in vitro study, and nude mouse xenograft models were used for in vivo investigations. A bioinformatic method was utilized for the prediction of RNA expression patterns and molecular interactions. RT-qPCR was performed for the detection of miR-138-5p and CENPN expression. Luciferase activity detection and RNA pulldown experiments were used for verification of gene interaction. Flow cytometry and colony formation assays were conducted to evaluate cell cycle distribution, proliferative capacity, and apoptosis rate. Furthermore, extracellular acidification rate, lactate generation, and glucose uptake were assessed to explore the regulatory effects of miR-138-5p and CENPN on glycolysis in NPC cells. Protein levels of CENPN and key molecules associated with cell cycle, apoptosis, glycolysis, and the PI3K signaling pathway were quantified by western blot analysis. CENPN expression is analyzed to be upregulated in head and neck cancer samples, and its high expression is associated with unfavorable clinical prognosis. In NPC cells, miR-138-5p was markedly downregulated and was verified to directly target the 3' untranslated region of CENPN, thereby negatively regulating its expression. Functionally, overexpressing miR-138-5p obstructed malignant phenotype, glycolysis, and tumor growth of NPC cells, where these inhibitory effects were significantly counteracted by enforced CENPN expression. Moreover, miR-138-5p overexpression inactivated the PI3K/Akt/mTOR signaling by reducing CENPN expression in NPC cells. In conlusion, miR-138-5p inhibits cell growth, glycolysis, and tumorigenesis in NPC by directly targeting CENPN, thereby inhibiting the PI3K/Akt/mTOR signaling pathway. These findings highlight the potential utility of miR-138-5p as both a diagnostic indicator and a therapeutic intervention target for NPC management.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 8","pages":"e70943"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148591705","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":"O-Glycosylation of E-Cadherin Induced by Endoplasmic Reticulum Stress Negatively Regulates Cell Polarity and Proliferation in Acute Kidney Injury.","authors":"Yingjia Zhang, Weidong Zhang, Qingwu Liao, Zhaoxing Sun, Weize Chen, Xiaoqiang Ding, Shuan Zhao","doi":"10.1002/jbt.71061","DOIUrl":"10.1002/jbt.71061","url":null,"abstract":"<p><p>The loss of polarity and cell cycle arrest of renal tubular epithelial cells (RTECs) represent important mechanisms of acute kidney injury (AKI). Endoplasmic reticulum stress (ER stress) often occurs in the kidneys during AKI, regulating protein translation and post-translational modification. E-cadherin, a key regulator of cell polarity, undergoes O-glycosylated during ER stress. However, the role of E-cadherin O-glycosylation in kidney injury and repair remains to be elucidated. Cisplatin (CP)/lipopolysaccharide (LPS)-induced AKI mouse models and cell models were established to evaluate ER stress in the RTECs. The glycan modification and localization of E-cadherin, as well as its interaction with β-catenin, were evaluated in vitro through Western blot, immunoprecipitation, and immunofluorescence. Small molecular inhibitors targeting ER stress (4-PBA) or O-glycosylation (OSMI-1) were utilized to investigate the effects on E-cadherin O-glycosylation, RTECs polarity and proliferation in vivo and in vitro. Both CP- and LPS-induced AKI triggered ER stress in RTECs, which led to O‑glycosylation of E‑cadherin, loss of cell polarity, and impaired proliferation. Notably, removal of a brief ER stress pulse allowed RTECs to regain normal polarity and proliferation, indicating the reversibility of this process. Consistently, pharmacological inhibition of ER stress or O‑glycosylation effectively restored these phenotypes in vitro. Moreover, in vivo suppression of ER stress in CP‑induced AKI mice significantly recovered renal function and promoted tubular cell proliferation. Together, these results establish ER stress‑driven E‑cadherin O‑glycosylation as a critical upstream event in AKI‑associated tubular repair failure and suggest that targeting this axis holds therapeutic promise. These findings establish ER stress-driven E-cadherin O-glycosylation as a critical upstream mechanism of tubular repair failure in AKI, and suggest that targeting this axis represents a promising therapeutic strategy for restoring renal function.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 8","pages":"e71061"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701466","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":"SGLT2 Inhibition Attenuates Hippocampal Injury and Cognitive Impairment in Adult-Onset Hypothyroidism.","authors":"Soner Bitiktaş, Serdar Yiğit, İsa Yeşilyurt, Huseyin Fatih Gul, Orhan Erkan, Başak Gulakar, Zeynep Cansu Aydın, Ali Alper Kahraman","doi":"10.1002/jbt.71059","DOIUrl":"10.1002/jbt.71059","url":null,"abstract":"<p><p>Thyroid hormones play a critical role in the maturation of developing brain regions. The aim of this study is to determine the effects of the SGLT2 inhibitor empagliflozin on learning and memory, locomotor activity, neuroinflammation, and oxidative stress levels in adult rats with hypothyroidism induced by propylthiouracil administration. 60 adult male Sprague-Dawley rats (250-350 g) were used in the study. The rats were randomly divided into 5 groups of 12 each: Con, PTU, Vehicle, EMP, and PTU+EMP. The Con and EMP groups were allowed free access to drinking water. For the PTU, Vehicle, and PTU+EMP groups, propylthiouracil was added to the rats' drinking water at a concentration of 0.05% w/v for 21 days. Starting from day 15, the EMP and PTU+EMP groups received i.p. empagliflozin injections at a dose of 10 mg/kg/day for 7 days, while the Vehicle group received empagliflozin solvent (DMSO, 5% w/w). Morris water maze test and open field test were performed. SOD and CAT enzyme activities, GSH, and MDA levels were determined from serum samples. CREB and nNOS levels and p-CREB immunoreactivity were examined in the hippocampus tissue using immunohistochemical methods. In the PTU group, locomotor activity decreased, and anxiety-like behaviors were observed. Escape latency (EL) was prolonged, and time spent in the target quadrant (TSTQ) decreased. Antioxidant enzyme activities decreased while MDA levels increased. Significant reductions in CREB, p-CREB, and nNOS levels, which are critical for learning and memory processes, and hippocampal degeneration were recorded. Empagliflozin treatment improved cognitive and morphological impairments caused by hypothyroidism to control group levels by reducing anxiety-like behavior, suppressing oxidative stress, and restoring CREB/nNOS signaling pathways. The data obtained show that thyroid hormone deficiency developing in adulthood leads to serious cognitive losses by disrupting the ERK/CREB/BDNF and nNOS/NO pathways. Empagliflozin emerges as a potential new therapeutic option for treating cognitive impairments caused by hypothyroidism by modulating these molecular cascades.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 8","pages":"e71059"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669326","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":"Correction to \"Dimethyl Fumarate Suppresses Collagen-Induced Arthritis by Regulating Inflammatory Responses\".","authors":"","doi":"10.1002/jbt.71068","DOIUrl":"10.1002/jbt.71068","url":null,"abstract":"","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 8","pages":"e71068"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701440","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":"Contrasting Effects of HT-2 Toxin Exposure and ZIP6 Knockdown on Chondrocyte Extracellular Matrix Metabolism.","authors":"Yang Liu, Yu Zhang, Ruitian Huang, Lulu Bai, Lian Liu, Chaowei Wang, Yirong Qin, Hui Wang, Xiong Guo, Xi Wang, Yujie Ning","doi":"10.1002/jbt.71056","DOIUrl":"10.1002/jbt.71056","url":null,"abstract":"<p><p>Kashin-Beck disease (KBD) is a chronic, endemic osteoarticular disorder associated with T-2 toxin exposure, which is rapidly metabolized to HT-2 toxin in vivo. However, the role of zinc transporter ZIP6 in HT-2 toxin-induced extracellular matrix metabolic disturbance in chondrocytes remains unclear. This study established HT-2 toxin intervention and ZIP6 knockdown chondrocyte models, combined with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and transcriptome sequencing, to investigate the regulatory mechanisms of ZIP6 in chondrocyte injury. Following HT-2 toxin exposure, altered chondrocyte morphology and reduced cell viability were observed; ZIP6, COL2A1, MTF1, and MTF2 expression were significantly downregulated, whereas MMP1, MMP13, and COL10A1 were upregulated. ZIP6 knockdown significantly upregulated COL2A1, MTF1, and MTF2, downregulated MMP1 and COL10A1, but did not alter MMP13 expression. Differentially expressed genes following ZIP6 knockdown were predominantly enriched in FoxO, cAMP, and TNF signaling pathways. qRT-PCR validation confirmed consistent expression changes in FOXO4, TNFSF10, COLEC10, UCA1, and LRRC17 with transcriptome sequencing results. Collectively, HT-2 toxin suppresses ZIP6, MTF1, and MTF2 expression, disrupting chondrocyte extracellular matrix metabolism; conversely, ZIP6 knockdown ameliorates matrix metabolic abnormalities through modulation of relevant signaling pathways. These findings reveal differential regulatory effects of HT-2 toxin and ZIP6 on cartilage matrix metabolism, providing experimental evidence for elucidating molecular mechanisms underlying cartilage injury-related diseases.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 8","pages":"e71056"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13424907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148630631","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":"Protective Role of Thymoquinone Against TCE-Induced Liver Damage Through HSP70 Modulation.","authors":"Arzu Güneş, Neriman Çolakoğlu","doi":"10.1002/jbt.71053","DOIUrl":"10.1002/jbt.71053","url":null,"abstract":"<p><p>Trichloroethylene (TCE) is a widely used industrial solvent and a common environmental pollutant. Prolonged or high-dose exposure to TCE has been associated with oxidative stress, hepatotoxicity, and carcinogenesis. Accordingly, identifying compounds capable of preventing or attenuating TCE-induced hepatotoxicity has become increasingly important. Thymoquinone (TQ), a bioactive compound derived from Nigella sativa, exhibits potent antioxidant, anti-inflammatory, and hepatoprotective properties. This study aimed to investigate the protective effects of TQ against TCE-induced liver injury. Twenty-five male Wistar-Albino rats were randomly assigned to five groups: Control, TCE, TCE + TQ, TQ, and DMSO. Liver tissues were harvested, processed for histopathological evaluation, and analyzed for Heat Shock Protein 70 (HSP70) immunoreactivity. TCE exposure resulted in significant histopathological alterations, including vascular congestion, necrosis, inflammation, and sinusoidal dilatation. Moreover, TCE exposure caused a marked increase in HSP70 immunoreactivity (p < 0.05) compared with the control group. In contrast, TQ treatment alleviated these histopathological alterations and significantly reduced HSP70 immunoreactivity compared with the TCE group (p < 0.05), indicating attenuation of hepatic cellular injury. These findings suggest that TQ may exert hepatoprotective effects against TCE-induced liver injury and support further investigation of its potential role in mitigating environmentally induced hepatotoxicity.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 8","pages":"e71053"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669352","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":"Isobavachin Attenuates Renal and Cardiac Injury in Chronic Hyperuricemia via Modulation of NF-κB and NLRP3 Signaling Pathways.","authors":"Yongmei Li, Yuexin Xu, Wenjie Ye, Zeqi Yu, Zhenkun Wu, Xinyi Liu, Xuhong Huang, Jianxin Pang, Zean Zhao, Ting Wu","doi":"10.1002/jbt.71058","DOIUrl":"10.1002/jbt.71058","url":null,"abstract":"<p><p>Hyperuricaemia (HUA) is a recognized risk factor for cardiovascular and renal diseases. Isobavachin, a dihydroflavone derivative, demonstrates significant efficacy in reducing uric acid levels. This study investigated the nephroprotective and cardioprotective effects and molecular mechanisms of isobavachin. Through integrative network pharmacology, pathway enrichment analysis, and molecular docking, NF-κB was identified as a potential target of isobavachin in the context of hyperuricemia-related cardiac and renal injury. Isobavachin treatment inhibited the activation of the NF-κB pathway, leading to cytoprotection in uric acid (UA)-stimulated mRTEC and H9C2 cells. In chronic HUA mice, isobavachin treatment significantly improved renal pathology and reduced renal collagen deposition by inhibiting epithelial-to-mesenchymal transition. Isobavachin administration demonstrated therapeutic efficacy in attenuating myocardial injury, hypertrophy, and fibrotic remodeling. Notably, the anti-inflammatory effects of isobavachin were particularly evident in both renal and cardiac tissues, primarily mediated through its dual regulatory capacity in suppressing NF-κB pathway activation and NLRP3 inflammasome formation. In conclusion, isobavachin ameliorated cardiac and renal damage caused by chronic HUA, suggesting a new strategy to prevent HUA.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 8","pages":"e71058"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669567","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":"4-FPAC-Modulated Tumor-Associated Macrophage Conditioned Media Suppresses Malignant Phenotypes and Promotes Cell-Cycle Arrest and Apoptosis in NSCLC.","authors":"Anjali Singh, Dhanush Danes, Suresh Balakrishnan","doi":"10.1002/jbt.71066","DOIUrl":"10.1002/jbt.71066","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) progression is strongly influenced by tumor-associated macrophages (TAMs), which frequently acquire an M2-like phenotype that promotes proliferation, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, and therapy resistance. Previous studies from our group established the direct cytostatic and macrophage-polarizing effects of the synthetic coumarin derivative 4-fluorophenylacetamide-acetyl coumarin (4-FPAC), including ROS-mediated apoptosis, G0/G1 cell-cycle arrest, suppression of EMT-associated signaling in A549 cells, and promotion of M1-like macrophage polarization. In the present study, we investigated whether 4-FPAC-modulated TAM-derived conditioned media could suppress tumor-promoting behavior in A549 NSCLC cells. THP-1 monocytes were differentiated into macrophages and polarized using A549-conditioned medium to generate TAM-like macrophages. These TAMs were subsequently treated with 4-FPAC, and conditioned media from control or treated TAMs were applied to A549 cells to evaluate macrophage-associated anti-tumor effects. MTT analysis further showed that direct exposure of A549 cells to 4-FPAC under TAM-CM-supported conditions reduced cell viability in a dose-dependent manner. Functional assays demonstrated that conditioned media derived from 4-FPAC-treated TAMs significantly reduced A549 proliferation, inhibited migration and invasion, and impaired angiogenic responses in a chick chorioallantoic membrane model. Flow cytometry revealed G0/G1 cell-cycle arrest and reduced NANOG-positive stem-like cells, while DNA fragmentation and TUNEL assays confirmed enhanced apoptosis. Mechanistically, qRT-PCR and immunoblotting demonstrated EMT reversal, suppression of AKT signaling, VEGFα, IL8, OCT3/4, and NANOG, and upregulation of p21, p53, and caspase-3/cleaved caspase-3. Collectively, these findings demonstrate that 4-FPAC directly suppresses A549 viability under TAM-CM-supported conditions and modulates TAM-derived conditioned-media activity, highlighting its potential to target both tumor cells and tumor-macrophage interactions within the NSCLC microenvironment.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"40 8","pages":"e71066"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701435","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}