Toxicology and applied pharmacology最新文献

{"title":"Tectorigenin alleviates irinotecan-induced intestinal inflammation by activating the Nrf2/Keap1 pathway and synergistically enhances the anti-colon cancer efficacy of irinotecan","authors":"Rui Ma ,&nbsp;Xiaoya Liu ,&nbsp;Peng Zheng ,&nbsp;Guijun Zou ,&nbsp;Chaojun Zhang","doi":"10.1016/j.taap.2025.117416","DOIUrl":"10.1016/j.taap.2025.117416","url":null,"abstract":"<div><h3>Background</h3><div>Gastrointestinal toxicity, primarily manifesting as colitis, is one of the most common adverse events during irinotecan (CPT-11) treatment for colon cancer, significantly impacting therapeutic efficacy and the general condition of patients. Tectorigenin (TEC) is a flavonoid compound extracted from Bupleurum and saponins, which are traditional Chinese medicines with anti-inflammatory properties. Previous experiments have found that it can alleviate CPT-11-induced diarrhoea and synergistically inhibit tumor growth with CPT-11, but the specific mechanisms remain unknown.</div></div><div><h3>Methods</h3><div>A CPT-11-induced diarrhoea mouse model was used to study the protective effect of TEC on CPT-11-induced diarrhoea in mouse by measuring levels of inflammatory cytokines and intestinal tight junction-related proteins in colon tissues. The chemopreventive effect of TEC was evaluated by measuring levels of inflammatory cytokines and intestinal tight junction-related proteins in Caco-2 cells exposed to CPT-11 and lipopolysaccharide (LPS). Finally, the synergistic effect of TEC combined with CPT-11 on tumor growth was investigated in a mouse model of colon tumors induced by subcutaneous implantation of CT26 colon cancer cells.</div></div><div><h3>Results</h3><div>TEC inhibited CPT-11-induced intestinal toxicity, as evidenced by reduced weight loss, decreased diarrhoea scores, and less intestinal shortening in mouse. Histological analysis demonstrated that TEC alleviated CPT-11-induced intestinal barrier damage. Additionally, TEC activated the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) signalling pathway, reduced the expression of inflammatory cytokines both in vivo and in vitro, alleviated intestinal inflammation, and increased the expression of intestinal tight junction proteins, thereby enhancing intestinal barrier function. Furthermore, TEC exhibited a synergistic effect with CPT-11 in anti-tumor therapy.</div></div><div><h3>Conclusions</h3><div>This study confirmed that TEC alleviates CPT-11-induced intestinal inflammation by activating the Nrf2/Keap1 signalling pathway and enhances the anti-tumor effect of CPT-11 in colon cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117416"},"PeriodicalIF":3.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177650","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}

{"title":"Epigenetic predictor of smoking status in buccal cells.","authors":"Ewelina Pośpiech, Aleksandra Pisarek-Pacek, Kinga Herda, Bożena Wysocka, Aneta Sitek, Magdalena Spólnicka, Wojciech Branicki, Andrzej Ossowski","doi":"10.1016/j.taap.2025.117415","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117415","url":null,"abstract":"<p><p>Smoking is the leading cause of accelerated aging and death worldwide. Therefore, identifying and intervening at smoke-responsive DNA methylation markers may be a primary way to reduce mortality risk in the population. Many studies have investigated the association between smoking and DNA methylation in blood samples. Only a few studies have examined saliva and buccal cells in this regard. Here, we determined DNA methylation profiles in buccal cells from a total of 280 individuals. Epigenome-wide association analysis (N = 200) uncovered 61 CpG markers, including novel ones, that were significantly associated with smoke exposure in this tissue type. Functional analysis showed that they were overrepresented in the Wnt signaling pathway and fatty acid metabolism. We confirmed that AHRR, a known smoking marker in blood, is also a top locus in buccal cells. However, cg06036945 (p = 1.76 × 10^-10) and cg04066994 (p = 1.36 × 10^-6) may be more informative for smoking in buccal epithelium than the commonly reported cg05575921. Moreover, unlike in blood, several other loci with a similar effect size were discovered in our study, including DKK3 cg16859537 (p = 3.10 × 10^-10) and CYP1B1 cg02162897 (p = 5.67 × 10^-10). The CYP1B1 and AHRR genes are known to interact through the Ah receptor pathway and play an important role in oxidative stress and mediating toxicity. Finally, logistic regression was employed for variable selection and to derive a novel DNA methylation-based classifier for smoking in buccal cells. Four CpG sites, CYP1B1 cg02162897, DKK3 cg16859537, AXIN1 cg12969952 and PKN1 cg12581991 predicted tobacco use with a cross-validated AUC = 0.8, sensitivity of 65.7 % and specificity of 81.5 %. The model was further validated in an independent set of N = 80 samples. The identified genes and pathways may serve as targets for intervention or risk stratification in respiratory diseases, while the developed models can also be instrumental in monitoring patient compliance with treatment recommendations and in behavioral profiling within forensic contexts.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117415"},"PeriodicalIF":3.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181295","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}

{"title":"Isoginkgetin inhibits macrophage activation and ferroptosis of lung epithelial cells under lipopolysaccharide-induced immunological stress via HOXA5-dependent inhibition of the TLR4/NF-κΒ signaling pathway.","authors":"Jian Lu, Aiming Li, Qiaoyan Feng","doi":"10.1016/j.taap.2025.117413","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117413","url":null,"abstract":"<p><p>Sepsis-related acute lung injury (ALI) is a life-endangering respiratory disease. Isoginkgetin (IGK), a natural bioflavonoid, has antioxidant and immunoregulatory activities. This research examined the impacts of IGK on lipopolysaccharide (LPS)-stimulated ALI and investigated the underlying mechanisms. In this study, ferroptosis was assessed by detecting cell viability, Fe²⁺, malondialdehyde, reactive oxygen species, and glutathione levels. Macrophage polarization was evaluated by flow cytometry. The mRNA levels of inducible nitric oxide synthase and arginase 1 were determined by RT-qPCR. The protein levels of HOXA5, toll-like receptor 4 (TLR4), and phosphorylated nuclear factor-kappa B (NF-κB) were determined by western blot. The contents of tumor necrosis factor-α and interleukin-1β were assessed by enzyme-linked immunosorbent assay. Bioinformatics analysis was applied to predict targets of IGK, sepsis-induced ALI, and HOXA5. Results showed that IGK attenuated ferroptosis in LPS-stimulated human lung epithelial cells (BEAS-2B). IGK improved the imbalance of M1/M2 polarization caused by LPS stimulation in murine alveolar macrophages (MH-S). IGK reversed LPS-stimulated downregulation of HOXA5 in BEAS-2B and MH-S cells. Moreover, HOXA5 knockdown attenuated the protective effects of IGK against LPS-stimulated ferroptosis in BEAS-2B cells. HOXA5 knockdown also disrupted IGK's regulatory effects on M1/M2 polarization in alveolar macrophages under LPS-induced inflammation. IGK restrained LPS-stimulated activation of the TLR4/NF-κB signaling, but this effect was partially reversed by HOXA5 knockdown. Additionally, TAK-242 (a TLR4 inhibitor) attenuated the promotive effects of HOXA5 silencing on ferroptosis of BEAS-2B cells and the inflammatory activation of MH-S cells. In conclusion, IGK alleviates LPS-stimulated ferroptosis in BEAS-2B cells and improves the imbalance of M1/M2 polarization in LPS-stimulated macrophages via HOXA5-mediated inhibition of the TLR4/NF-κΒ signaling pathway.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117413"},"PeriodicalIF":3.3,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161125","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}

{"title":"3,4-Dimethoxycinnamic acid from coffee silverskin biowaste ameliorates bleomycin-induced pulmonary fibrosis via modulating caveolin-1-dependent activation of NF-κB, TGF-β1/Smad3, and ERK1/2 signaling pathways","authors":"Mahmoud Elshal ,&nbsp;Abdelrahman Hamdi ,&nbsp;Ibrahim T. Khalil ,&nbsp;El-Shaimaa A. Arafa ,&nbsp;Musaad M. Althobaiti ,&nbsp;Hany H. Arab ,&nbsp;Abdullah Haikal","doi":"10.1016/j.taap.2025.117414","DOIUrl":"10.1016/j.taap.2025.117414","url":null,"abstract":"<div><div>The aim of the current study was to explore the potential beneficial effect of 3,4-dimethoxycinnamic acid (DMCA), obtained from coffee silverskin (CS) biowaste, on bleomycin-induced lung fibrosis in rats and elucidate its possible underlying mechanisms. Lung fibrosis was induced in rats by a single intratracheal administration of bleomycin. DMCA (25 and 50 mg/kg) and pirfenidone (50 mg/kg) were orally administered. Our results showed that DMCA markedly reduced lactate dehydrogenase activity, total protein content, and total and differential inflammatory cell counts in the bronchoalveolar lavage fluid. DMCA also inhibited oxidative stress and nuclear factor kappa B (NF-κB)-mediated tumor necrosis factor and interleukin-1β production. Furthermore, DMCA markedly downregulated the pulmonary levels of transforming growth factor beta 1 (TGF-β1), SMAD family member 3 (Smad3), and extracellular signal-regulated kinase 1/2 (ERK1/2), concurrently with a marked reduction in collagen-1 expression in the lung. Contrarily, DMCA upregulated lung caveolin-1 expression. These findings were concomitantly accompanied by remarkable improvement in the lung histopathology. In conclusion, DMCA effectively mitigates bleomycin-induced lung fibrosis in rats, which is comparable to pirfenidone, through antioxidant, anti-inflammatory, and anti-fibrotic effects. These beneficial effects are mainly mediated through boosting caveolin-1 expression that halts NF-κB, TGF-β1/smad3, and ERK1/2 signaling pathways.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"501 ","pages":"Article 117414"},"PeriodicalIF":3.3,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148035","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}

{"title":"Preclinical evaluation of N-acetyl-cysteine in association with liposomes of lung surfactant's lipids for the treatment of pulmonary fibrosis and asthma","authors":"Estefanía N. Morales ,&nbsp;Constanza Confino Malecki ,&nbsp;Alejandro Maruri ,&nbsp;Vanesa R. Sánchez ,&nbsp;Agustina Portu ,&nbsp;Alejandra Goldman ,&nbsp;Nadia S. Chiaramoni ,&nbsp;Ignacio M. Fenoy","doi":"10.1016/j.taap.2025.117412","DOIUrl":"10.1016/j.taap.2025.117412","url":null,"abstract":"<div><h3>Purpose</h3><div>There is a need to generate new treatments against pulmonary diseases such as idiopathic fibrosis and asthma. <em>N</em>-acetylcysteine (NAC) has multiple clinical applications, but its unstable nature and route of administration limits its effectiveness. New pulmonary delivery strategies, such as liposomes made of lung surfactant lipids, could overcome NAC's limitations. This work aims to evaluate the efficacy of NAC combined with liposomes as a treatment for asthma and in preventing fibrotic development.</div></div><div><h3>Methods</h3><div>Unilamellar vesicles were obtained through the dehydration-rehydration method followed by multiple membrane extrusion and characterized by Dynamic Light Scattering and Transmission electron microscopy. Lung fibrosis was induced by bleomycin administration, and liposomal formulation of NAC (LipoNAC) was evaluated as a preventive treatment. LipoNAC formulation was also evaluated in a therapeutic regimen for asthma using the classic ovalbumin model. For both models, the administration of the treatment was via the intranasal route.</div></div><div><h3>Results</h3><div>NAC treatments (free NAC and LipoNAC) improved lung histopathology and decreased collagen deposition when tested in the lung fibrosis model. Only LipoNAC decreased serum levels of lactate dehydrogenase, myeloperoxidase activity in lung fluid and lung TGF-β. Although both treatments decreased Th2 cytokine and histopathological inflammation in the asthma model, only LipoNAC treatment significantly decreased mucus in asthmatic mice.</div></div><div><h3>Conclusions</h3><div>These results indicate that surfactant liposomal delivery of NAC potentiates its anti-inflammatory, mucolytic, and antioxidant activity, rendering it a promising therapy for respiratory diseases.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117412"},"PeriodicalIF":3.3,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161130","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}

{"title":"Alleviation of LPS-induced oxidative stress and inflammation by lesbicoumestan (7) via the increase of Nrf2 expression in mouse Kupffer cells","authors":"Xiangying Li ,&nbsp;Lulu Yao ,&nbsp;Young-Chang Cho ,&nbsp;Da Young Lee ,&nbsp;Namki Cho ,&nbsp;Guijae Yoo ,&nbsp;Sang Yoon Choi ,&nbsp;Somy Yoon ,&nbsp;Jae Sung Lim","doi":"10.1016/j.taap.2025.117405","DOIUrl":"10.1016/j.taap.2025.117405","url":null,"abstract":"<div><div>Lesbicoumestans are a class of bioactive compounds isolated from the roots of <em>Lespedeza bicolor</em> (<em>L. bicolor</em>). These compounds have been reported to exhibit anticancer and antiproliferative activities. In this study, our primary focus was to examine the antioxidant capabilities of lesbicoumestan (7) (LC-7), a newly isolated coumestan from roots of L. <em>bicolor</em>, using lipopolysaccharide (LPS)-stimulated immortalized mouse Kupffer cells (ImKCs) as the experimental model. The investigation revealed that LC-7 played a pivotal role in inhibiting the production of reactive oxygen species (ROS). Additionally, LC-7 effectively restored the imbalanced glutathione(GSH)/glutathione disulfide ratio and enhanced the activity of glutathione peroxidase (GPx) following cellular exposure to LPS. Moreover, our investigation revealed that LC-7 exhibited the capacity to enhance the expression of heme oxygenase-1 (HO-1), leading to inhibition of nitric oxide (NO) and proinflammatory cytokines production induced by LPS. Notably, LC-7 did not significantly impact the nuclear factor kappa B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Intriguingly, LC-7 modulated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway by direct interaction with Kelch-like-ECH-associated protein 1 (Keap1). These findings suggest that LC-7 possesses antioxidant and anti-inflammatory properties in LPS-stimulated ImKCs by upregulating Nrf2 expression.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"501 ","pages":"Article 117405"},"PeriodicalIF":3.3,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144139196","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}

{"title":"Curcumin induces apoptosis via downregulation of SKP2 and induction of GADD45A/CDKN1A expression through generation of ROS in cutaneous T-cell lymphoma cells","authors":"Shilpa Kuttikrishnan ,&nbsp;Muhammad Suleman ,&nbsp;Fareed Ahmad ,&nbsp;Zahwa Mariyam ,&nbsp;Ummu Habeeba ,&nbsp;Kirti S. Prabhu ,&nbsp;Joerg Buddenkotte ,&nbsp;Martin Steinhoff ,&nbsp;Shahab Uddin","doi":"10.1016/j.taap.2025.117403","DOIUrl":"10.1016/j.taap.2025.117403","url":null,"abstract":"<div><div>Curcumin, a plant derived natural product isolated from <em>Curcuma longa</em>. The aim of this study is to investigate the anti-proliferative effects and the underlying mechanisms of curcumin in Cutaneous T cell lymphoma (CTCL), a type of non-Hodgkin lymphoma that primarily affects the skin. The study found that curcumin induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases leading to growth inhibition. Furthermore, Curcumin treatment downregulated the expression of S-phase kinase protein (SKP2) with concomitant upregulation of GADD45A, CDKN1A and CDKN1B. Curcumin also suppresses the expression of anti-apoptotic molecules including XIAP and cIAPs. Curcumin treatment of CTCL cells generates reactive oxygen species (ROS) and depletion of glutathione. Pretreatment of CTCL with <em>N</em>-acetyl cysteine prevented curcumin-mediated generation of ROS and prevention caspase activity. Co-treatment of CTCL with subtoxic doses of curcumin and bortezomib potentiated the anticancer action.</div><div>Co-treatment of CTCL with subtoxic doses of curcumin and bortezomib potentiated the anticancer action. Molecular docking studies revealed a strong binding affinity of curcumin to the active site of SKP2, primarily involving key residues crucial for its activity.</div><div>Altogether, our results suggest that targeting SKP2 and GADD45A signaling by curcumin could be an attractive strategy for the treatment of CTCL.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"501 ","pages":"Article 117403"},"PeriodicalIF":3.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133246","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}

{"title":"Spermidine exerts cardiometabolic protection in estrogen-deprived rats via mitigating cardiac mitochondrial dysfunction and apoptosis","authors":"Wichida Kaorop ,&nbsp;Chayodom Maneechote ,&nbsp;Wasana Pratchayasakul ,&nbsp;Sirinart Kumfu ,&nbsp;Busarin Arunsak ,&nbsp;Apisek Kongkaew ,&nbsp;Siriporn C. Chattipakorn ,&nbsp;Nipon Chattipakorn","doi":"10.1016/j.taap.2025.117399","DOIUrl":"10.1016/j.taap.2025.117399","url":null,"abstract":"<div><div>Postmenopausal conditions are linked to elevated risks of various complications, particularly cardiovascular diseases (CVDs). While estrogen supplementation is a standard intervention, it increase adverse effects of CVDs and breast cancer prevalence in postmenopausal women. Spermidine, a naturally occurring polyamine, has recently emerged attention for its protective effects in heart pathologies. However, the cardioprotective effects of spermidine against estrogen deprivation-related cardiac dysfunctions remain unclear. We hypothesized that spermidine exerted cardiometabolic protection by mitigating mitochondrial dysfunction, mitochondrial dynamics alterations, oxidative stress, inflammation, and cardiac cell death in female rats with ovariectomy (OVX)-induced estrogen deprivation. Fifty female Wistar rats were divided into a sham group (n = 10) and a 12-week-OVX-operated group (n = 40). The OVX rats were randomly assigned to receive either vehicle treatment, spermidine (OS, 20 mg/kg/day, p.o., n = 10), or estradiol (OE, 50 mg/kg/day, s.c., n = 10) for 8 weeks. Echocardiography and heart rate variability (HRV) were assessed, followed by euthanasia for cardiac tissue collection and blood sampling. OVX rats exhibited impaired metabolic, mitochondrial, and autophagic functions, along with elevated oxidative stress, inflammation, and apoptosis, leading to LV dysfunction. Spermidine and estrogen equally ameliorated all cardiometabolic adverse effects in OVX-induced estrogen-deprived female rats, suggesting spermidine as a promising alternative therapy for preventing cardiometabolic dysfunction in postmenopausal women.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"501 ","pages":"Article 117399"},"PeriodicalIF":3.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133175","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}

{"title":"Dual therapy for amanita phalloides-induced acute liver failure in mice: A combination of etanercept and alpha-1 antitrypsin","authors":"Nils Jedicke ,&nbsp;Nataliia Petriv ,&nbsp;Huizhen Suo ,&nbsp;Inga Hochnadel ,&nbsp;Danny Jonigk ,&nbsp;Ralf Lichtinghagen ,&nbsp;Julia Held ,&nbsp;Paco Pino ,&nbsp;Divor Kiseljak ,&nbsp;Florian M. Wurm ,&nbsp;Maria J. Wurm ,&nbsp;Michael Peter Manns ,&nbsp;Hans Heinrich Wedemeyer ,&nbsp;Sabina Janciauskiene ,&nbsp;Tetyana Yevsa","doi":"10.1016/j.taap.2025.117400","DOIUrl":"10.1016/j.taap.2025.117400","url":null,"abstract":"<div><h3>Background</h3><div>The toxin α-amanitin from <em>Amanita phalloides</em> induces hepatocyte death and disrupts local and systemic immune responses, key drivers of acute liver failure (ALF). Although TNF-α plays a central role in ALF, TNF-α-targeted therapies alone have shown limited efficacy.</div></div><div><h3>Methods</h3><div>Serum alpha1-globulin levels were measured retrospectively in a cohort of patients with amanita-induced ALF. Additionally, a murine interventional study was conducted, incorporating flow cytometry (FACS)-based immunophenotyping to analyze immune cell populations in the liver and lung to assess systemic versus liver-specific immune effects.</div></div><div><h3>Results</h3><div>We observed a correlation between lower serum alpha1-globulin levels—primarily comprising α1-antitrypsin (AAT)—and increased disease severity in patients with amanita-induced ALF. In a murine interventional study aiming to evaluate the therapeutic potential of alpha1-antitrypsin and TNF-α inhibition—alone and in combination—, the combined administration of etanercept (Enbrel®), a TNF-α scavenger, and recombinant AAT (recAAT) produced in CHO cells significantly improved survival rates in mice with amanita-induced ALF. Reduced liver damage markers, including lower cleaved caspase-3 levels, and decreased activation of liver CD4+ T cells and natural killer (NK) cells, accompanied this protective effect. Additionally, there was an increase in liver dendritic cells and IL-6+ TNF-α + macrophages, suggesting their potential role in mitigating liver injury. Immune changes in the lung were less pronounced and showed only modest reductions in CD4⁺ and NK1.1⁺ cells, with no significant shifts in innate immune populations.</div></div><div><h3>Conclusions</h3><div>Our findings from the mouse model suggest a promising approach for treating ALF caused by α-amanitin from <em>Amanita phalloides</em>: the combined use of AAT (broad-spectrum protease inhibitor) and a TNF-α inhibitor. This dual therapy offers a novel and potentially effective treatment strategy for ALF patients.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117400"},"PeriodicalIF":3.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108208","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}

{"title":"Evaluating N-acetylcysteine for mitigating cisplatin-induced oxidative stress and ionocyte damage in a zebrafish model","authors":"Szu-Jung Chen ,&nbsp;Ciao-Ling Wu ,&nbsp;Li-Yih Lin ,&nbsp;Jiun-Lin Horng","doi":"10.1016/j.taap.2025.117401","DOIUrl":"10.1016/j.taap.2025.117401","url":null,"abstract":"<div><div>In this study, we examined the protective effects of <em>N</em>-acetylcysteine (NAC) against cisplatin-induced toxicity in zebrafish embryos. Cisplatin (<em>cis</em>-diamminedichloroplatinum II), a widely used anticancer drug, is associated with significant cytotoxic effects toward non-target tissues, including renal and ototoxic damage. Using zebrafish embryos exposed to cisplatin, we evaluated survival rates, hatching rates, ionocyte densities, oxidative stress, and platinum accumulation. NAC co-treatment significantly enhanced survival and hatching rates, preserved ionocyte density, mitigated oxidative stress, and reduced platinum accumulation. These findings highlight ionocytes as an effective model for assessing non-renal toxicity due to their high metabolic activity and mitochondrial abundance. The results suggest that NAC might serve as a co-therapeutic agent to alleviate cisplatin-induced toxicity during chemotherapy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"501 ","pages":"Article 117401"},"PeriodicalIF":3.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120927","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}