Toxicology and applied pharmacology最新文献

{"title":"T-2 toxin triggers immune toxicity by enhancing glycolysis and activating TLR2/4-MAPK signaling pathways in bovine","authors":"Zhengkai Wei ,&nbsp;Xin Guo ,&nbsp;Jiaxuan Wang ,&nbsp;Yueyin Sun ,&nbsp;Suzhen Yang ,&nbsp;Xinxin Gao ,&nbsp;Yuxiao Qian ,&nbsp;Yuqian Jiang ,&nbsp;Jingxi Zuo ,&nbsp;Dezhi Zhang ,&nbsp;Qianyong Li","doi":"10.1016/j.taap.2025.117485","DOIUrl":"10.1016/j.taap.2025.117485","url":null,"abstract":"<div><div>T-2 toxin, a potent immunotoxic trichothecene, has widely existed in the environment and grains, and been recognized for its detrimental effects on both animal and human immune systems. The recent elucidation of extracellular traps (ETs) as an innate immune response has highlighted their role in the release of heterophil extracellular traps (HETs) in chickens upon T-2 toxin exposure. However, the interplay between T-2 toxin and macrophage extracellular traps (METs) in bovine remains unexplored. In this study, we employed Pico Green staining to demonstrate that T-2 toxin induces METs formation in a dose-dependent manner. Subsequent immunofluorescence analysis confirmed the structures of METs, characterized by a DNA backbone co-localized with citrullinated histone 3 (citH3) and elastase. Additionally, our findings revealed a significant escalation in reactive oxygen species (ROS) levels (<em>P</em> &lt; 0.001) during T-2 toxin-induced METs formation, suggesting the ROS-dependent mechanism of this process. Inhibitor studies further delineated the reliance of T-2 toxin -induced METs on NADPH oxidase activity and the activation of extracellular signal-regulated kinases (ERK_1/2) and p38 signaling pathways. Moreover, our results suggest a synergistic relationship between glycolysis and Toll-like receptor (TLR) signaling in METs formation induced by T-2 toxin. Collectively, this study presents novel evidence that T-2 toxin is capable of eliciting METs formation in bovine macrophages, potentially offering novel strategies for mitigating tissue damage and addressing food safety concerns associated with chronic T-2 toxin exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117485"},"PeriodicalIF":3.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703359","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":"Phenanthrene and its halogenated derivative inhibit adipogenesis and decrease peroxisome proliferator-activated receptor gamma (PPARγ) expression independently of aryl hydrocarbon receptor (AhR) activation","authors":"Syed A. Syeddan ,&nbsp;Eunnara Cho ,&nbsp;Jennifer Crosthwait ,&nbsp;Alison C. Holloway ,&nbsp;Ella Atlas","doi":"10.1016/j.taap.2025.117486","DOIUrl":"10.1016/j.taap.2025.117486","url":null,"abstract":"<div><div>Polycyclic aromatic hydrocarbons (PAHs) are natural by-products of incomplete combustion of fossil fuels, wood, incinerator waste, and are also used in man-made dyes, plastics, and pesticides. Humans are mostly exposed to PAHs through air (ex. smoke inhalation), drinking water, and foods. Phenanthrene (Phe) is the most abundant PAH found in the environment, however there are very few studies that have examined either its systemic health effects or its effects on metabolism and adipogenesis. Halogenated-polycyclic aromatic hydrocarbons (HPAHs) are a class of PAHs that have a halogen bound to an aromatic ring of a PAH, leading to increased potency compared to their PAH derivatives and yet are studied even less so than PAHs. Extensive research on another PAH, and a strong AhR activator, Benzo[<em>a</em>]pyrene (BaP) showed that BaP inhibited adipogenesis <em>in vitro</em> amongst other effects. In this study, we proceeded to investigate the effects of Phe and its halogenated counterpart, 9-chloro-phenanthrene (9P), on adipogenesis in the 3 T3-L1 cell line. Our results show that Phe and 9P inhibited adipogenesis independently of AhR upregulation or activation, indicated by their inability to increase the expression of the AhR and its downstream target gene CYP1A1. We also show that both Phe and 9P decreased PPARγ mRNA, and more pronouncedly protein expression. Further, effects on expression of proteins in the insulin signaling pathway, and adipokines were also observed, suggesting a global effect on adipocyte function.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117486"},"PeriodicalIF":3.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694424","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":"Higenamine hydrochloride prevents renal inflammation and fibrosis in diabetic nephropathy by inhibiting the STAT3 signaling pathway","authors":"Ying Li ,&nbsp;Zhi-Hao Ma ,&nbsp;Xiao Liu ,&nbsp;Wenting Zhu ,&nbsp;Long Chen ,&nbsp;Wanyi Xu ,&nbsp;Lei Wang ,&nbsp;Jingquan Dong ,&nbsp;Zi-Bo Dong","doi":"10.1016/j.taap.2025.117483","DOIUrl":"10.1016/j.taap.2025.117483","url":null,"abstract":"<div><div>Higenamine Hydrochloride (HGN) is an alkaloid derived from the traditional Chinese medicinal herb Aconite, possesses pharmacological activities such as anti-inflammatory and antioxidant properties. Its specific role in diabetic nephropathy (DN) remains unknown. The purpose of this work was to investigate the protective impact of HGN against streptozotocin (STZ)-induced renal inflammation and fibrosis in DN mice, as well as to investigate its probable mechanism of action in vitro using high glucose (HG)-treated HK-2 cells. We constructed a mouse model of DN by intraperitoneal injection of STZ and a HK-2 cell model using HG treatment, followed by administration of HGN. Tissue distribution experiments, biochemical analysis, real-time PCR, immunoblotting, and histopathological examination were used to assess the effects of HGN on renal histopathology, inflammation, and fibrosis in DN mice and its molecular mechanisms. The results demonstrated that in the renal tissues of DN mice, HGN had the highest concentration. HGN treatment led to body weight increase, and blood glucose levels fell as well as the improvement in metabolic abnormalities. It further proved that HGN alleviated renal function damage by lowering serum creatinine (SCr), blood urea nitrogen (BUN), cystatin C (Cys-C), and renal index values. Moreover, HGN improved kidney histopathology, reduced renal tubular damage, and decreased interstitial inflammation. The kidneys had less collagen accumulation. At the same time, HGN decreased the expression of markers associated with inflammation (iNOS, IL-1β, IL-6, MCP-1) and fibrosis (Collagen-I, MMP9, α-SMA, CTGF). Mechanistic studies have shown that, in vitro, HGN inhibits STAT3 phosphorylation, thereby inhibiting the expression of inflammatory (iNOS, IL-1β, IL-6, and MCP-1) and fibrosis-related cytokines (Collagen-I, MMP9, α-SMA, and CTGF) in HK-2 cells under HG conditions. To summarize, HGN inhibits renal inflammation and fibrosis in DN mice by inhibiting the STAT3 pathway, and this discovery offers a new possible target for DN treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117483"},"PeriodicalIF":3.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694422","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":"Potential risks prompted from epicutaneous and intranasal exposure to indoxacarb in rats","authors":"Eman I. Hassanen ,&nbsp;Marwa H. Hassan ,&nbsp;Ahmed M. Hussien","doi":"10.1016/j.taap.2025.117479","DOIUrl":"10.1016/j.taap.2025.117479","url":null,"abstract":"<div><div>Indoxacarb (IDX) is a new highly selective insecticide with excellent activity against a wide variety of pests. This study evaluated the possibility of dermal and nasal mucosal absorption of indoxacarb in rats in order to assess the potential hazards to humans and animals. 28 female albino Wistar rats were randomly divided into 4 groups (<em>n</em> = 7) as follow: group 1 (Ctrl1) normal saline via intranasal route, group 2 (Ctrl2) normal saline via topical dressing, group 3 (IDX-IN) IDX via intranasal route (0.42 mg/L, 1/10 LC50), and group 4 (IDX-T) the same concentration of IDX via topical dressing. The results revealed the highest serum levels of ALT, AST, CPK, and LDH in the IDX-T group, but the lowest level of IgG and IgM were recorded in the IDX-IN group. Furthermore, the IDX-T group exhibited various degrees of histopathological changes in most organs including skin, liver, heart, and lungs, while IDX-IN group showed prominent lesions in the lungs, immune organs, and most brain areas. The histopathological lesions were confirmed by the caspase-3 immunostaining that demonstrated strong casp-3 expression in the lungs, spleen, thymus, and brain of IDX-IN group, whereas IDX-T group noticed higher casp-3 expression in liver, heart, and lungs sections than IDX-IN group.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117479"},"PeriodicalIF":3.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675651","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":"Significant enhancement of inhibitory strength of bisphenol A analogs against human and rat 5α-reductase 1 upon halogenation of the benzene ring: Potentially disrupting neurosteroid biosynthesis","authors":"Shihan Wang ,&nbsp;Shaowei Wang ,&nbsp;Han Lu ,&nbsp;Binbin Lu ,&nbsp;Huitao Li ,&nbsp;Yingfen Ying ,&nbsp;Ren-shan Ge ,&nbsp;Yunbing Tang","doi":"10.1016/j.taap.2025.117480","DOIUrl":"10.1016/j.taap.2025.117480","url":null,"abstract":"<div><div>Bisphenol A (BPA) halogenation derivatives, formed via radical or electrophilic substitution, constitute a class of emerging contaminants, with brominated variants dominating the flame-retardant market. Their effect on steroid 5α-reductase 1 (SRD5A1) activity in neural and testicular cells remains unclear. This study examined inhibitory effects of seven BPA analogs on SRD5A1, focusing on dihydrotestosterone synthesis. Using SRD5A1 in human brain SF126 cell and rat testicular microsomes, we found an inhibitory potency gradient. For human SRD5A1: tetrabromobisphenol A (12.71 μM) &gt; tetrachlorobisphenol A (16.01 μM) &gt; trichlorobisphenol A (18.95 μM) &gt; 3-chlorobisphenol A (45.37 μM) &gt; BPA = bisphenol S (BPS) = tetrabromobisphenol S (no effect at 100 μM). For rat enzyme: tetrabromobisphenol A (3.60 μM) &gt; tetrachlorobisphenol A (9.27 μM) &gt; trichlorobisphenol A (12.43 μM) &gt; 3-chlorobisphenol A (26.37 μM) &gt; BPA (over 100 μM) = BPS (over 100 μM) &gt; tetrabromobisphenol S (no effect at 100 μM). The inhibition was mixed/competitive. Structure-activity relationship (SAR) analysis showed negative correlations between IC₅₀ values and logarithm of the partition coefficient (LogP), heavy atoms, and hetero atoms of these chemicals for both enzymes. 3D-QSAR pharmacophore analysis showed key binding features to human SRD5A1. Tetrabromobisphenol A has all, while 3-chlorobisphenol A only has hydrophobic sites. Computational docking explained molecular interactions with SRD5A1 binding sites, linking to physicochemical properties. These findings demonstrate SRD5A1 inhibition nuances by halogenated BPA analogs with direct relevance to potential implications. Our data establish the inhibitory potential of halogenated BPA analogs on human brain SRD5A1, revealing distinct SAR and molecular interactions. The inclusion of the rat model provided comparative insight into species-specific responses, underscoring the importance of considering both human relevance and interspecies variability in evaluating endocrine-disrupting risks.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117480"},"PeriodicalIF":3.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675652","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":"Glycosylation on breast cancer cell surface promotes the internalization and enhances therapeutic efficacy of cationic antimicrobial peptide L-K6","authors":"Bo Wang ,&nbsp;Yiwei Zhao ,&nbsp;Qiuju Zhang ,&nbsp;Jiaqi Zhao ,&nbsp;Che Wang ,&nbsp;Dejing Shang","doi":"10.1016/j.taap.2025.117481","DOIUrl":"10.1016/j.taap.2025.117481","url":null,"abstract":"<div><div>Cationic antimicrobial peptides (CAPs) have demonstrated anticancer activity, which is thought to arise from interactions with negatively charged molecules on cancer cell membranes. However, the precise cellular and molecular mechanisms underlying this process remain unclear. In this study, we investigated the role of negatively charged glycosylated molecules, located on the cell surface and endosomal membranes, in the internalization and anticancer activity of L-K6, a synthetic lysine/leucine-rich CAP, using three human breast cancer cell lines. Our findings revealed that sialic acid on cell membrane critically impacts L-K6's binding and internalization. Specifically, monosialotetrahexosylganglioside (GM1) and O-glycosylated Mucin-1 (bearing sialic acid) promoted L-K6 entry via caveolae-mediated endocytosis and macropinocytosis, whereas N-glycoproteins inhibited uptake. Furthermore, sialic acid on endosomal membranes enhanced L-K6 escape from endosomes, preventing intracellular degradation and enabling cytotoxic activity. Collectively, our results demonstrate that glycosylated molecules on breast cancer cells regulate L-K6 internalization and cytotoxicity, providing a foundation for developing novel peptide-based anticancer therapies targeting cell surface glycosylation.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117481"},"PeriodicalIF":3.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675650","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":"Pharmacodynamics, safety pharmacology and local tolerance of rotigotine behenate extended-release microspheres","authors":"Yumeng Chen ,&nbsp;Zhicong Yin ,&nbsp;Caiyi Qin ,&nbsp;Mengting Wu ,&nbsp;Wenjing Lv ,&nbsp;Xinyu Zhao ,&nbsp;Xiaoyin Zhu ,&nbsp;Guangying Du ,&nbsp;Jingwei Tian ,&nbsp;Xin Yu ,&nbsp;Wanhui Liu ,&nbsp;Yuanyingzhu Liang ,&nbsp;Wei Guo ,&nbsp;Xiaobo Cen","doi":"10.1016/j.taap.2025.117478","DOIUrl":"10.1016/j.taap.2025.117478","url":null,"abstract":"<div><div>Continuous dopaminergic stimulation (CDS) is a key strategy in Parkinson's disease (PD) treatment. We developed Rotigotine Behenate Extended-Release Microspheres (RBEM), an injectable 28-day sustained-release formulation that hydrolyzes <em>in vivo</em> to release active rotigotine, maintaining therapeutic levels. RBEM shows improved PK profiles-longer duration and more stable drug concentrations-<em>versus</em> existing CDS therapies. Its monthly dosing also enhances patient compliance, potentially optimizing efficacy and safety. Thus RBEM represents a promising advance in CDS for PD. A comprehensive preclinical assessment of RBEM was conducted to support clinical trial initiation. Gi Cell-based functional assay demonstrated that Rotigotine (active metabolite) showed potent agonism at dopamine D₃ (EC₅₀ = 0.53 nM), D_2S (11.6 nM), and D_2L (21 nM) receptors. Its prodrug, rotigotine behenate, exhibited selective D_2S agonism (EC₅₀ = 42 nM). Electrophysiological assessment using manual patch clamp technique revealed that RBEM showed weak hERG inhibition (IC₅₀ = 0.12 μM) but no cardiotoxicity in 20-week primate studies. Whole-body plethysmography studies demonstrated that dose-dependent increases in respiratory rate/min volume were observed in rats (180–540 mg/kg), but not in primates. No significant CNS effects (FOB assay, SD rats) or hemolysis (rabbit erythrocytes, ≤ 227 mg/mL). Intramuscular injection caused reversible irritation attributable to PLGA excipient, consistent with marketed microsphere formulations.</div><div>In summary, RBEM's pharmacological activity is mediated by rotigotine release, with a favorable preclinical safety profile supporting clinical development. Respiratory, cardiovascular, and injection-site reactions should be prioritized in clinical monitoring.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117478"},"PeriodicalIF":3.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668575","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":"Biodistribution and toxicity following a single or repeated pharyngeal aspiration of titanium dioxide nanoparticles: Determination of maximum allowable dose level","authors":"Wonkyun Jung ,&nbsp;Cheolho Yoon ,&nbsp;Sujin Jeon ,&nbsp;Taekyung Yu ,&nbsp;Mi-Jin Yang ,&nbsp;Nam Chul Kwon ,&nbsp;Seong-Jin Choi ,&nbsp;Eun-Jung Park","doi":"10.1016/j.taap.2025.117477","DOIUrl":"10.1016/j.taap.2025.117477","url":null,"abstract":"<div><div>Establishing reasonable exposure conditions is crucial for maximizing the potential benefits of nanomaterials while ensuring their safety. We first identified the effects of overdose on lung tissue damage and deposition levels under different exposure scenarios (50 μg four times, 100 μg twice, and 200 μg once). Blood levels of IP and K changed significantly in the group that received a single 200 μg dose. In all TiONP-treated groups, the amount of TiONPs remaining in the lung tissues increased dramatically, accompanied by an increase in the total number of pulmonary cells and a decrease in the proportion of macrophages. A type I helper T cell-dominant inflammatory response was observed across all TiONP-treated groups, and the accumulation of pigmented macrophages was most notable in the lung tissue of mice exposed to a single dose of 200 μg of TiONPs. We then investigated biodistribution and clearance levels over time after a single dose (25 and 50 μg/lung). The amount of TiONPs remaining in the lung decreased over time. However, approximately32.6 % and 58.3 % of the amounts detected on Day 1 after a single dose persisted until Day 28 in the lungs of mice given 25 μg and 50 μg, respectively. Translocation to other tissues was more notable in mice exposed to the highest dose, and more interestingly, the TiONPs that moved to the liver showed limited clearance by Day 28 after a single dose. In conclusion, overdosed TiONPs may facilitate tissue accumulation and translocation by affecting the function of alveolar macrophages. Additionally, considering the high tissue deposition rate, we suggest that the maximum allowable dose level for the respiratory tract should be carefully determined.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117477"},"PeriodicalIF":3.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668574","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":"Metabolism disrupting effects in human pre-adipocytes: Influence of donor sex and body composition","authors":"Praneeth Goli,&nbsp;Thomas A. Kocarek,&nbsp;Christopher D. Kassotis","doi":"10.1016/j.taap.2025.117463","DOIUrl":"10.1016/j.taap.2025.117463","url":null,"abstract":"<div><div>There is growing attention on the global, worsening rates of metabolic disorders, including obesity. Numerous attempted interventions have provided only modest effects, with current rates of obesity in the United States remaining high (e.g., 42.4 % of adults and 8.9 % of infants and toddlers). Metabolism-disrupting chemicals (MDCs) are one proposed causal factor and are chemicals that can disrupt adipocyte development and differentiation in vitro and/or metabolism in vivo (e.g., increased weight, adipose). High costs prohibit comprehensive rodent screening for MDCs, necessitating the use of in vitro models to better screen and prioritize chemicals for higher-order testing. This study aimed to evaluate human adipose-derived pre-adipocytes as a potential model for determining MDCs, focusing on donor sex and body composition impacts on adipogenesis. Adipogenesis assays were performed on male and female human subcutaneous pre-adipocytes isolated from lean and obese donors. The response of each donor cell line to hormones and chemicals known to promote adipogenesis was examined, evaluating both sex and body composition impacts on triglyceride accumulation and pre-adipocyte proliferation. Results showed considerable variability between and within donor groups, complicating the findings of MDCs' consistent effects. While human pre-adipocyte models appear to offer a closer mimic of real-life responses, a careful assessment of variability is needed. Despite challenges, this model provides valuable insights into how MDCs impact individuals variably based on sex, body composition, and genetic makeup.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117463"},"PeriodicalIF":3.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660350","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":"Clarithromycin attenuates severe steroid hyporesponsive asthma by regulating type 2/type 17 inflammation balance and inhibiting mast cell activation","authors":"Yongjing Zhang ,&nbsp;Xinping Zhang ,&nbsp;Chenjia Li ,&nbsp;Mengyang Ma ,&nbsp;Jie Gao ,&nbsp;Tingting Deng ,&nbsp;Chang Gao ,&nbsp;Nan Wang","doi":"10.1016/j.taap.2025.117476","DOIUrl":"10.1016/j.taap.2025.117476","url":null,"abstract":"<div><div>Asthma is a global notifiable disease that is mainly treated with glucocorticoids and airway relaxants. Some patients with neutrophilic airway inflammation are not sensitive to glucocorticoids therapy and there is no effective treatment available. Clarithromycin (CLA) is a commonly used macrolide antibiotic in clinical practice and is used in the treatment of lower respiratory tract infections. However, the underlying mechanism remain unclear. The inhibitory effect of CLA on epithelial cells inflammation and mast cells (MCs) activation <em>in vitro</em> or <em>in vivo</em> were measured. LPS/OVA induced severe steroid hyporesponsive asthma (SSHA) mice were used to evaluate CLA relief on pulmonary inflammation, bronchoalveolar lavage fluid (BALF) cytokines release, and airway hyperresponsiveness (AHR). CLA inhibited the secretion of inflammatory mediators from epithelial cells induced by LPS + IL-13 and modulated type 2/type 17 inflammation balance induced by IL-13 + TNF-α or IL-17 A. Besides, CLA inhibited MRGPRX2 induced MCs activation directly <em>in vitro</em> and pseudo-allergic reaction <em>in vivo</em>. Furthermore, the activation and proliferation of MCs incubated with LPS + IL-13 induced epithelial cell supernatant was inhibited when CLA was applied. <em>In vivo</em> study confirmed that CLA attenuated SSHA mice symptoms. CLA has the potential as a therapeutic drug for SSHA by regulating epithelial cells type 2/type 17 inflammation balance and inhibiting mast cell activation.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117476"},"PeriodicalIF":3.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660349","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}