Chemico-Biological Interactions最新文献

{"title":"The role of mitochondrial dysfunction and calcium dysregulation in 2C-I and 25I-NBOMe-induced neurotoxicity","authors":"Eva Gil-Martins ,&nbsp;Fernando Cagide ,&nbsp;Ana Borer ,&nbsp;Daniel José Barbosa ,&nbsp;Carlos Fernandes ,&nbsp;Daniel Chavarria ,&nbsp;Fernando Remião ,&nbsp;Fernanda Borges ,&nbsp;Renata Silva","doi":"10.1016/j.cbi.2025.111425","DOIUrl":"10.1016/j.cbi.2025.111425","url":null,"abstract":"<div><div>New psychoactive substances (NPS) are designed to evade legal regulation while mimicking the effects of classic illicit drugs such as 3,4-methylenedioxymethamphetamine (MDMA). This category includes phenethylamine derivatives, such as the psychedelic 2C and NBOMe drugs. Given the lack of data regarding the toxicological profile of these substances, the goal of this study was to evaluate the neurotoxicity of 2C-I and 25I-NBOMe and explore their neurotoxic pathways. Lower EC₅₀ values, in both NR uptake and MTT reduction assays in differentiated SH-SY5Y cells and primary rat cortical cultures, revealed that 25I-NBOMe is significantly more cytotoxic than 2C-I, likely due to its higher lipophilicity. Both drugs triggered severe mitochondrial dysfunction, characterized by decreased intracellular ATP levels and mitochondrial membrane depolarization, although no significant changes in intracellular ROS/RNS levels were observed. Additionally, 25I-NBOMe increased the intracellular Ca²⁺ levels. Apoptosis was an observed mechanism of cell death for both drugs, as demonstrated by a significant increase in the number of cells undergoing early apoptosis (AnV⁺/PI⁻) and late apoptosis/necrosis (AnV⁺/PI⁺). However, only 2C-I induced autophagy and strongly triggered caspase-3 activation. This suggests that 2C-I induces caspase-3-dependent apoptosis, whereas 25I-NBOMe may also induce apoptosis through a caspase-3-independent pathway, possibly involving increased intracellular Ca²⁺ levels and direct mitochondrial damage.</div><div>These findings underscore the complex interplay between mitochondrial dysfunction, calcium dysregulation, and cell death pathways, highlighting the central role of mitochondria in the cytotoxicity of 2C-I and 25I-NBOMe.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"411 ","pages":"Article 111425"},"PeriodicalIF":4.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimony-induced hippocampal neuronal impairment through ferroptosis activation from NCOA4-mediated ferritinophagy","authors":"Shali Yu ,&nbsp;Ziyu Qin ,&nbsp;Yuqing Chen ,&nbsp;Fengxu Wang ,&nbsp;Zhijie Li ,&nbsp;Ruiyao Huang ,&nbsp;Zhengnan Gao ,&nbsp;Yi Qu ,&nbsp;Peng Xue ,&nbsp;Yonghua Luo ,&nbsp;Xiaoke Wang ,&nbsp;Xinyuan Zhao","doi":"10.1016/j.cbi.2025.111415","DOIUrl":"10.1016/j.cbi.2025.111415","url":null,"abstract":"<div><div>Recently, our group identified antimony (Sb) as a novel nerve pollutant, can lead to neuronal injure. However, Sb-associated neurotoxicological mechanisms yet remain unclear. Herein, we found Sb induced hippocampal neuronal ferroptosis in <em>vivo</em> and in <em>vitro</em>. Moreover, ferroptosis inhibition using ferrostatin-1 effectively attenuated Sb-induced neuronal damage in PC12 cells and mice hippocampal regions. Furthermore, iron chelator deferoxamine (DFO) also effectively attenuated ferroptosis and cytotoxicity in PC12 cells. In vitro, Sb treatment reduced expression of the heavy (H)- and light (L)-chain subunits of ferritin (FTH1 and FTL). Moreover, Sb accelerated FTH1 and FTL protein degradation, while ferritin overexpression by plasmid or hippocampal AAV injections dramatically weaken Sb-induced ferroptosis. Sb exposure accelerated autophagic flux, and autophagy inhibition with beclin1 knockdown effectively reduced Sb-mediated ferroptosis. 3-methyladenine treatment in Sb-exposed mice prevented the decrease of FTH1 and FTL protein, resulting in recovery of Sb-induced hippocampal ferroptosis as well as neuronal loss, suggesting that Sb triggered hippocampal neuronal ferritinophagy. Finally, we found Sb upregulated NCOA4 protein expression, while NCOA4 knockdown significantly attenuated Sb-triggered ferroptosis. Collectively, our results proved that Sb triggers hippocampal neuronal ferroptosis through NCOA4-dependent ferritinophagy.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"409 ","pages":"Article 111415"},"PeriodicalIF":4.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pulsatilla saponin D inhibited the growth of osteosarcoma by regulating the JNK/ATF3 signaling pathway","authors":"Kaipeng Jin ,&nbsp;Chengchun Shen ,&nbsp;Wei Yu ,&nbsp;Jinti Lin ,&nbsp;Jian Zhu ,&nbsp;Huimin Tao ,&nbsp;Bing Liu","doi":"10.1016/j.cbi.2025.111420","DOIUrl":"10.1016/j.cbi.2025.111420","url":null,"abstract":"<div><div>Osteosarcoma (OS) is a highly malignant and aggressive bone tumor associated with early lung metastasis and high mortality. Traditional chemotherapy does not effectively improve the efficacy and survival rate of patients with OS. Thus, it is vital to search for alternative therapies. Pulsatilla saponin D (PSD) is a potent bioactive compound that has been widely employed in cancer therapy due to its diverse bioactivities and minimal adverse effects. However, any effect on OS remains unclear. We found that PSD induced apoptosis of OS cells and investigated the mechanisms thereof. In vitro, PSD dose-dependently induced apoptosis and inhibited the viability of HOS and K7M2 cells. Furthermore, PSD significantly suppressed cell migration and invasion, and caused cell cycle arrest at the G0/G1 phase. Mechanistically, PSD upregulated ATF3 and JUN transcription by controlling JNK expression. Compared to cells treated with PSD alone, cells pre-treated with SP600125 (a JNK inhibitor), or in which ATF3 had been knocked down ATF3 with siRNA, did not exhibit PSD-mediated cell apoptosis. In a murine OS model, PSD exhibited a powerful anti-cancer effect and an excellent safety profile. Our data imply that PSD could effectively prevent OS occurrence and progression.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"410 ","pages":"Article 111420"},"PeriodicalIF":4.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockout of TRPM2 protects against cyclophosphamide-induced premature ovarian failure via inhibiting AMPK/p53 signaling pathway","authors":"Penghui Nie ,&nbsp;Ruiying Zhang ,&nbsp;Tiantian Jia ,&nbsp;Jialyu Huang ,&nbsp;Hengyi Xu","doi":"10.1016/j.cbi.2025.111426","DOIUrl":"10.1016/j.cbi.2025.111426","url":null,"abstract":"<div><div>The global prevalence of premature ovarian failure (POF) is from 3.1 % to 4.3 %, which is a multifactorial disease including genetics, environmental and medical factors. However, the occurrence of POF is not well understood. To further explore the potential mechanism of POF, cyclophosphamide (CTX) was used to construct the model of POF. Additionally, the occurrence of POF was related to oxidative stress, apoptosis, proliferation and others. Ca²⁺ is essential for almost all life processes. Therefore, TRPM2-deficient mice was used to explore the role of Ca²⁺ in POF. The results indicated that the mouse serum E₂ and AMH levels decreased, FSH and LH levels increased, and the activity of antioxidant enzymes including CAT, SOD and GSH decreased with mtROS accumulation in the ovary, thereby causing ovarian DNA damage, promoting ovarian cell apoptosis and inhibiting cell proliferation after wild-type mice exposed to CTX. Notably, these indicators have improved after TRPM2^−/−. Based on these, we have further proved that the activation TRPM2 channel could lead to intracellular Ca²⁺ overload, plentiful Ca²⁺ bind to calmodulin accompanied with mitochondrial ROS accumulation, thereby activating AMPK/p53 signaling pathway, inducing proliferation arrest and excessive apoptosis. We hope to provide therapeutic targets to prevent the occurrence of POF by studying the potential mechanism of POF.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"409 ","pages":"Article 111426"},"PeriodicalIF":4.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicokinetics and reproductive toxicity of maternal bisphenol AF exposure during gestation in offspring of Sprague Dawley rats","authors":"Yaxuan Zhu ,&nbsp;Xiuxiang Liu ,&nbsp;Xiuying Liu ,&nbsp;Yijiao Shi ,&nbsp;Huaxin Li ,&nbsp;Shaoguo Ru ,&nbsp;Hua Tian","doi":"10.1016/j.cbi.2025.111424","DOIUrl":"10.1016/j.cbi.2025.111424","url":null,"abstract":"<div><div>Bisphenol AF (BPAF) has been widely used as a main alternative to bisphenol A (BPA), and previous <em>in vitro</em> studies have shown that BPAF has higher reproductive toxicity potentials than BPA. However, data on <em>in vivo</em> toxicity of BPAF is still limited. In this study, Sprague Dawley rats were exposed to BPAF (0, 50, and 100 mg/kg/day) during gestation to study toxicokinetics and reproductive toxicity in offspring. The results showed that plasma concentrations BPAF peaked within 6 h after birth, followed by a two-phase decay, with clearance rates of approximately 3.0 l/h and terminal half-life values ranging from 77 h to 114 h, suggesting fast absorption and high persistence of BPAF. At postnatal day 21 (PND21), BPAF was found to be bioaccumulated in reproductive organs (testes and ovaries) of the offspring, resulting in adverse effects on reproduction in both sexes. Lower anogenital distance, reduced relative testicular weight, dissolved interstitial cells, fewer primary spermatocytes, decreased testosterone levels, and increased luteinizing hormone levels were detected in male offspring. In female offspring, vacuolization in follicular antrum, fewer follicles, increased 17<em>β</em>-estradiol levels, and increased luteinizing hormone levels in female offspring were found. Gene expression of <em>scavenger receptor class B type I</em> (<em>SR-B1</em>), <em>3-hydroxy-3-methylglutaryl-CoA reductase</em> (<em>HMGR</em>), <em>sterol regulatory element-binding protein-1c</em> (<em>SREBP-1c</em>), and several steroidogenic enzymes was significantly decreased in male offspring following maternal exposure to BPAF, suggesting that the decreases in testosterone levels is a result of inhibited cholesterol uptake, cholesterol <em>de novo</em> synthesis, and steroidogenesis. In addition, inhibition of pathways of phagosome and cell adhesion molecules might be the underlying molecular mechanism involved in BPAF-induced reproductive disorders in male offspring. This study provides the scientific basis for a comprehensive assessment of the safety of BPAF.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"409 ","pages":"Article 111424"},"PeriodicalIF":4.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Warning on the inhalation of silica nanoparticles: Experimental evidence for its easy passage through the air-blood barrier, resulting in systemic distribution and pathological injuries","authors":"Hailin Xu ,&nbsp;Yurou Zhu ,&nbsp;Lingnan Zhu ,&nbsp;Donglei Wang ,&nbsp;Songqing Lv ,&nbsp;Xueyan Li ,&nbsp;Caixia Guo ,&nbsp;Yanbo Li","doi":"10.1016/j.cbi.2025.111423","DOIUrl":"10.1016/j.cbi.2025.111423","url":null,"abstract":"<div><div>As a result of accumulating data, silica nanoparticles (SiNPs) are known to be harmful when inhaled. Nevertheless, the systemic research on its biological processes remains incompletely understood. In our work, we investigated the systemic effects in rats in response to the respiratory exposure of SiNPs, and in-depth clarified the particle distribution <em>in vivo</em>. Moreover, a model of the air-blood barrier was developed to assess the interplay of SiNPs with the epithelium/endothelium interface <em>in vitro</em>. The model was established <em>via</em> a transwell co-culturing of the alveolar epithelium (MLE-12) and the pulmonary microvascular epithelium (MPVECs). Consequently, our data revealed a systemic particle distribution and ensuing multi-tissue pathological injuries in SiNPs-instilled rats, including the heart, spleen, and kidneys. Simultaneously, the translocation of SiNPs passing through the air-blood barrier was verified <em>in vitro</em>. Also, a dose-dependent interruption to the air-blood barrier integrity by SiNPs was noticed <em>in vitro</em>, accompanied by the damage of tight junctions. SiNPs translocation across the air-blood barrier can inevitably facilitate the extra-pulmonary distribution of SiNPs and ensuing systemic effects. Overall, this study provides evidence on the systemic toxicity potential of SiNPs, while highlighting the significance of comprehending SiNPs toxicity and ultimately controlling the health hazards.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"409 ","pages":"Article 111423"},"PeriodicalIF":4.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MjTX-II, a Lys49-PLA2 from Bothrops moojeni snake venom, restricts Toxoplasma gondii infection via ROS and VEGF regulation","authors":"Samuel Cota Teixeira ,&nbsp;Thales Alves de Melo Fernandes ,&nbsp;Guilherme de Souza ,&nbsp;Alessandra Monteiro Rosini ,&nbsp;Aryani Felixa Fajardo Martínez ,&nbsp;Angelica Oliveira Gomes ,&nbsp;Rosiane Nascimento Alves ,&nbsp;Daiana Silva Lopes ,&nbsp;Maria Vitoria da Silva ,&nbsp;Emidio Beraldo-Neto ,&nbsp;Patrícia Bianca Clissa ,&nbsp;Bellisa Freitas Barbosa ,&nbsp;Veridiana de Melo Rodrigues Ávila ,&nbsp;Eloisa Amália Vieira Ferro","doi":"10.1016/j.cbi.2025.111417","DOIUrl":"10.1016/j.cbi.2025.111417","url":null,"abstract":"<div><div>Owing to the lack of efficient therapy and emerging resistance strains, toxoplasmosis affects about one-third of the world's population. Also, pregnancy-related infection can cause vertical transmission and result in fetal death. Despite the global efforts to combat <em>Toxoplasma gondii</em> infection, conventional therapies have been associated with serious side effects. Therefore, it is relevant to search for effective and less-toxic treatments of toxoplasmosis. In this scenario, snake venoms emerged as a promising source of therapeutic molecules due to their wide variety of biological effects. The present study investigated the anti-<em>T. gondii</em> effects of MjTX-II, a Lys49-PLA₂ isolated from <em>Bothrops moojeni,</em> in trophoblast cells and villous explants from the third trimester of pregnancy. We found that non-cytotoxic doses of MjTX-II impaired parasite invasion and intracellular growth in BeWo cells. Also, MjTX–II–pre-treated <em>T. gondii</em> tachyzoites exhibited irregular rough surfaces, papules, and dimples, suggesting a possible action directly on the parasites. Moreover, MjTX-II was able to modulate the host environment by increasing ROS and cytokine levels involved in the control of infection. In addition, we observed that MjTX-II decreased VEGF levels and the addition of rVEGF increased <em>T. gondii</em> growth in BeWo cells. Through molecular docking simulations, we verified that MjTX-II is able to bind VEGFR2 and ICAM-1 receptors associated with parasite proliferation and dissemination. This work contributes to the discovery of therapeutic targets against <em>T. gondii</em> infection and for the development of effective and low-toxic antiparasitic molecules against congenital toxoplasmosis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"409 ","pages":"Article 111417"},"PeriodicalIF":4.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate-triggered histone lactylation contributes to podocyte epithelial-mesenchymal transition in diabetic nephropathy in mice","authors":"Ting Zheng ,&nbsp;Yan-Ping Gu ,&nbsp;Jiang-Meng Wang ,&nbsp;Ting-Ting Huang ,&nbsp;Ling-Shan Gou ,&nbsp;Yao-Wu Liu","doi":"10.1016/j.cbi.2025.111418","DOIUrl":"10.1016/j.cbi.2025.111418","url":null,"abstract":"<div><div>Diabetic nephropathy (DN) closely relates to morphological and functional changes of podocytes, and anaerobic glycolysis represents the predominant energy source of podocytes. However, it is unknown whether lactate accumulation in chronic high glucose causes epithelial-mesenchymal transition (EMT) of podocytes through lactate-derived histone lysine lactylation (HKla). Lactate levels increased in high glucose-stimulated mouse podocyte cell line MPC and blood and the kidney of diabetic mice. High glucose or exogenous lactate decreased nephrin levels while increased collagen IV and HKla levels in MPC, but co-treatment with oxamate or dichloroacetate reduced lactate levels and alleviated the decreases in nephrin and zonula occludens- 1 levels and the increases in collagen IV and α-smooth muscle actin as well as HKla levels in high glucose-cultured MPC. However, co-treatment with rotenone diversely affected these indices. Eleven intersection genes were screened in lactate raising and lowering interventions in podocytes using RNA sequencing and four genes were validated by qPCR. Furthermore, lactate-lowering treatments attenuated renal functions, EMT, and histone lactylation in the kidney of diabetic mice. Additionally, the increased lactate might result from the upregulated monocarboxylate transporter 2 in the mitochondria and the decreased pyruvate dehydrogenase activity. Together, we reveal the role of histone lactylation in driving the EMT phenotype of podocytes in chronic high glucose state, subsequently promoting the pathological process of DN. Our study provides a reference for the study of the relationship between lactate-induced histone lactylation modification and diabetic complications.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"408 ","pages":"Article 111418"},"PeriodicalIF":4.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acid binding protein 4 regulates doxorubicin-induced renal injury via mediating lipid metabolism and apoptosis","authors":"Chuchu Wang ,&nbsp;Tao Zhang ,&nbsp;Yufeng Guan ,&nbsp;Boye Han ,&nbsp;Shang Wu ,&nbsp;Xu Wang ,&nbsp;Jing Yu ,&nbsp;Junxia Zhang ,&nbsp;Guoqiang Zhang ,&nbsp;Qingfeng Miao ,&nbsp;Suwen Su","doi":"10.1016/j.cbi.2025.111419","DOIUrl":"10.1016/j.cbi.2025.111419","url":null,"abstract":"<div><div>Doxorubicin(DOX) is an anthracycline chemotherapeutic drug used in the treatment of a wide range of tumors. However, the nephrotoxicity has limited the clinical application of DOX. Fatty acid-binding protein 4 (FABP4), a key adipokine mainly expressed in adipocytes, is strongly associated with kidney dysfunction and kidney disease. This study aims to investigate the role of FABP4 in DOX-induced nephrotoxicity. <em>In vivo</em> experiments, the mice were divided into 4 groups randomly: CON group, DOX group, 4T1 group, and 4T1 + DOX group respectively. DOX was given by intraperitoneal injection at a dose of 15 mg/kg. The kidney function indicators, the morphology and lipid deposition in renal tissues and the preliminary mechanism were assessed. <em>In vitro</em> experiment, HK-2 cell was used to detect DOX-induced kidney cell injury with or without BMS309403. DOX caused renal dysfunction in both DOX group and 4T1 + DOX group, with a more severe kidney injury in DOX group. DOX also induced kidney lipid deposition, glycerophospholipids metabolism dysfunction, apoptosis accompanied by increased FABP4 and decreased Peroxisome Proliferator Activated Receptor- γ (PPAR-γ) levels in the kidney tissues. The decreased cell viability, increased apoptotic ratio, elevated protein levels of apoptosis and the lipid deposition caused by DOX were all alleviated by BMS309403. FABP4 mediated DOX induced kidney damage in normal mice and tumor-bearing mice by lipid metabolism disorders and cell apoptosis. This study may enhance the clinical management of DOX-induced kidney injury and provide new therapeutic targets and preventive strategies for the clinical application of DOX.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"408 ","pages":"Article 111419"},"PeriodicalIF":4.7,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143369848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple mechanisms of action of a triazole-derived salt against Leishmania amazonensis: Apoptosis-like death and autophagy","authors":"Andrezza Rodrigues de Souza ,&nbsp;Luciana Maria Ribeiro Antinarelli ,&nbsp;Ari Sergio de Oliveira Lemos ,&nbsp;Nicolas Glanzmann ,&nbsp;Bruno Vicente ,&nbsp;Victor do Valle Midlej ,&nbsp;Adolfo Firmino da Silva Neto ,&nbsp;Rachel Rocha Pinheiro Machado ,&nbsp;Adilson David da Silva ,&nbsp;Elaine Soares Coimbra","doi":"10.1016/j.cbi.2025.111409","DOIUrl":"10.1016/j.cbi.2025.111409","url":null,"abstract":"<div><div>Current chemotherapy for leishmaniasis faces significant limitations due to high toxicity, prolonged treatment regimens, and increasing parasite resistance, highlighting the urgent need for innovative treatment strategies. This study aimed to evaluate the <em>in vitro</em> activity of 1,2,3-triazole derivatives against promastigotes and amastigotes of <em>Leishmania amazonensis</em>, as well as their cytotoxicity in murine macrophages. Additionally, we investigated the mechanism of parasite death through different biochemical and cellular indicators of cell death parameters. Our results underscored the importance of the salt form, as the neutral form showed no inhibition of parasite growth. In contrast, the triazole-derived salt demonstrated promising selective index (SI = 34.28) and antileishmanial activity (IC₅₀ = 0.13 μM and IC₅₀ = 2.06 μM against promastigote and amastigote forms, respectively), proving more active than miltefosine, the standard drug. Regarding the mode of action of the triazole-derived salt, this compound induced significant mitochondrial alterations in the parasite, characterized by an increase in mitochondrial membrane potential (ΔΨm), elevated levels of total and mitochondrial Reactive Oxygen Species (ROS), and lipid body accumulation in the cytoplasm. Treatment with triazole-derived salt also produced several ultrastructural, biochemical, and cellular changes in the promastigote forms, such as the occurrence of apoptosis-<em>like</em> death, including cell shrinkage and reduction in length, as well as exposure of phosphatidylserine in the outer leaflet of the plasma membrane and marked cell cycle interruption, in addition to DNA fragmentation. Despite MDC positive and the presence of membrane-bound vacuoles resembling autophagosomal structures observed by TEM analysis, autophagy is not a predominant process, with severe mitochondrial damage emerging as the primary event leading to parasite death. These findings demonstrate the promising antileishmanial potential of the triazole-derived salt, with its effect on multiple targets in parasite cells. Moreover, the association of the active compound with miltefosine showed an additive effect in treating <em>L. amazonensis</em>-infected macrophages. Altogether, these results highlight the therapeutic potential of the evaluated salt and support further studies to assess its <em>in vivo</em> efficacy in a murine model of cutaneous leishmaniasis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"409 ","pages":"Article 111409"},"PeriodicalIF":4.7,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}