Pub Date : 2025-12-16DOI: 10.1016/j.cbi.2025.111864
Qian Wang, Jin Wang, Hongmei Wang, Meng Jin, Runli Gao, Xiaogang Lu
Organophosphorus nerve agents (OPNAs) are highly toxic compounds that disrupt the central nervous system through irreversible inhibition of acetylcholinesterase. Classified as chemical weapons under the Chemical Weapons Convention (CWC), OPNAs necessitate reliable and extended-window detection methods for exposure verification. To expand the range of biomarker candidates for OPNA exposure in food matrices, this study investigated the in vitro formation of adducts between ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO)—a predominant protein in spinach—and V-type OPNAs. Mass spectrometry identified 13 reproducibly adducted peptides; notably, 5 peptides showed conserved covalent modification sites across all three OPNAs investigated in this study (VX, VR, and Vs), indicating agent-independent targeting. The modified sequences GHYLNATAGTCEDMMK (Y239/C247), WSPELAAACEVWK (C459), YGRPLLGCTIKPK (Y165), and FLFC∗AEALYK (C221) exhibited high adduct stability. These stable and modified peptides are promising biomarkers for OPNA-exposure tracking. Thus, this study provides a basis for the forensic analysis of organophosphorus toxicant residues and food safety incident investigations.
{"title":"Protein adduct formation between RuBisCO and V-type organophosphorus nerve agents","authors":"Qian Wang, Jin Wang, Hongmei Wang, Meng Jin, Runli Gao, Xiaogang Lu","doi":"10.1016/j.cbi.2025.111864","DOIUrl":"10.1016/j.cbi.2025.111864","url":null,"abstract":"<div><div>Organophosphorus nerve agents (OPNAs) are highly toxic compounds that disrupt the central nervous system through irreversible inhibition of acetylcholinesterase. Classified as chemical weapons under the Chemical Weapons Convention (CWC), OPNAs necessitate reliable and extended-window detection methods for exposure verification. To expand the range of biomarker candidates for OPNA exposure in food matrices, this study investigated the <em>in vitro</em> formation of adducts between ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO)—a predominant protein in spinach—and V-type OPNAs. Mass spectrometry identified 13 reproducibly adducted peptides; notably, 5 peptides showed conserved covalent modification sites across all three OPNAs investigated in this study (VX, VR, and Vs), indicating agent-independent targeting. The modified sequences GHYLNATAGTCEDMMK (Y239/C247), WSPELAAACEVWK (C459), YGRPLLGCTIKPK (Y165), and FLFC∗AEALYK (C221) exhibited high adduct stability. These stable and modified peptides are promising biomarkers for OPNA-exposure tracking. Thus, this study provides a basis for the forensic analysis of organophosphorus toxicant residues and food safety incident investigations.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111864"},"PeriodicalIF":5.4,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783769","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}
Pub Date : 2025-12-16DOI: 10.1016/j.cbi.2025.111873
Weisheng Chen , Brendon R. Herring , Jasmine Watts , Caroline MacVicar , David Crossman , Nilesh Kumar , M. Shahid Mukhtar , Flavio Rocha , Kris V. Kowdley , J. Bart Rose
Cholangiocarcinoma is often very challenging to diagnose due to high false negative biopsy rates. There are known precursors to cholangiocarcinoma such as primary sclerosing cholangitis and hepatitis; however, identifying early and sensitive biomarkers for liver injury and tumor progression could enhance cancer diagnosis, prognosis, and management. Recent studies have suggested blood and bile-based microRNA (miRNA) panels performed better than existing tumor markers. To further investigate this, we conducted next-generation sequencing of thioacetamide (TAA) induced cholangiocarcinoma in an established rat model. We identified 2938 unique differentially expressed genes (DEGs) and 27 differentially expressed miRNAs (DEMs) between tumor bearing rats and normal controls. Pathway analyses on the DEGs and DEMs revealed the molecular mechanisms of hepatic hyperplasia and nephritis. To filter for ideal biomarkers, we further performed qPCR on bile and serum. Three miRNAs (miR-146b-5p, miR-223–3p and miR-214–3p) overlapped with the DEMs from solid tumors. Therefore, those miRNAs have the potential to serve as early and sensitive biomarkers for TAA-induced cholangiocarcinoma. Notably, no previous study has demonstrated the role of miR-146–5p on cancer development.
{"title":"Novel MicroRNA biomarkers revealed in the serum and bile of thioacetamide induced cholangiocarcinoma","authors":"Weisheng Chen , Brendon R. Herring , Jasmine Watts , Caroline MacVicar , David Crossman , Nilesh Kumar , M. Shahid Mukhtar , Flavio Rocha , Kris V. Kowdley , J. Bart Rose","doi":"10.1016/j.cbi.2025.111873","DOIUrl":"10.1016/j.cbi.2025.111873","url":null,"abstract":"<div><div>Cholangiocarcinoma is often very challenging to diagnose due to high false negative biopsy rates. There are known precursors to cholangiocarcinoma such as primary sclerosing cholangitis and hepatitis; however, identifying early and sensitive biomarkers for liver injury and tumor progression could enhance cancer diagnosis, prognosis, and management. Recent studies have suggested blood and bile-based microRNA (miRNA) panels performed better than existing tumor markers. To further investigate this, we conducted next-generation sequencing of thioacetamide (TAA) induced cholangiocarcinoma in an established rat model. We identified 2938 unique differentially expressed genes (DEGs) and 27 differentially expressed miRNAs (DEMs) between tumor bearing rats and normal controls. Pathway analyses on the DEGs and DEMs revealed the molecular mechanisms of hepatic hyperplasia and nephritis. To filter for ideal biomarkers, we further performed qPCR on bile and serum. Three miRNAs (miR-146b-5p, miR-223–3p and miR-214–3p) overlapped with the DEMs from solid tumors. Therefore, those miRNAs have the potential to serve as early and sensitive biomarkers for TAA-induced cholangiocarcinoma. Notably, no previous study has demonstrated the role of miR-146–5p on cancer development.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111873"},"PeriodicalIF":5.4,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783819","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}
Pub Date : 2025-12-15DOI: 10.1016/j.cbi.2025.111883
Dinara Afrose , Sofía Alfonso-Sánchez , Ashleigh Philp , Philip M. Hansbro , Qian Peter Su , Lana McClements
Preeclampsia is a multifactorial pregnancy disorder characterized by the new onset of hypertension and organ damage. Mitochondrial dysfunction is central to preeclampsia pathogenesis leading to placental dysfunction and oxidative stress. This study aims to elucidate the mechanisms of mitochondrial dysfunction in first-trimester trophoblast cells and to assess the therapeutic potential of aspirin, metformin, resveratrol, and a FKBPL-based peptide (AD-01) as a strategy to improve trophoblast mitochondrial health. A 2D in vitro model using the first trimester ACH-3Ps trophoblasts were developed to mimic preeclampsia-like conditions, including hypoxia-inducible factor (HIF)-1α activation (DMOG, 100 μM), mitochondrial dysfunction (Rho-6G, 1 μg/mL), or inflammation (TNF-α, 10 ng/ml). Cells were treated for 48 h with metformin (0.5 mM), resveratrol (15 μM), AD-01 (100 nM), or aspirin (0.5 mM), in the presence of DMOG, Rho-6G or TNF--α. Mitochondrial dynamics were assessed by immunofluorescence staining, the Seahorse XF Mito Stress Test, and RT-qPCR for key genes expression regulating mitochondrial fusion (mfn1), fission (dnm1l), and autophagy (atg5, map1lc3b). Preeclampsia-mimicking stimuli significantly altered mitochondrial networks by reducing mitochondrial size (p <0.05-0.0001), increasing circularity (p < 0.05-0.0001), and decreasing mitochondrial number per cell (p < 0.0001). Metformin notably restored mitochondrial architecture under inflammatory stress, normalized mfn1 (p < 0.05) and atg5 expression (p < 0.001), and improved cellular bioenergetics. Aspirin improved mitochondrial morphology under hypoxic conditions and reduced oxygen consumption (p < 0.01). Resveratrol and AD-01 showed context-dependent protective effects, including reduced basal respiration under inflammatory stress (p < 0.0001). These findings demonstrate that hypoxia, inflammation, and mitochondrial dysfunction contribute to mitochondrial pathology in preeclampsia and highlight aspirin, metformin, resveratrol, and AD-01 as promising targeted therapies. Tailored interventions may improve mitochondrial health and pregnancy outcomes in women with preeclampsia.
{"title":"Targeting trophoblast cell mitochondrial dysfunction in preeclampsia via drug repurposing","authors":"Dinara Afrose , Sofía Alfonso-Sánchez , Ashleigh Philp , Philip M. Hansbro , Qian Peter Su , Lana McClements","doi":"10.1016/j.cbi.2025.111883","DOIUrl":"10.1016/j.cbi.2025.111883","url":null,"abstract":"<div><div>Preeclampsia is a multifactorial pregnancy disorder characterized by the new onset of hypertension and organ damage. Mitochondrial dysfunction is central to preeclampsia pathogenesis leading to placental dysfunction and oxidative stress. This study aims to elucidate the mechanisms of mitochondrial dysfunction in first-trimester trophoblast cells and to assess the therapeutic potential of aspirin, metformin, resveratrol, and a FKBPL-based peptide (AD-01) as a strategy to improve trophoblast mitochondrial health. A 2D <em>in vitro</em> model using the first trimester ACH-3Ps trophoblasts were developed to mimic preeclampsia-like conditions, including hypoxia-inducible factor (HIF)-1α activation (DMOG, 100 μM), mitochondrial dysfunction (Rho-6G, 1 μg/mL), or inflammation (TNF-α, 10 ng/ml). Cells were treated for 48 h with metformin (0.5 mM), resveratrol (15 μM), AD-01 (100 nM), or aspirin (0.5 mM), in the presence of DMOG, Rho-6G or TNF--α. Mitochondrial dynamics were assessed by immunofluorescence staining, the Seahorse XF Mito Stress Test, and RT-qPCR for key genes expression regulating mitochondrial fusion (<em>mfn1</em>), fission (<em>dnm1l</em>), and autophagy (<em>atg5, map1lc3b</em>). Preeclampsia-mimicking stimuli significantly altered mitochondrial networks by reducing mitochondrial size (p <0.05-0.0001), increasing circularity (p < 0.05-0.0001), and decreasing mitochondrial number per cell (p < 0.0001). Metformin notably restored mitochondrial architecture under inflammatory stress, normalized <em>mfn1</em> (p < 0.05) and <em>atg5</em> expression (p < 0.001), and improved cellular bioenergetics. Aspirin improved mitochondrial morphology under hypoxic conditions and reduced oxygen consumption (p < 0.01). Resveratrol and AD-01 showed context-dependent protective effects, including reduced basal respiration under inflammatory stress (p < 0.0001). These findings demonstrate that hypoxia, inflammation, and mitochondrial dysfunction contribute to mitochondrial pathology in preeclampsia and highlight aspirin, metformin, resveratrol, and AD-01 as promising targeted therapies. Tailored interventions may improve mitochondrial health and pregnancy outcomes in women with preeclampsia.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111883"},"PeriodicalIF":5.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776494","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}
Pub Date : 2025-12-15DOI: 10.1016/j.cbi.2025.111886
Yasemin Aydin, Banu Orta Yilmaz
5-Hydroxymethylfurfural (HMF) is a heat-induced food contaminant commonly present in processed products and regularly ingested through the diet. Although its genotoxic, neurotoxic, and carcinogenic effects have been demonstrated in various tissues, the cellular effects of HMF on the male reproductive system are still not sufficiently elucidated. For the first time, this study comprehensively evaluated the toxic effects of HMF on Sertoli (TM4) and type B spermatogonium (GC-1) cell lines. HMF was administered to TM4 and GC-1 cells at concentrations of 0.1, 1, and 10 mM for 24 h. The findings revealed that HMF caused concentration-dependent cytotoxicity in both cell types. HMF was found to cause significant increases in total reactive oxygen species and lipid peroxidation levels in germ cells. Gene expression analyses indicated disruptions in the Nrf2, Keap1, and Parp1 genes that affect cell defense mechanisms. HMF exposure led to significant increases in Trp53, Bax, and Casp3 gene expression, a decrease in the anti-apoptotic Bcl2 gene, and elevated CASP3 protein levels in both cell lines. Furthermore, significant increases in autophagy-related Atg5, Lc3a/b, and Beclin-1 genes and proteins were observed following HMF administration. Also, our study demonstrated that the PI3K/AKT/mTOR signaling pathway was suppressed, and cellular death mechanisms were modulated through this pathway. Our results suggest that the toxic effects of HMF vary depending on the cell type and elicit a more pronounced response, particularly in GC-1 cells. In conclusion, HMF can cause cytotoxic effects in male germ cells by activating oxidative stress, apoptosis, and autophagy pathways.
{"title":"5-Hydroxymethylfurfural triggers autophagy and apoptosis in sertoli and spermatogonial cells via suppression of the PI3K/AKT/mTOR pathway","authors":"Yasemin Aydin, Banu Orta Yilmaz","doi":"10.1016/j.cbi.2025.111886","DOIUrl":"10.1016/j.cbi.2025.111886","url":null,"abstract":"<div><div>5-Hydroxymethylfurfural (HMF) is a heat-induced food contaminant commonly present in processed products and regularly ingested through the diet. Although its genotoxic, neurotoxic, and carcinogenic effects have been demonstrated in various tissues, the cellular effects of HMF on the male reproductive system are still not sufficiently elucidated. For the first time, this study comprehensively evaluated the toxic effects of HMF on Sertoli (TM4) and type B spermatogonium (GC-1) cell lines. HMF was administered to TM4 and GC-1 cells at concentrations of 0.1, 1, and 10 mM for 24 h. The findings revealed that HMF caused concentration-dependent cytotoxicity in both cell types. HMF was found to cause significant increases in total reactive oxygen species and lipid peroxidation levels in germ cells. Gene expression analyses indicated disruptions in the <em>Nrf2</em>, <em>Keap1</em>, and <em>Parp1</em> genes that affect cell defense mechanisms. HMF exposure led to significant increases in <em>Trp53</em>, <em>Bax</em>, and <em>Casp3</em> gene expression, a decrease in the anti-apoptotic <em>Bcl2</em> gene, and elevated CASP3 protein levels in both cell lines. Furthermore, significant increases in autophagy-related Atg5, Lc3a/b, and Beclin-1 genes and proteins were observed following HMF administration. Also, our study demonstrated that the PI3K/AKT/mTOR signaling pathway was suppressed, and cellular death mechanisms were modulated through this pathway. Our results suggest that the toxic effects of HMF vary depending on the cell type and elicit a more pronounced response, particularly in GC-1 cells. In conclusion, HMF can cause cytotoxic effects in male germ cells by activating oxidative stress, apoptosis, and autophagy pathways.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111886"},"PeriodicalIF":5.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775520","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}
Pub Date : 2025-12-15DOI: 10.1016/j.cbi.2025.111884
Hagyu Kim , YuJin Shin , Hong-Hee Choi , Kyungmin Kim , Hye-Jin Kim , Haewon Kim , Wonsik Lee , Sung Jae Shin
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major infectious disease with high mortality globally. Polyhexamethylene guanidine (PHMG), a cationic polymer and major ingredient of humidifier disinfectants, was implicated in an outbreak of severe pulmonary diseases including TB in the Republic of Korea. During the period when humidifier disinfectants were widely used, the incidence of TB exhibited a rising trend. In this study, we aimed to investigate whether PHMG aggravates TB pathogenesis and elucidate the underlying mechanisms by which PHMG exposure modulates TB progression. In a murine model of Mtb infection, PHMG exposure accelerated TB progression, characterized by increased Mtb burden, alveolar macrophage (AM) depletion, excessive neutrophil accumulation-mediated severe pulmonary inflammation, and impaired Th1 immunity. Transcriptomic profiling of PHMG-exposed Mtb-infected AMs revealed induction of type I interferon (IFN) signatures, inflammatory cytokines including Il1a, Tnf, and Il6, and chemokines for neutrophil recruitment such as Cxcl2 and Cxcl3, indicating a pathway associated with aggravated TB outcomes. Consistently, blockade of type I IFN receptor signaling or depletion of neutrophils by relevant antibodies significantly reduced inflammation and Mtb burden in the lungs. Our study demonstrated that PHMG exacerbated TB via the elevated type I IFN signaling and neutrophilic inflammation and uncovered how environmental toxicants such as PHMG would influence host defense system and act as risk factors for TB progression.
{"title":"Exposure to polyhexamethylene guanidine, a humidifier disinfectant, disrupts protective immunity and accelerates tuberculosis progression via type I IFN signaling and neutrophil influx in mice","authors":"Hagyu Kim , YuJin Shin , Hong-Hee Choi , Kyungmin Kim , Hye-Jin Kim , Haewon Kim , Wonsik Lee , Sung Jae Shin","doi":"10.1016/j.cbi.2025.111884","DOIUrl":"10.1016/j.cbi.2025.111884","url":null,"abstract":"<div><div>Tuberculosis (TB), caused by <em>Mycobacterium tuberculosis</em> (Mtb), remains a major infectious disease with high mortality globally. Polyhexamethylene guanidine (PHMG), a cationic polymer and major ingredient of humidifier disinfectants, was implicated in an outbreak of severe pulmonary diseases including TB in the Republic of Korea. During the period when humidifier disinfectants were widely used, the incidence of TB exhibited a rising trend. In this study, we aimed to investigate whether PHMG aggravates TB pathogenesis and elucidate the underlying mechanisms by which PHMG exposure modulates TB progression. In a murine model of Mtb infection, PHMG exposure accelerated TB progression, characterized by increased Mtb burden, alveolar macrophage (AM) depletion, excessive neutrophil accumulation-mediated severe pulmonary inflammation, and impaired Th1 immunity. Transcriptomic profiling of PHMG-exposed Mtb-infected AMs revealed induction of type I interferon (IFN) signatures, inflammatory cytokines including <em>Il1a</em>, <em>Tnf</em>, and <em>Il6</em>, and chemokines for neutrophil recruitment such as <em>Cxcl2</em> and <em>Cxcl3</em>, indicating a pathway associated with aggravated TB outcomes. Consistently, blockade of type I IFN receptor signaling or depletion of neutrophils by relevant antibodies significantly reduced inflammation and Mtb burden in the lungs. Our study demonstrated that PHMG exacerbated TB via the elevated type I IFN signaling and neutrophilic inflammation and uncovered how environmental toxicants such as PHMG would influence host defense system and act as risk factors for TB progression.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111884"},"PeriodicalIF":5.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775472","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}
Pub Date : 2025-12-15DOI: 10.1016/j.cbi.2025.111878
Daohua Cao , Xiaoyang Zhou , Jiaolong Huang , Peng Duan , Zhen Zhang , Ying Liu , Huiyu Luo
Midazolam (MDZ), a widely used short-acting benzodiazepine, has been linked to developmental and neurotoxic effects, yet its underlying molecular mechanisms during early development remain unclear. This study examined the impact of MDZ on zebrafish embryos and larvae through phenotypic, behavioural, and transcriptomic analyses. Embryos were exposed to MDZ at 2 and 4 mg/L from 6 to 96 h post-fertilisation (hpf). MDZ exposure significantly increased mortality, delayed hatching, and induced morphological abnormalities, indicating developmental toxicity. Neurotoxic effects included elevated apoptosis in both brain and heart regions, reduced spontaneous movement, and altered motor responses to light–dark stimulation. MDZ also decreased heart rate and body size, highlighting its detrimental impact on growth and cardiac function. Transcriptomic profiling identified 1496 DEGs (380 up-regulated and 1116 down-regulated) and revealed altered expression of genes involved in GABAergic synapse, PPAR signalling, cardiac muscle contraction, oestrogen and MAPK signalling, apoptosis, phototransduction, and osteoclast differentiation. These molecular changes likely underpin the observed developmental and neurotoxic outcomes. Notably, locomotor impairments persisted up to 5 days post-fertilisation (dpf), partially recovered by 7 dpf, and approached normalization by 10 dpf. Collectively, these findings underscore the developmental risks of MDZ exposure and provide molecular insights that may inform safer clinical practice.
{"title":"Midazolam-induced developmental toxicity and neurotoxicity in zebrafish embryos: Insights from phenotypic, behavioural, and transcriptomic analyses","authors":"Daohua Cao , Xiaoyang Zhou , Jiaolong Huang , Peng Duan , Zhen Zhang , Ying Liu , Huiyu Luo","doi":"10.1016/j.cbi.2025.111878","DOIUrl":"10.1016/j.cbi.2025.111878","url":null,"abstract":"<div><div>Midazolam (MDZ), a widely used short-acting benzodiazepine, has been linked to developmental and neurotoxic effects, yet its underlying molecular mechanisms during early development remain unclear. This study examined the impact of MDZ on zebrafish embryos and larvae through phenotypic, behavioural, and transcriptomic analyses. Embryos were exposed to MDZ at 2 and 4 mg/L from 6 to 96 h post-fertilisation (hpf). MDZ exposure significantly increased mortality, delayed hatching, and induced morphological abnormalities, indicating developmental toxicity. Neurotoxic effects included elevated apoptosis in both brain and heart regions, reduced spontaneous movement, and altered motor responses to light–dark stimulation. MDZ also decreased heart rate and body size, highlighting its detrimental impact on growth and cardiac function. Transcriptomic profiling identified 1496 DEGs (380 up-regulated and 1116 down-regulated) and revealed altered expression of genes involved in GABAergic synapse, PPAR signalling, cardiac muscle contraction, oestrogen and MAPK signalling, apoptosis, phototransduction, and osteoclast differentiation. These molecular changes likely underpin the observed developmental and neurotoxic outcomes. Notably, locomotor impairments persisted up to 5 days post-fertilisation (dpf), partially recovered by 7 dpf, and approached normalization by 10 dpf. Collectively, these findings underscore the developmental risks of MDZ exposure and provide molecular insights that may inform safer clinical practice.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111878"},"PeriodicalIF":5.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776423","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}
Pub Date : 2025-12-13DOI: 10.1016/j.cbi.2025.111877
Juan Perdomo , Henoc del Rosario , Ester Saavedra , Mercedes Said , Celina García , Lía Cruces , Susana Abdala , Ignacio Brouard , José Quintana , Francisco Estévez
Chalcones are biosynthetic precursors of flavonoids and are considered potential anticancer drugs. Here, twenty-two chalcones were synthesized and evaluated for their effects on the viability of eight human leukaemia cells. This series of chalcones was characterized by the presence or absence of a benzyloxy group on the A ring and one or two substituents on the B ring including halogen, methoxy, trifluoromethyl, benzyloxy, morpholine and pyridine in the chalcone skeleton. Chalcones with the lowest IC50 values against leukaemia cells contained a benzyloxy group at position 2′ on the A ring and one or two halogens, or a 2-pyridyl group at position 4 on the B ring. The chalcone 6′-benzyloxy-2′-hydroxy-4-(2-pyridyl)chalcone (BHP) exhibited potency comparable to the antitumor agent etoposide against U-937 cells while showing lower toxicity against human peripheral blood mononuclear cells. BHP-induced viability inhibition was not linked to cell cycle arrest but was associated with apoptosis. Overexpression of the antiapoptotic protein Bcl-2 and the P-glycoprotein did not prevent its activity. In U-937 and HL-60 cells, BHP triggered mitochondrial cytochrome c release, activation of caspases and poly(ADP-ribose) polymerase cleavage and increased annexin-V positive cells. Cell death triggered by BHP was (i) blocked by a pan-caspase inhibitor and by a specific caspase-9 inhibitor, (ii) associated with the phosphorylation of the mitogen-activated protein kinases and (iii) dependent of the generation of reactive oxygen species.
{"title":"Structure-activity relationships reveal a 4-(2-pyridyl)chalcone as a potent cell death inducer","authors":"Juan Perdomo , Henoc del Rosario , Ester Saavedra , Mercedes Said , Celina García , Lía Cruces , Susana Abdala , Ignacio Brouard , José Quintana , Francisco Estévez","doi":"10.1016/j.cbi.2025.111877","DOIUrl":"10.1016/j.cbi.2025.111877","url":null,"abstract":"<div><div>Chalcones are biosynthetic precursors of flavonoids and are considered potential anticancer drugs. Here, twenty-two chalcones were synthesized and evaluated for their effects on the viability of eight human leukaemia cells. This series of chalcones was characterized by the presence or absence of a benzyloxy group on the A ring and one or two substituents on the B ring including halogen, methoxy, trifluoromethyl, benzyloxy, morpholine and pyridine in the chalcone skeleton. Chalcones with the lowest IC<sub>50</sub> values against leukaemia cells contained a benzyloxy group at position 2′ on the A ring and one or two halogens, or a 2-pyridyl group at position 4 on the B ring. The chalcone 6′-benzyloxy-2′-hydroxy-4-(2-pyridyl)chalcone (BHP) exhibited potency comparable to the antitumor agent etoposide against U-937 cells while showing lower toxicity against human peripheral blood mononuclear cells. BHP-induced viability inhibition was not linked to cell cycle arrest but was associated with apoptosis. Overexpression of the antiapoptotic protein Bcl-2 and the P-glycoprotein did not prevent its activity. In U-937 and HL-60 cells, BHP triggered mitochondrial cytochrome <em>c</em> release, activation of caspases and poly(ADP-ribose) polymerase cleavage and increased annexin-V positive cells. Cell death triggered by BHP was (<em>i</em>) blocked by a pan-caspase inhibitor and by a specific caspase-9 inhibitor, (<em>ii</em>) associated with the phosphorylation of the mitogen-activated protein kinases and (<em>iii</em>) dependent of the generation of reactive oxygen species.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111877"},"PeriodicalIF":5.4,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764659","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}
Pub Date : 2025-12-13DOI: 10.1016/j.cbi.2025.111876
Ming Xia , Xiaoli Liu , Kun Wang , Boping Liang , Peilin Xiao
Aspartame, a widely used non-nutritive sweetener, has been epidemiologically linked to coronary heart disease (CHD), although the underlying mechanisms remain unclear. This study employed an integrative computational strategy combining network toxicology, molecular docking, and molecular dynamics to decode aspartame's CHD-promoting mechanisms. Initially, the toxicity profile of aspartame was predicted using ProTox 3.0 and ADMETlab 3.0, which highlighted significant cardiotoxicity. Through multi-source target screening of aspartame (PharmMapper, SEA, etc.) and CHD (GeneCards, OMIM), 216 shared targets were identified. Protein-protein interaction network analysis revealed 10 hub targets (INS, PPARGC1A, TNF, AKT1, IL6, MMP9, IGF1, PTGS2, SIRT1, PPARG). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed significant enrichment in lipid metabolism, inflammatory responses, insulin resistance, and atherosclerosis-related pathways. Molecular docking and molecular dynamics simulations (MDS) demonstrated high-affinity binding of aspartame to three core targets (PTGS2, TNF, and PPARGC1A), with a binding energy ≤ −7.0 kcal/mol, and confirmed high binding stability. This study reveals that aspartame may promote the pathogenesis of CHD by disrupting cardiovascular homeostasis through multi-target interactions, including inflammatory response, metabolic dysregulation, and vascular remodeling. These findings provide molecular evidence for re-evaluating the safety profile of aspartame and establish a computational framework to guide experimental validation and preventive strategies.
{"title":"From sweetener to risk factor: Network toxicology, molecular docking and molecular dynamics reveal the mechanism of aspartame in promoting coronary heart disease","authors":"Ming Xia , Xiaoli Liu , Kun Wang , Boping Liang , Peilin Xiao","doi":"10.1016/j.cbi.2025.111876","DOIUrl":"10.1016/j.cbi.2025.111876","url":null,"abstract":"<div><div>Aspartame, a widely used non-nutritive sweetener, has been epidemiologically linked to coronary heart disease (CHD), although the underlying mechanisms remain unclear. This study employed an integrative computational strategy combining network toxicology, molecular docking, and molecular dynamics to decode aspartame's CHD-promoting mechanisms. Initially, the toxicity profile of aspartame was predicted using ProTox 3.0 and ADMETlab 3.0, which highlighted significant cardiotoxicity. Through multi-source target screening of aspartame (PharmMapper, SEA, etc.) and CHD (GeneCards, OMIM), 216 shared targets were identified. Protein-protein interaction network analysis revealed 10 hub targets (INS, PPARGC1A, TNF, AKT1, IL6, MMP9, IGF1, PTGS2, SIRT1, PPARG). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed significant enrichment in lipid metabolism, inflammatory responses, insulin resistance, and atherosclerosis-related pathways. Molecular docking and molecular dynamics simulations (MDS) demonstrated high-affinity binding of aspartame to three core targets (PTGS2, TNF, and PPARGC1A), with a binding energy ≤ −7.0 kcal/mol, and confirmed high binding stability. This study reveals that aspartame may promote the pathogenesis of CHD by disrupting cardiovascular homeostasis through multi-target interactions, including inflammatory response, metabolic dysregulation, and vascular remodeling. These findings provide molecular evidence for re-evaluating the safety profile of aspartame and establish a computational framework to guide experimental validation and preventive strategies.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111876"},"PeriodicalIF":5.4,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145758381","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}
Pub Date : 2025-12-12DOI: 10.1016/j.cbi.2025.111880
N Anirudh Singh, Saikat Sen
|Glomerulonephritis (GN) is a rare kidney disorder associated with prolonged inflammation, fibrosis, and mitochondrial dysfunction at the glomeruli layer and nearby capillaries, which leads to the loss of glomeruli integrity and function. A pathogen-driven immune response is most often responsible for acute glomerulonephritis (AGN). In contrast, chronic glomerulonephritis (CGN) is more severe and characterized by irreversible loss of glomerular integrity with excessive fibrosis, often leading to progression to end-stage renal disease. Few pathways, such as WNT, Notch, PI3K/AKT, JAK-STAT, Complement, cGAS-STING, and TGF-β, have been linked to the progression and development of glomerular injury, characterized by mitochondrial dysfunction, inflammation, and fibrosis. However, the AMPK pathway has been reported to be protective against glomerular deterioration. Additionally, the dopaminergic system in the kidney has been linked to protecting glomerular integrity by downregulating mitochondrial dysfunction, inflammation, and fibrosis. This review highlights pathways that can potentially deteriorate and protect glomerular health. Additionally, it also provides an overview of the role of the dopaminergic system in attenuating glomerular injury. Suchdiscussion will provide a comprehensive understanding of potential therapeutic targets for attenuating CGN.
{"title":"Molecular insights into chronic glomerulonephritis and dopamine interplay","authors":"N Anirudh Singh, Saikat Sen","doi":"10.1016/j.cbi.2025.111880","DOIUrl":"10.1016/j.cbi.2025.111880","url":null,"abstract":"<div><div>|Glomerulonephritis (GN) is a rare kidney disorder associated with prolonged inflammation, fibrosis, and mitochondrial dysfunction at the glomeruli layer and nearby capillaries, which leads to the loss of glomeruli integrity and function. A pathogen-driven immune response is most often responsible for acute glomerulonephritis (AGN). In contrast, chronic glomerulonephritis (CGN) is more severe and characterized by irreversible loss of glomerular integrity with excessive fibrosis, often leading to progression to end-stage renal disease. Few pathways, such as WNT, Notch, PI3K/AKT, JAK-STAT, Complement, cGAS-STING, and TGF-β, have been linked to the progression and development of glomerular injury, characterized by mitochondrial dysfunction, inflammation, and fibrosis. However, the AMPK pathway has been reported to be protective against glomerular deterioration. Additionally, the dopaminergic system in the kidney has been linked to protecting glomerular integrity by downregulating mitochondrial dysfunction, inflammation, and fibrosis. This review highlights pathways that can potentially deteriorate and protect glomerular health. Additionally, it also provides an overview of the role of the dopaminergic system in attenuating glomerular injury. Suchdiscussion will provide a comprehensive understanding of potential therapeutic targets for attenuating CGN.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111880"},"PeriodicalIF":5.4,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752411","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}
Pub Date : 2025-12-11DOI: 10.1016/j.cbi.2025.111879
Yixian Wang , Mingyue Zhou , Jin Lan , Tongyao Hu , Tao Wang , Changjing Zuo
Copper, an essential trace element, orchestrates diverse cellular metabolic processes through tightly regulated homeostasis. Intracellular copper homeostasis, governed by key regulators such as the copper transporter 1 (CTR1), is critical for maintaining physiological functions. Dysregulation of copper homeostasis, whether resulting in deficiency or overload, constitutes a central driver of disease pathogenesis. Notably, copper overload induces cuproptosis, a novel form of programmed cell death that has recently emerged as a promising therapeutic target across multiple diseases. Deciphering the regulatory mechanisms of cuproptosis may unlock new avenues for targeted therapy development. This review delves into the mechanisms of copper homeostasis and the pathogenic consequences of its imbalance, with a particular emphasis on cuproptosis-based strategies for cancer treatment.
{"title":"Copper homeostasis and its dysregulation in diseases: A focus on cuproptosis","authors":"Yixian Wang , Mingyue Zhou , Jin Lan , Tongyao Hu , Tao Wang , Changjing Zuo","doi":"10.1016/j.cbi.2025.111879","DOIUrl":"10.1016/j.cbi.2025.111879","url":null,"abstract":"<div><div>Copper, an essential trace element, orchestrates diverse cellular metabolic processes through tightly regulated homeostasis. Intracellular copper homeostasis, governed by key regulators such as the copper transporter 1 (CTR1), is critical for maintaining physiological functions. Dysregulation of copper homeostasis, whether resulting in deficiency or overload, constitutes a central driver of disease pathogenesis. Notably, copper overload induces cuproptosis, a novel form of programmed cell death that has recently emerged as a promising therapeutic target across multiple diseases. Deciphering the regulatory mechanisms of cuproptosis may unlock new avenues for targeted therapy development. This review delves into the mechanisms of copper homeostasis and the pathogenic consequences of its imbalance, with a particular emphasis on cuproptosis-based strategies for cancer treatment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111879"},"PeriodicalIF":5.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752402","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}
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