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Variant-Specific Temporal Transcriptomic Responses of Ex Vivo Dog Lung Explants to SARS-CoV-2 Delta and Omicron Infection. 狗离体肺外植体对SARS-CoV-2 δ型和组粒感染的变异特异性时间转录组学反应
IF 4.9 2区 生物学
International Journal of Molecular Sciences Pub Date : 2026-10-20 DOI: 10.3390/ijms27209319
Anuradha Panwar, Ashwin Ashok Raut, Amod Kumar, Sonal Sharma, Abhishek Jangir, Suneela Saran, Pushpendra Kumar, Piyush Joshi, Raj Kumar Singh, Anamika Mishra
{"title":"Variant-Specific Temporal Transcriptomic Responses of Ex Vivo Dog Lung Explants to SARS-CoV-2 Delta and Omicron Infection.","authors":"Anuradha Panwar, Ashwin Ashok Raut, Amod Kumar, Sonal Sharma, Abhishek Jangir, Suneela Saran, Pushpendra Kumar, Piyush Joshi, Raj Kumar Singh, Anamika Mishra","doi":"10.3390/ijms27209319","DOIUrl":"https://doi.org/10.3390/ijms27209319","url":null,"abstract":"<p><p>The rapid evolution and emergence of SARS-CoV-2 variants have posed significant public health challenges due to enhanced transmissibility and diverse clinical outcomes. While the effects of these variants in humans have been extensively investigated, their impact on domestic animals remains insufficiently understood. Given the close interaction between humans and dogs, along with documented cases of human-to-animal transmission and the potential role of companion animals as reservoirs for viral evolution, understanding the molecular dynamics of SARS-CoV-2 infection in dogs is of considerable importance. However, in vivo infection studies in non-laboratory animal species are highly resource intensive, time-consuming, require ABSL3 facilities, and involve ethical constraints, limiting their widespread application. In this context, ex vivo culture systems provide a practical and physiologically relevant alternative. Therefore, in the present study, we employed an ex vivo lung explant culture model derived from domestic dogs to investigate host responses to the SARS-CoV-2 Delta and Omicron variants. Comprehensive transcriptomic profiling across multiple time points post-infection revealed significant alterations in genes associated with cell adhesion, structural components, extracellular matrix (ECM) organization and regulation, immune responses, mitochondrial activity, oxidative phosphorylation, and ribosomal function. Both variants induced marked downregulation of ECM-associated and T-cell-related genes, suggesting disruption of tissue integrity and suppression of adaptive immune responses. The Delta variant was characterized by early and sustained suppression of immune-associated signaling pathways, particularly T-cell receptor signaling, whereas the Omicron variant induced stronger activation of genes associated with mitochondrial activity, oxidative phosphorylation, and translational responses. At later stages of infection, especially at 24 h post-infection (hpi), canine lung explants exhibited increased expression of genes related to tissue repair, epithelial maintenance, mitochondrial function, and ribosomal activity, suggesting activation of compensatory responses aimed at maintaining cellular stability under viral stress. Notably, several hub genes were identified, including <i>CD2</i>, <i>CD3D</i>, <i>CD3E</i>, <i>CD27</i>, <i>PTPRC</i>, <i>ZAP70</i>, <i>SYK</i>, and <i>LCP2</i> in Delta infection, and <i>FLT3LG</i>, <i>MRPL2</i>, <i>MRPL4</i>, <i>MRPS11</i>, <i>MRPS12</i>, <i>RPS13</i>, and <i>RPS5</i> in Omicron infection, which are involved in critical pathways associated with immune signaling, mitochondrial function, metabolic regulation, and protein synthesis. Furthermore, the observed mitochondrial and ribosomal responses may indicate that therapeutic strategies aimed at supporting mitochondrial function and modulating excessive inflammation could potentially help reduce lung damage during severe infection. Overall, this study p","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Single-Cell Transcriptomic Analysis Reveals Distinct Pathogenic Subtypes in Hepatocyte- and Cholangiocyte-Directed Autoimmune Liver Injury. 单细胞转录组学分析揭示肝细胞和胆管细胞导向的自身免疫性肝损伤的不同致病亚型。
IF 4.9 2区 生物学
International Journal of Molecular Sciences Pub Date : 2026-10-20 DOI: 10.3390/ijms27209323
Peiyi Zhao, Li Zhao, Huayang Zhang, Xiting Pu, Jun Qian, Yudong Zhao, Zhengrui You, Xiong Ma
{"title":"Single-Cell Transcriptomic Analysis Reveals Distinct Pathogenic Subtypes in Hepatocyte- and Cholangiocyte-Directed Autoimmune Liver Injury.","authors":"Peiyi Zhao, Li Zhao, Huayang Zhang, Xiting Pu, Jun Qian, Yudong Zhao, Zhengrui You, Xiong Ma","doi":"10.3390/ijms27209323","DOIUrl":"https://doi.org/10.3390/ijms27209323","url":null,"abstract":"<p><p>Autoimmune liver diseases (AILDs) involve a group of distinct disorders, but the differences in pathogenic subpopulations that drive hepatocyte or bile duct injury remain unclear. This study characterizes immune niche heterogeneity across AILD subtypes using single-cell RNA sequencing and verifies findings with animal models. We identified distinct immune cell states and functions by analyzing the heterogeneity of T cell and macrophage subsets and the impact of non-immune cell-derived signals on macrophage identity. This allowed us to characterize two distinct immunopathogenic ecotypes between hepatitis and cholestatic phenotypes. Mechanistic analysis predicted the Bmp-Acvrl1/Eng-Fosb signaling axis as a critical transcriptional regulator driving the repair phenotype of macrophages. Notably, Eng (endoglin) emerged as a regulatory receptor controlling macrophage phenotypic transition, especially during the recovery phase of cholestatic disease. Collectively, this study provides a comprehensive atlas of immune cell niches across AILDs, offering new mechanistic insights into disease heterogeneity and identifying macrophage maturation as a promising target for stratified therapeutic intervention in cholestatic disease.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
L1CAM-Enriched Extracellular Vesicle MicroRNAs in Mild Cognitive Impairment and Alzheimer's Disease: An Exploratory Study. 轻度认知障碍和阿尔茨海默病中富集l1cam的细胞外小泡MicroRNAs:一项探索性研究
IF 4.9 2区 生物学
International Journal of Molecular Sciences Pub Date : 2026-10-20 DOI: 10.3390/ijms27209301
Selene De Benedittis, Patrizia Spadafora, Beatrice Maria Greco, Armando Di Palo, Olivier Gallo, Domenico Nuzzo, Pasquale Picone, Elvira Brunelli, Settimio Sesti, Alberto Montesanto, Giuseppe Passarino, Katia Risoleo, Francesca Ferrise, Rosanna Colao, Raffaele Maletta, Giovanna Marchese, Francesca Cavalcanti
{"title":"L1CAM-Enriched Extracellular Vesicle MicroRNAs in Mild Cognitive Impairment and Alzheimer's Disease: An Exploratory Study.","authors":"Selene De Benedittis, Patrizia Spadafora, Beatrice Maria Greco, Armando Di Palo, Olivier Gallo, Domenico Nuzzo, Pasquale Picone, Elvira Brunelli, Settimio Sesti, Alberto Montesanto, Giuseppe Passarino, Katia Risoleo, Francesca Ferrise, Rosanna Colao, Raffaele Maletta, Giovanna Marchese, Francesca Cavalcanti","doi":"10.3390/ijms27209301","DOIUrl":"https://doi.org/10.3390/ijms27209301","url":null,"abstract":"<p><p>Early diagnosis of Alzheimer's disease (AD) and the identification of reliable molecular biomarkers remain critical clinical needs. In this context, extracellular vesicles (EVs) enriched by L1CAM immunocapture-L1CAM-enriched EVs-a fraction widely used to obtain material of putative neuronal origin, have been proposed as a minimally invasive source of information on brain molecular changes. We conducted next-generation sequencing (NGS) of microRNAs (miRNAs) from L1CAM-enriched EVs isolated from the plasma of 11 AD patients, 11 mild cognitive impairment (MCI) individuals, and 14 healthy controls (CTRs) to identify a candidate molecular signature. Our analysis identified five differentially expressed miRNAs-miR-423-5p, miR-122-5p, miR-151b, miR-16-5p, and miR-149-3p-in MCI individuals. Three of these-miR-423-5p, miR-122-5p and miR-151b-were higher in MCI and lower in AD, a pattern that differentiated the two clinically defined groups. Furthermore, enrichment analysis of the predicted targets of the differentially expressed miRNAs identified processes relevant to neurodegeneration, including synaptic organisation, cytoskeletal dynamics, and protein degradation. Overall, these preliminary findings identify blood-based L1CAM-enriched EV miRNAs as candidates for further evaluation in cognitive impairment. While validation in larger, biomarker-confirmed and independent cohorts is required, this exploratory study provides data that may guide the design of future biomarker studies.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Phenotypic and Genotypic Evaluation of Carbapenemases in Carbapenem-Resistant Klebsiella pneumoniae Isolates and Investigation of Ceftazidime-Avibactam and Colistin Susceptibility. 耐碳青霉烯肺炎克雷伯菌碳青霉烯酶表型和基因型评价及头孢他啶-阿维巴坦和粘菌素敏感性调查。
IF 4.9 2区 生物学
International Journal of Molecular Sciences Pub Date : 2026-10-20 DOI: 10.3390/ijms27209307
Elif Gülsüm Torun, Elif Okumuş, Esra Kaya
{"title":"Phenotypic and Genotypic Evaluation of Carbapenemases in Carbapenem-Resistant <i>Klebsiella pneumoniae</i> Isolates and Investigation of Ceftazidime-Avibactam and Colistin Susceptibility.","authors":"Elif Gülsüm Torun, Elif Okumuş, Esra Kaya","doi":"10.3390/ijms27209307","DOIUrl":"https://doi.org/10.3390/ijms27209307","url":null,"abstract":"<p><p>Carbapenem-resistant <i>Klebsiella pneumoniae</i> (CR-Kp) is a major healthcare-associated pathogen, and the coexistence of different carbapenemases may complicate phenotypic detection and antimicrobial treatment. This study evaluated carbapenemase profiles in 123 CR-Kp isolates from two centers in Türkiye and compared the modified carbapenem inactivation method (mCIM) and EDTA-modified carbapenem inactivation method (eCIM) with multiplex real-time PCR targeting KPC, NDM, VIM, IMP, and OXA-48. Ceftazidime-avibactam (CZA) and colistin susceptibility were also assessed. Carbapenemase genes were detected in 122/123 isolates (99.2%), predominantly NDM + OXA-48 (45.5%), followed by OXA-48 alone (26.8%), KPC alone (18.7%), and NDM alone (8.1%). mCIM showed 99.2% sensitivity, whereas eCIM showed 87.7% sensitivity and 100% specificity for NDM detection. All eight false-negative eCIM results occurred among NDM + OXA-48 co-producing isolates (8/55), whereas no false-negative results were observed among isolates carrying NDM alone (0/10); this difference was not statistically significant (<i>p</i> = 0.339). CZA resistance was observed in 49.6% of isolates, with a higher likelihood of resistance among NDM-positive isolates in the exploratory analysis (OR, 9.03; 95% CI, 3.97-20.54; <i>p</i> < 0.001). Colistin resistance was observed in 36.6% of isolates, with no statistically significant association with carbapenemase profiles in the analyses performed. These exploratory findings suggest that combined molecular and phenotypic testing may be useful for carbapenemase characterization and highlight the occurrence of false-negative eCIM results in some NDM + OXA-48 co-producing isolates. Given the absence of adjustment for multiple comparisons, the observed associations should be interpreted cautiously and considered hypothesis-generating.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Special Issue: Prostate Cancer Research Update: Molecular Diagnostic Biomarkers. 特刊:前列腺癌研究最新进展:分子诊断生物标志物。
IF 4.9 2区 生物学
International Journal of Molecular Sciences Pub Date : 2026-10-20 DOI: 10.3390/ijms27209311
Mikhail Baryshev
{"title":"Special Issue: Prostate Cancer Research Update: Molecular Diagnostic Biomarkers.","authors":"Mikhail Baryshev","doi":"10.3390/ijms27209311","DOIUrl":"https://doi.org/10.3390/ijms27209311","url":null,"abstract":"<p><p>Prostate cancer remains a major health burden and presents a particular challenge for precision oncology because of its substantial molecular heterogeneity and variable clinical behavior [...].</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CAV1 as a Potential Regulator of Endothelial-Macrophage Communication Through the CD74/MIF Pathway in Breast Cancer. CAV1在乳腺癌中通过CD74/MIF通路调控内皮-巨噬细胞通讯
IF 4.9 2区 生物学
International Journal of Molecular Sciences Pub Date : 2026-10-20 DOI: 10.3390/ijms27209298
Liangshuang Li, Kaiyuan Xing, Shuang Feng, Zhen Wang, Lingling Zou, Haotian Guo, Jiang Zhu
{"title":"CAV1 as a Potential Regulator of Endothelial-Macrophage Communication Through the CD74/MIF Pathway in Breast Cancer.","authors":"Liangshuang Li, Kaiyuan Xing, Shuang Feng, Zhen Wang, Lingling Zou, Haotian Guo, Jiang Zhu","doi":"10.3390/ijms27209298","DOIUrl":"https://doi.org/10.3390/ijms27209298","url":null,"abstract":"<p><p>Breast cancer (BRCA) is one of the most common malignancies and a leading cause of cancer-related mortality in women. We integrated predicted compound targets of Fufang Banmao Capsules with BRCA-associated genes and prioritized candidates using LASSO regression, correlation analysis, and ROC analysis. Single-cell RNA sequencing analysis then characterized their expression patterns, endothelial heterogeneity, and inferred endothelial-macrophage communication. The four key genes CAV1, CES1, PPARG, and RUNX1T1 showed the highest AUCell scores in endothelial cells. Cell-cell communication analysis inferred MIF signaling involving CD74-containing receptor complexes between endothelial cells and macrophages. Virtual knockout analysis identified CD74 among the genes predicted to be perturbed following CAV1, CES1, or RUNX1T1 knockout in endothelial cells. Further analysis revealed heterogeneous CAV1 expression across endothelial subpopulations, with relatively higher expression in ACKR1-positive and metabolic endothelial cells. Pseudotime analysis characterized variation in CAV1 expression along inferred trajectories, while regulon analysis identified distinct regulatory programs across endothelial subpopulations. Together, these findings prioritize candidate genes linked to the predicted targets of Fufang Banmao Capsules and generate hypotheses concerning their cellular context in BRCA.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction: Mamat @ Yusof et al. Expression of PD-1 and PD-L1 in Endometrial Cancer: Molecular and Clinical Significance. Int. J. Mol. Sci. 2023, 24, 15233. 更正:Mamat @ Yusof等人。PD-1和PD-L1在子宫内膜癌中的表达:分子和临床意义。Int。[j] .生物医学工程学报,2004,24(2):533 - 533。
IF 4.9 2区 生物学
International Journal of Molecular Sciences Pub Date : 2026-10-20 DOI: 10.3390/ijms27209316
Mohd Nazzary Mamat Yusof, Kah Teik Chew, Nirmala Chandralega Kampan, Mohamad Nasir Shafiee
{"title":"Correction: Mamat @ Yusof et al. Expression of PD-1 and PD-L1 in Endometrial Cancer: Molecular and Clinical Significance. <i>Int. J. Mol. Sci.</i> 2023, <i>24</i>, 15233.","authors":"Mohd Nazzary Mamat Yusof, Kah Teik Chew, Nirmala Chandralega Kampan, Mohamad Nasir Shafiee","doi":"10.3390/ijms27209316","DOIUrl":"https://doi.org/10.3390/ijms27209316","url":null,"abstract":"<p><p>The journal's Editorial Office and Editorial Board are jointly issuing a resolution and removal of the Journal Notice linked to this article [...].</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Serum Trace Elements and Concurrent Renal, Hepatic, and Electrolyte Biomarkers: A Secondary Cross-Sectional Analysis of SPES. 血清微量元素和并发肾、肝和电解质生物标志物:SPES的二次横断面分析。
IF 4.9 2区 生物学
International Journal of Molecular Sciences Pub Date : 2026-10-20 DOI: 10.3390/ijms27209313
Pellegrino Cerino, Fabrizio Minichilli, Elvira De Rosa, Maria Triassi, Paolo Montuori, Carlo Buonerba
{"title":"Serum Trace Elements and Concurrent Renal, Hepatic, and Electrolyte Biomarkers: A Secondary Cross-Sectional Analysis of SPES.","authors":"Pellegrino Cerino, Fabrizio Minichilli, Elvira De Rosa, Maria Triassi, Paolo Montuori, Carlo Buonerba","doi":"10.3390/ijms27209313","DOIUrl":"https://doi.org/10.3390/ijms27209313","url":null,"abstract":"<p><p>The relationships between circulating trace elements and routinely measured renal, hepatic, and electrolyte biomarkers remain incompletely characterized. We conducted a secondary cross-sectional analysis of 19 serum elements and concurrent biochemistry in 4137 adults from the Exposure Study on Susceptible People (SPES), Campania, Italy. Creatinine, alanine aminotransferase (ALT), gamma-glutamyl transferase, and potassium were primary outcomes; additional renal, hepatic, mineral, and protein-related measurements were secondary or exploratory. Associations were estimated with covariate adjustment, multiple imputation, and within-family false-discovery-rate control. Per doubling of concentration, lithium was associated with 0.54% higher creatinine (95% confidence interval, 0.22-0.86%). Antimony associations with ALT and potassium were sensitive to the handling of below-quantification concentrations and were not established among directly quantified measurements. Secondary and exploratory findings included higher bilirubin with iron and lower bilirubin with copper; higher ferritin with iron and lower ferritin with cobalt; higher uric acid with strontium, selenium, lithium, and arsenic; and higher albumin, total protein, and total calcium with selenium. Additional albumin adjustment approximately halved the selenium coefficients for total calcium and total protein. The primary associations were small, and their biological and clinical relevance remains uncertain. These cross-sectional findings identify hypotheses concerning renal handling, iron status, and overlapping protein-associated biochemistry.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Heme-Mediated Danger Signaling Suppresses Osteogenesis Through TLR4-Dependent Inhibition of β-Catenin Signaling. 血红素介导的危险信号通过tlr4依赖性抑制β-Catenin信号抑制成骨。
IF 4.9 2区 生物学
International Journal of Molecular Sciences Pub Date : 2026-10-20 DOI: 10.3390/ijms27209305
Xiaosong Xiang, Christiaan M Suttorp, Peng Wang, Edwin M Ongkosuwito, Marjon Bloemen, Johannes W Von den Hoff, Frank A D T G Wagener
{"title":"Heme-Mediated Danger Signaling Suppresses Osteogenesis Through TLR4-Dependent Inhibition of β-Catenin Signaling.","authors":"Xiaosong Xiang, Christiaan M Suttorp, Peng Wang, Edwin M Ongkosuwito, Marjon Bloemen, Johannes W Von den Hoff, Frank A D T G Wagener","doi":"10.3390/ijms27209305","DOIUrl":"https://doi.org/10.3390/ijms27209305","url":null,"abstract":"<p><p>Extracellular heme is a damage-associated molecular pattern (DAMP) released during hemolysis, hemorrhage, and tissue injury. Although its pro-inflammatory and cytotoxic effects are well established, its impact on osteoblast differentiation and bone formation remains incompletely understood. Here, we investigated the effects of extracellular heme on osteoblast differentiation and defined the signaling pathways involved. In MC3T3-E1 pre-osteoblasts, heme suppressed alkaline phosphatase (ALP) activity, calcium deposition, matrix mineralization, and expression of osteogenic markers, including Runx2 and Sp7 at day 3, Col1a1 and Alpl at day 7, and Bsp and Bglap at day 10, without affecting cell viability. Mechanistically, heme reduced AKT phosphorylation and inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, consistent with increased GSK-3β activity. This was accompanied by decreased accumulation of transcriptionally active β-catenin, impaired nuclear β-catenin localization, and suppression of canonical Wnt target genes (Axin2, Lef1, Ccnd1, c-Myc). Pharmacological inhibition of GSK-3β partially restored β-catenin signaling and osteogenic differentiation, whereas inhibition of Toll-like receptor 4 (TLR4) attenuated heme-induced suppression of the AKT/GSK-3β pathway. Combined inhibition of TLR4 and GSK-3β produced the most pronounced restoration of osteogenesis in the presence of heme. Consistent with the in vitro findings, maternal heme administration during pregnancy significantly reduced ALP activity in multiple fetal craniofacial ossification centers in vivo. Collectively, these findings demonstrate that extracellular heme suppresses osteogenesis and supports a model in which TLR4-associated dysregulation of the AKT/GSK-3β/β-catenin axis contributes to impaired osteogenic differentiation.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Zamzam Water in Cancer and Beyond: Preclinical Cellular Effects and Proposed Mechanistic Hypotheses. Zamzam水在癌症及其他疾病中的作用:临床前细胞效应和提出的机制假设。
IF 4.9 2区 生物学
International Journal of Molecular Sciences Pub Date : 2026-10-20 DOI: 10.3390/ijms27209308
Md Sanower Hossain, Anwar Parvez, Md Tarakul Islam, Shakil Ahmmed, Md Hasibul Hasan, Peni Indrayudha, Hamzeh Alkhatib, Md Hanif Munshi, Hasna Banu, Erindyah Retno Wikantyasning, Iswandi, Ambarwati Ambarwati
{"title":"Zamzam Water in Cancer and Beyond: Preclinical Cellular Effects and Proposed Mechanistic Hypotheses.","authors":"Md Sanower Hossain, Anwar Parvez, Md Tarakul Islam, Shakil Ahmmed, Md Hasibul Hasan, Peni Indrayudha, Hamzeh Alkhatib, Md Hanif Munshi, Hasna Banu, Erindyah Retno Wikantyasning, Iswandi, Ambarwati Ambarwati","doi":"10.3390/ijms27209308","DOIUrl":"https://doi.org/10.3390/ijms27209308","url":null,"abstract":"<p><p>Zamzam water (ZW), a naturally occurring alkaline mineral water with a distinctive ionic and trace-element composition, has attracted growing scientific interest due to its reported pharmacological properties and emerging biological effects relevant to cancer research. This review provides a comprehensive mechanistic synthesis that links the physicochemical characteristics of ZW to molecular and cellular processes implicated in cancer biology. Integrating evidence from cancer biology, redox pharmacology, mitochondrial physiology, and cellular signaling, this review examines how the unique mineral composition and mildly alkaline pH of ZW may collectively influence pathways associated with the hallmarks of cancer. Preclinical studies demonstrate context-dependent modulation of cell proliferation, apoptosis, oxidative stress, mitochondrial function, cell-cycle progression, and signaling pathways, including mitogen-activated protein kinase (MAPK) and cyclic AMP (cAMP) networks, across multiple cancer models. Beyond its reported antiproliferative activity, ZW also exhibits antioxidant, anti-inflammatory, and organ-protective effects in non-malignant systems. Importantly, this review proposes a conceptual framework for investigating the relative contributions of mineral ions, ionic homeostasis, redox regulation, and physicochemical properties to the biological effects of ZW, and identifies key mechanistic and methodological gaps. ZW has exhibited cancer-associated biological effects in experimental animals; however, its therapeutic effectiveness has yet to be validated. Future studies integrating standardized physicochemical characterization, molecular validation, multi-omics approaches, and clinical investigations are required to establish its translational relevance in complementary oncology.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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