Pathophysiology : the official journal of the International Society for Pathophysiology最新文献

{"title":"Dapagliflozin Beyond Glucose Lowering: Mechanisms of Renal and Systemic Protection.","authors":"Madison L Wise, Abdel A Alli","doi":"10.3390/pathophysiology33030068","DOIUrl":"10.3390/pathophysiology33030068","url":null,"abstract":"<p><p>Sodium glucose cotransporter-2 inhibitors (SGLT2is) have rapidly evolved from glucose-lowering agents to multifaceted therapies with significant renoprotective and cardioprotective potential. Although originally developed to inhibit glucose reabsorption within the renal proximal tubule for the treatment of Type 2 diabetes mellitus (T2DM), growing evidence indicates that SGLT2is exert broad systemic actions extending beyond glycemic control. Among this drug class, dapagliflozin has emerged as a clinically important agent with pleiotropic effects involving renal hemodynamics, inflammatory signaling, mitochondrial function, fibrosis regulation, and cellular stress adaptation. This review outlines the historical progression from the discovery of phlorizin to the development of highly selective modern SGLT2 inhibitors while emphasizing mechanistic insights gained from experimental and clinical studies of dapagliflozin. In addition to the established effects on sodium-glucose transport, dapagliflozin modulates multiple epithelial transport proteins including NHE3, NaPi-2a, NCC, and NCX1, highlighting complex regulatory effects on sodium handling and tubular electrolyte transport. Emerging evidence further demonstrates that dapagliflozin suppresses inflammatory and profibrotic pathways involving YAP/TAZ, STAT1, TGF-β, NLRP3, and NF-KB signaling. Restoration of tubuloglomerular feedback, attenuation of oxidative stress, and preservation of mitochondrial function also appear to contribute substantially to the renoprotective actions of SGLT2 inhibition. Beyond the kidney, dapagliflozin and related SGLT2is exert cardioprotective effects through coordinated improvements in cardiac energetics, inflammatory regulation, and hemodynamic function. Emerging studies additionally suggest potential pulmonary benefits, including reductions in inflammatory signaling, pulmonary edema, and respiratory complications. Collectively, these findings support a shift in understanding SGLT2is from targeted metabolic therapies to broader regulators of cellular and organ function. Continued investigation into the glucose-independent mechanisms of dapagliflozin may reveal additional therapeutic applications across chronic metabolic, cardiovascular, and inflammatory diseases.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149043392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placental Pathophysiology and Developmental Programming of Adult Cardiometabolic Risk: A Narrative Review of Pregnancy Exposures.","authors":"Eleftherios Panteris, Ioanna Kakatsaki, Zoi Koukou, Charalambos Kolvatzis, Styliani Papanikolaou, Eleftheria Hatzidaki","doi":"10.3390/pathophysiology33030067","DOIUrl":"10.3390/pathophysiology33030067","url":null,"abstract":"<p><p>Non-communicable diseases remain the dominant cause of adult morbidity and mortality, yet cardiometabolic, vascular and renal risk may originate before birth. This structured narrative review critically evaluates human evidence linking pregnancy-related exposures, placental pathophysiology and later offspring health within a maternal-placental-fetal-life-course framework. Evidence published from 2020 to 2026 was emphasised, while seminal earlier cohorts were retained when they provided uniquely long follow-up or direct placental measurements. The most consistent associations concern maternal obesity, gestational diabetes, excessive gestational weight gain and hypertensive disorders, which are linked with higher offspring blood pressure, greater adiposity and adverse glucose-insulin profiles. Human placental studies implicate vascular malperfusion, altered nutrient transport, inflammatory and oxidative signalling, endocrine function and epigenetic regulation. Few studies, however, have measured the prenatal exposure, a specific placental phenotype and a long-term offspring outcome within the same longitudinal design; most proposed placental pathways are supported by convergent evidence or biological plausibility rather than demonstrated mediation. Preterm birth and fetal growth restriction are clinically observable, etiologically heterogeneous sentinel phenotypes, not obligatory mediators. Placental and offspring epigenetic signatures, telomere biology and mitochondrial function represent distinct domains of biological embedding; their causal and prognostic significance remains uncertain. Longitudinal studies integrating maternal exposures, placental histopathology and molecular phenotypes, fetal organ development, childhood cardiometabolic trajectories and adult clinical outcomes are needed to determine whether, and under what circumstances, the placenta plays an intermediary role rather than merely serving as a marker of an adverse pregnancy environment.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13609975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149043394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subchronic Exposure to Low-Dose Cannabidiol (CBD) and Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) Nanoemulsions Suggests Low Renal Toxicity: A Preliminary Study.","authors":"Thiago Guedes Pinto, Barbara Dos Anjos Rosario, Pedro Everson Alexandre de Aquino, Glauce Socorro de Barros Viana, Nágila Maria Pontes Silva Ricardo, Edilberto Rocha Silveira, Débora Hellen Almeida de Brito, Dávila Zampieri, Milena de Barros Viana, Daniel Araki Ribeiro","doi":"10.3390/pathophysiology33030065","DOIUrl":"10.3390/pathophysiology33030065","url":null,"abstract":"<p><p><b>Background/Objectives:</b> The increasing therapeutic use of cannabinoid-based formulations highlights the need to better characterize their safety profile, particularly in organs involved in xenobiotic elimination, such as the kidneys. This study evaluated the renal effects of cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (Δ⁹-THC) nanoemulsions following subchronic oral administration in male Wistar rats. <b>Methods:</b> Forty animals (<i>n</i> = 8/group) were randomly allocated into five groups: vehicle control (Licuri oil + Pluronic^® F127), CBD 2.5 mg/kg, CBD 5 mg/kg, CBD+THC 2.5 mg/kg, and CBD+THC 5 mg/kg. Treatments were administered daily by oral gavage for 21 consecutive days. Kidney samples were analyzed by histopathology and immunohistochemistry (Ki-67, GST-P, and cleaved caspase-3). <b>Results:</b> High-dose groups (5 mg/kg) exhibited marked histopathological alterations, including tubular and glomerular damage, hemorrhagic areas, inflammatory infiltration, and necrosis. These groups also showed increased Ki-67 and cleaved caspase-3 immunoexpression compared to controls. GST-P expression was significantly increased only in the CBD 5 mg/kg group. No significant changes were observed in the low-dose groups. <b>Conclusions:</b> These findings suggest dose-dependent morphological and molecular alterations in renal tissue associated with cannabinoid nanoemulsion exposure under experimental conditions.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149043365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microplastics in the Female Genital Tract and Fetoplacental Continuum: A Lesion-Based Framework for Pathophysiological Interpretation.","authors":"Sayandeep K Das, Prithviraj Karak, Afsona Parveen, Swastika N Das, Savitri M Nerune","doi":"10.3390/pathophysiology33030066","DOIUrl":"10.3390/pathophysiology33030066","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;b&gt;Background/Objectives&lt;/b&gt;: Microplastics (MPs) are increasingly reported in human reproductive tissues and fluids, but detection alone does not establish tissue injury or disease. Recent reviews have synthesised occurrence, reproductive toxicity, placental transfer, fertility, and pregnancy outcomes. The unresolved problem is that occurrence, model-response, lesion-comparison, clinical-association, and causal evidence are not interchangeable. This review asks what minimum evidence is required for an MP finding in the female genital tract (FGT) or fetoplacental continuum to become lesion-relevant and where inference must stop. &lt;b&gt;Methods&lt;/b&gt;: We performed a critical narrative search of PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar from database inception through 10 July 2026. The final synthesis comprised 59 sources: 28 primary studies, 24 reviews or systematic syntheses, and 7 regulatory, consensus, or professional-guidance documents.. Methodological recommendations were graded as claim-essential, context-dependent, or exploratory and as routine, specialised, or research-intensive. &lt;b&gt;Results&lt;/b&gt;: The distinct contribution is an FGT-specific mechanistic and claim-to-evidence architecture rather than another environmental or reproductive-toxicity catalogue. We propose an ordered, claim-calibrated evidence ladder linking external exposure, internal dose, reproductive-fluid burden, spatial localisation, lesion response, and clinically annotated phenotype. The framework specifies the minimum evidence for occurrence, localisation, lesion, clinical, and causal claims and provides explicit stopping and downgrading rules rather than treating all desirable measurements as mandatory. The FGT Lesion Atlas is a compartment-by-compartment map of prioritised, non-exhaustive endpoints and sampling requirements. The FGT Lesionome is a cross-compartment synthesis of recurring barrier-receptivity, stromal-fibrotic, vascular-perfusion, immune-microbiome, endocrine-steroidogenic, and particle-cargo axes. An integrated hypothesis-generating pathway links systemic or local exposure, internal and target-compartment burden, physicochemical conditioning in reproductive-fluid microenvironments, particle or particle-associated-constituent interaction with compartment-specific cells and matrices, the six response axes, physiological dysfunction, and clinically annotated outcomes. A reproductive-fluid model, an assisted-reproductive-technology sentinel sequence, and an FGT Microplastic Pathology Reporting Checklist rank study elements by evidentiary necessity, feasibility, and interpretive consequence. &lt;b&gt;Conclusions&lt;/b&gt;: The framework is hypothesis-generating, not a validated causal map or a universal core outcome set. It separates essential validity safeguards from context-dependent best practices and exploratory endpoints. Human reproductive and fetoplacental disease causation remains unproven without contamination-controlled sampling, polymer","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149043399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of miR-155 and miR-103 in Oxidative Stress in Cardiovascular Disease: A Narrative Review.","authors":"Martina Cacciapuoti, Lucia Federica Stefanelli, Ilaria Caputo, Giulia Driussi, Monica Ceol, Giovanna Priante, Lorenzo A Calò, Federico Nalesso","doi":"10.3390/pathophysiology33030064","DOIUrl":"10.3390/pathophysiology33030064","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Oxidative stress is a major contributor to the pathogenesis of cardiovascular diseases, including hypertension, ischemic cardiomyopathy, and heart failure. MicroRNAs (miRNAs) have been extensively investigated in various contexts, and some of them have been identified to play a role in cardiovascular disease. This narrative review focuses on miR-103 and miR-155, two miRNAs implicated in the modulation of oxidative stress and cardiovascular remodeling. <b>Methods</b>: The following queries were used in PubMed since inception until May 2026: ((\"miR-155\" OR \"microRNA-155\" OR miR155) AND (\"oxidative stress\" OR ROS OR \"reactive oxygen species\") AND (\"cardiovascular disease\" OR cardiovascular OR cardiac OR heart OR vascular)); ((\"miR-103\" OR \"microRNA-103\" OR miR103) AND (\"oxidative stress\" OR ROS OR \"reactive oxygen species\") AND (\"cardiovascular disease\" OR cardiovascular OR cardiac OR heart OR vascular)). <b>Results</b>: A total of seven citations for miR-103 and 79 citations for miR-155 were identified. Reviews and papers about diseases other than those on cardiac/vascular involvement were excluded. miR-155 emerges as a potential regulator of inflammatory-redox signaling, whereas miR-103 appears more closely linked to cell fate and metabolic pathways. In both cases, available evidence supports a context-dependent role that challenges simplistic classification as pro- or antioxidant miRNAs. <b>Conclusions</b>: Available evidence suggests that both miR-103 and miR-155 are important regulators of oxidative stress-related pathways in cardiovascular disease. Nevertheless, the context-dependent effects observed across different cardiovascular disorders raise concerns regarding the safety of systemic miRNA modulation-based therapeutic strategies. Future studies should clarify the determinants of this context-dependent behavior and identify the specific conditions under which these miRNAs exert protective or harmful effects, which might pave the way for the development of miRNA-based therapeutic strategies targeting oxidative stress and cardiovascular remodeling.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13609973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149043397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of Exercise Intolerance and Evaluation for HFpEF: A Literature Review of Pathophysiology, Diagnosis, and Management.","authors":"Ali Moradi, Kurt Ramey, Kutiba Tabbaa, Abdullah Sahyouni, Kevin Sanchez Garcez, Shivanshu Kumar, Elaine Pan, Grant Barton, Olugbenga Oyesanmi, Robert Subbiondo","doi":"10.3390/pathophysiology33030063","DOIUrl":"10.3390/pathophysiology33030063","url":null,"abstract":"<p><p>Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure in which the ejection fraction remains within the normal range (≥50%); however, patients still experience typical symptoms of heart failure. One of the most common manifestations in this population is exercise intolerance, which in some cases may be the only presenting symptom. Exercise intolerance refers to a reduced capacity to perform physical activity. Several processes, including impaired cGMP-PKG signaling, increased collagen deposition, endothelial dysfunction, increased arterial stiffness, pulmonary hypertension, and vascular remodeling, contribute to the pathophysiology of HFpEF. The disruption of these fundamental physiological processes significantly impairs exercise capacity, leading to attenuated increases in heart rate, stroke volume, and/or contractility, along with abnormal ventricular-vascular coupling during exertion. When EI is suspected, a spectrum of diagnostic modalities-from simple, low-cost tools such as the 6 min walk test to advanced imaging-can be used to evaluate its presence and its association with HFpEF. When EI in HFpEF is diagnosed, management should focus on addressing this limitation to improve quality of life and reduce morbidity and mortality. Exercise training and pharmacological therapies, such as SGLT2 inhibitors, may be beneficial in this population. In conclusion, EI is a common manifestation of HFpEF that significantly impacts patients' quality of life. Understanding its underlying mechanisms and addressing it appropriately are essential to improving patient outcomes.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148836093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erythropoiesis-Targeted Doping in Sports: From Improved Oxygen Transport to Cardiovascular Risk.","authors":"Gabriela Chlebowska, Krzysztof Michalak, Łukasz Mazur, Wioletta Szczurek-Wasilewicz","doi":"10.3390/pathophysiology33030062","DOIUrl":"10.3390/pathophysiology33030062","url":null,"abstract":"<p><p>Erythropoiesis-targeted doping remains a major challenge for sports medicine because pharmacological and genetic manipulation of erythropoiesis can improve oxygen transport and endurance performance while increasing the risk of serious cardiovascular complications. Erythropoiesis-targeting strategies extend beyond recombinant erythropoietin (EPO) to include hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), modified erythropoietin receptor (EPOR) agonists, transforming growth factor beta (TGF-β) signaling inhibitors, cytoprotective EPO derivatives, and gene- or cell-based approaches, and require complementary detection strategies based on direct analytical methods and the Athlete Biological Passport (ABP). Although they may enhance oxygen delivery and endurance performance, excessive stimulation of erythropoiesis may increase blood viscosity, impair vascular function, and elevate the risk of hypertension, thromboembolic complications, and other cardiovascular (CV) events. Erythropoiesis-targeted doping has evolved beyond recombinant EPO into a diverse group of pharmacological and genetic strategies that require increasingly sophisticated detection approaches. A thorough understanding of their molecular mechanisms and cardiovascular consequences is essential for improving anti-doping surveillance and protecting athlete health. This review summarizes current erythropoiesis-targeting agents, their mechanisms of action, detection strategies, cardiovascular risks, and implications for anti-doping practice.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13511168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148836079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reproductive and Cardiometabolic Characterization of a Letrozole- and High-Fat Diet-Induced PMOS-like Rat Model: An Experimental Study.","authors":"Milica Milinkovic Sorgic, Aleksandar Matic, Vladimir Jakovljevic, Nikola Jovic, Sladjana Novakovic, Teodora Todorovic, Jovan Milosavljevic, Bozidar Pindovic, Jasmina Sretenovic, Petar Canovic, Jovana Jakovljevic Uzelac, Jovana Joksimovic Jovic","doi":"10.3390/pathophysiology33030061","DOIUrl":"10.3390/pathophysiology33030061","url":null,"abstract":"<p><strong>Background/objectives: </strong>Polyendocrine metabolic ovarian syndrome (PMOS) is a complex endocrine-metabolic disorder of multifactorial etiology, driven by interactions among hyperandrogenism, metabolic dysfunction, oxidative stress, and chronic low-grade inflammation that interact to promote reproductive dysfunction and increase risk of cardiometabolic complications. Although the combination of letrozole and high-fat diet (LET + HFD) represents a widely used experimental approach for inducing a PMOS-like phenotype in rats, its multisystem pathophysiological features remain incompletely characterized. The present study aimed to characterize reproductive, cardiometabolic, hormonal, inflammatory, oxidative, and morphometric alterations associated with a LET + HFD-induced PMOS-like phenotype in rats.</p><p><strong>Methods: </strong>PMOS-like model was induced in rats over a 21-day period of orally administered letrozole combined with a high-fat diet.</p><p><strong>Results: </strong>Body weight gain was higher, while uterine weight was lower in the PMOS group compared with controls. Metabolic parameters suggested insulin resistance, while hormonal profiling revealed increased total testosterone and LH levels, accompanied by reduced FSH, estradiol, and progesterone levels. Elevated triglycerides and reduced HDL levels were also observed in the PMOS group. Morphometric analysis revealed numerous atretic and large thin-walled cystic follicles in the ovaries, accompanied by thinning of the uterine luminal and glandular epithelium, stromal layer, and hypoplasia of endometrial glands. Both the longitudinal diameter and cross-sectional area of cardiomyocytes were increased in the PMOS group, together with nuclear hypertrophy and enhanced myocardial collagen deposition. In addition, altered oxidative stress markers, including increased lipid peroxidation and reduced glutathione levels, were observed, whereas IL-6, IL-1β, and IL-23 were not significantly altered.</p><p><strong>Conclusions: </strong>The LET + HFD model reproduces key reproductive and cardiometabolic features of PMOS, extending beyond reproductive dysfunction to involve oxidative and structural alterations in multiple organs. These findings support its use for investigating PMOS pathophysiology and evaluating potential preventive and therapeutic strategies.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148836116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive Meta-Analysis of the Cardiovascular Adverse Effects of Bispecific Antibody Therapy in Hematologic Malignancies.","authors":"Derek Tai, Navneet Sandhu, Aren Dermarderosian, Norayr Mkrtchyan, Daniel Park, Vinisha Garg, Angel Nguyen, Mojtaba Akhtari","doi":"10.3390/pathophysiology33030060","DOIUrl":"10.3390/pathophysiology33030060","url":null,"abstract":"<p><p><b>Introduction:</b> Bispecific antibodies (BsAbs) are a promising and potent therapeutic intervention for relapsed or refractory (R/R) hematologic malignancies, including acute lymphoblastic leukemia (ALL), multiple myeloma (MM), and B-cell lymphomas. These recombinant molecules are designed to target two distinct antigens or epitopes. While BsAbs have shown significant efficacy in managing hematologic malignancies, toxicities must be carefully monitored and their safety profiles require further investigation. This meta-analysis investigates cardiovascular adverse effects associated with seven BsAbs across multiple clinical trials. <b>Methods:</b> A systematic literature review identified seven BsAbs, blinatumomab, elranatamab, epcoritamab, glofitamab, mosunetuzumab, talquetamab, and teclistamab, analyzing 25 clinical trials (Phase I-III) that included monotherapy regimens. The cardiovascular adverse events studied were arrhythmias, heart failure, blood pressure changes, and myocardial infarctions. A meta-analysis using the R meta package calculated proportions and 95% confidence intervals (CIs) and employed a random-effects model to assess heterogeneity. <b>Results:</b> Among 3215 patients, pooled analysis revealed significant findings with 13.6% cardiac arrhythmia (95% CI 10.1-18.2%, <i>p</i> = 0.05), 13.3% hypotension (95% CI 10-17.3%, <i>p</i> < 0.0001), 10.2% tachycardia (95% CI 7.6-13.5%, <i>p</i> = 0.0003), and 3.4% sudden death (95% CI 0-80%, <i>p</i> = 0.046). Less frequent events were hypertension (8%), acute myocardial infarction (1.5%), heart failure (1.4%), and atrial fibrillation (1.3%). <b>Discussion:</b> As BsAbs see increased use in R/R hematologic malignancies, cardiovascular complications must be closely monitored. This analysis highlights hypotension, cardiac arrhythmias, tachycardia, and sudden death as significant adverse effects. Although study heterogeneity and limited patient-level data may have influenced incidence estimates, these findings support routine cardiovascular monitoring and underscore the need for prospective studies to identify high-risk patients and optimize prevention and management strategies. Oncologists, cardiologists, and pharmacists should establish strategies for early detection and management to optimize patients' outcomes.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148836080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time-Varying Low-Frequency Electromagnetic Fields and Endothelial Angiogenesis: From Early In Vitro Discoveries to Emerging Mechanisms.","authors":"Linghong Li, Wayne F Patton","doi":"10.3390/pathophysiology33030057","DOIUrl":"10.3390/pathophysiology33030057","url":null,"abstract":"<p><strong>Background/objectives: </strong>Time-varying low-frequency electromagnetic fields (LF-EMFs), including pulsed electromagnetic fields (PEMFs) and sinusoidal low-frequency electromagnetic fields, have been investigated as modulators of tissue repair and vascular remodeling. Although numerous studies report pro-angiogenic effects in endothelial systems, the underlying mechanisms remain incompletely understood. This review synthesizes evidence for LF-EMF-induced endothelial angiogenesis and evaluates emerging mechanistic explanations.</p><p><strong>Methods: </strong>Literature was identified through searches of PubMed, Web of Science, and Google Scholar through March 2026. Peer-reviewed studies emphasizing in vitro endothelial angiogenesis models were prioritized, with selected in vivo studies included when relevant to mechanistic interpretation. The review was conducted as a narrative synthesis rather than a systematic review or meta-analysis.</p><p><strong>Results: </strong>Experimental evidence indicates that LF-EMF exposure can enhance endothelial proliferation, migration, sprouting, tube formation, and survival across diverse model systems. Reported mechanisms include modulation of growth factor signaling, calcium-dependent pathways, nitric oxide production, cytoskeletal remodeling, and mechanotransduction. Reexamination of early ultrastructural studies suggests that membrane ruffling, vacuole formation, and vesicular structures observed following LF-EMF exposure may be interpreted within the framework of macropinocytosis and vesicular trafficking, providing a potential mechanistic link between electromagnetic stimulation and endothelial morphogenesis.</p><p><strong>Conclusions: </strong>Current evidence supports the conclusion that LF-EMFs can modulate key endothelial processes involved in angiogenesis and vascular remodeling. Membrane trafficking and macropinocytosis provide a biologically plausible framework linking historical observations with contemporary endothelial cell biology, although direct experimental validation is needed. Future progress will require standardized exposure paradigms and mechanistic studies using physiologically relevant angiogenesis models.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13511611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148836109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}