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

{"title":"Heart Meets Brain: Insights into Neurocardiac Pathophysiology.","authors":"Berk Rasheed, Jacob Freed, Ruhi Parikh, Aman Singh, Krishna K Singh","doi":"10.3390/pathophysiology33030058","DOIUrl":"10.3390/pathophysiology33030058","url":null,"abstract":"<p><p>The intricate relationship between the heart and the brain has transitioned from historical, cardio-centric theories to a modern, circuit-based, bi-directional framework known as neurocardiology. This review provides a comprehensive anatomical, physiological, and clinical synthesis of the bidirectional heart-brain axis, highlighting how disruptions in one organ systematically impact the other. Structurally, the heart-brain axis operates as a closed-loop feedback network. Vagal parasympathetic control dominates at rest, driven by an asymmetrical fiber distribution where sensory afferents actively supply interoceptive data to the brainstem. Hemodynamically, cerebral blood flow delivery is linked to cardiac output in an age-dependent fashion with the related vascular dysfunction. Clinically, brain-to-heart pathologies like acute brain injury trigger life-threatening catecholamine surges, neuroinflammation, and myocardial stunning, including Takotsubo cardiomyopathy. Conversely, heart-to-brain pathways reveal that atrial fibrillation and heart failure can independently trigger cardioembolic stroke, long-term neuroinflammation, and a profound, progressive burden of cognitive decline. The heart and brain are inexorably linked through complex structural, mechanical, and paracrine pathways. Ameliorating clinical outcomes demands integrated cross-specialty diagnostic screening, digital rhythm monitoring, and holistic neurocardioprotective 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":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148836094","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":"The Microbiota-Gut-Brain Axis and Nutritional Interventions in Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms, Neuroinflammation, and Non-Motor Manifestations-Scoping Review.","authors":"Elena Sanchis-Sanchis, José Enrique de la Rubia Ortí, David Sancho-Cantus, Cristina Cunha-Pérez, Jorge Casaña-Mohedo","doi":"10.3390/pathophysiology33030059","DOIUrl":"10.3390/pathophysiology33030059","url":null,"abstract":"<p><p>Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder in which systemic pathophysiological alterations significantly contribute to disease progression and non-motor manifestations, such as depression and anxiety. The microbiota-gut-brain axis represents a critical bidirectional pathway in which intestinal dysbiosis and epithelial barrier disruption catalyze central neuroinflammation. This scoping review synthesizes evidence from 43 empirical and analytical studies across 28 countries and maps the findings under the WHO International Classification of Functioning (ICF) framework. Pathophysiological data reveal a profound taxonomic shift in patients with ALS, characterized by severe depletion of neuroprotective, butyrate-producing genera (Akkermansia and Prevotella) and enrichment of pro-inflammatory Enterobacteriaceae. This dysbiotic state leads to structural damage to the intestinal mucosa, alteration of Paneth cells, and downregulation of tight junction proteins (zonulin), triggering a \"leaky gut\" phenomenon. Subsequent systemic translocation of lipopolysaccharides (LPS) induces TLR4-mediated endotoxemia, microglial hyperactivation, and accelerated motor neuron apoptosis. Conversely, therapeutic modulation via Fecal Microbiota Transplantation (FMT), psychobiotics, and metabolic interventions (ketogenic or Mediterranean diets) has demonstrated significant efficacy in restoring epithelial integrity, mitigating mitochondrial hypermetabolism, and reducing emotional distress. This review identifies a critical research gap in the microstructural characterization of the enteric nervous system in ALS. Incorporating microbiome-targeted biomarkers into clinical protocols is crucial for implementing a stratified, multi-systemic therapeutic strategy aimed at enhancing patient prognosis and psychological well-being.</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/PMC13511448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148836088","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":"Oxidative Phosphorylation and Fatty Acid Oxidation Are Central to Mitochondrial Metabolism Rewiring in CML Stem/Progenitor Cell Survival.","authors":"Jelena Milenkovic, Dijana Stojanovic, Branka Djordjevic, Sanja Velickovic, Vladana Stojiljkovic, Milica Veljkovic, Maja Milojkovic","doi":"10.3390/pathophysiology33030056","DOIUrl":"10.3390/pathophysiology33030056","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Quiescent leukemia stem cells (LSCs) are self-renewing, pluripotent cells that present a major obstacle to the successful curative treatment of chronic myeloid leukemia (CML). LSCs function independently of BCR::ABL1 signaling and persist following tyrosine kinase inhibitor treatment. The mechanisms enabling LSC survival are a central focus of current CML research. This review details the complex relationship between signaling pathways and discusses recent advancements in energy metabolism research within the pathogenesis of CML. <b>Discussion</b>: Energy metabolism is critical to the biology of CML LSCs. These cells depend on oxidative phosphorylation (OXPHOS) and mitochondrial homeostasis, utilizing fatty acid oxidation as their primary ATP source. Research highlights significant alterations in signaling networks, marked by a dynamic interplay among dominant pathways within the CML clone. While TGF-β-FOXO signaling maintains the self-renewal capacity of quiescent LSCs, proliferating mature CML cells rely heavily on glycolysis and the PI3K/Akt pathway. Furthermore, unique metabolic traits of LSCs underscore the impact of leukemic cell-microenvironment interactions in fostering a permissive niche. <b>Conclusions</b>: Fatty acid oxidation is critical to the survival and self-renewal of CML LSCs. This adaptation of mitochondrial function is closely linked to signaling alterations and entails an adjustment of mitochondrial respiration alongside stimulated OXPHOS. Emerging research unveils many potential targets within metabolic signaling that can be exploited to overcome these survival mechanisms, highlighting the disruption of mitochondrial energy support as a promising strategy to selectively eradicate CML LSCs.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13511649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148836082","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":"Effects of Maternal Heartbeat Exposure on Neonatal Autonomic Regulation.","authors":"Sara Puddu, Stefano Vicentin, Filippo Zemin, Paola Veronese, Elisa Cainelli","doi":"10.3390/pathophysiology33030055","DOIUrl":"10.3390/pathophysiology33030055","url":null,"abstract":"<p><strong>Background: </strong>During intrauterine life, the fetus is continuously exposed to rhythmic sensory stimuli; among these, the maternal heartbeat is one of the earliest and most biologically salient, contributing to the early organization of physiological regulation. This exploratory longitudinal observational study examined whether exposure to the maternal heartbeat influences neonatal autonomic activity and whether this response is moderated by prenatal maternal psychological distress.</p><p><strong>Methods: </strong>Sixteen dyads of mother-child were included in the analyses. Pregnant women were first assessed between 24 and 28 weeks of gestation: maternal distress was measured using the Depression Anxiety Stress Scales-21 (DASS-21), and maternal heartbeat recordings were obtained. At 3-4 weeks postpartum, neonates were exposed to recordings of their own mother's heartbeat. Neonatal heart rate variability (HRV) was assessed using electrocardiography at rest and during the hearing of the maternal heartbeat.</p><p><strong>Results: </strong>Exposure to the heartbeat significantly reduced high-frequency (HF) HRV compared to baseline (<i>p</i> = 0.037), providing evidence for modulation of parasympathetic activity. Importantly, an interaction between condition and maternal distress was observed (<i>p</i> = 0.021), suggesting that neonatal autonomic responses differ as a function of maternal psychological state.</p><p><strong>Conclusions: </strong>Overall, these preliminary findings suggest that neonatal autonomic responses to maternal heartbeat exposure may not be uniform but may vary according to maternal psychological distress, highlighting the potential role of the maternal psychophysiological context in shaping early autonomic regulation.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13510906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148836092","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":"Are Sputum High Mobility Group Box 1 and D-Dimer Changes Relevant Markers of Tissue Damage and Fibrinolysis in Cystic Fibrosis?","authors":"Sante Di Gioia, Annalucia Carbone, Pamela Vitullo, Domenico Tierno, Domenico Larobina, Gabriele Grassi, Mario Grassi, Massimo Conese","doi":"10.3390/pathophysiology33030053","DOIUrl":"10.3390/pathophysiology33030053","url":null,"abstract":"<p><strong>Background/objectives: </strong>Cystic fibrosis (CF) is a genetic disease whose hallmarks include chronic inflammation of the airways causing tissue damage with increased levels of alarmins in the respiratory secretions, as well as activation of the coagulation/fibrinolytic systems that are linked to inflammation. However, no information is available about the fibrinolytic system and how fibrinolysis is involved in airway injury. On the road to understanding this issue, we determined levels of two key markers, High Mobility Group Box 1 (HMGB1), an alarmin, and D-dimers, associated with fibrin breakdown and airway inflammation, in the sputum from patients with cystic fibrosis.</p><p><strong>Methods: </strong>Sputum samples were collected from 13 individuals with CF and subjected to two different treatment protocols. In the first protocol, the sample was treated with dithiothreitol (DTT) and then centrifuged in order to collect the supernatant (SED). In the second protocol, the sample was centrifuged and the supernatant was obtained (SE). The pellet obtained was treated with DTT and then centrifuged in order to collect the supernatant (SPE). ELISA assays were performed on all samples.</p><p><strong>Results: </strong>HMGB1 and D-dimer levels were significantly lower in supernatants from sputum centrifuged before DTT treatment (SE) compared to those processed after DTT (SPE and SED). However, no significant difference was observed between SPE and SED samples for both markers. D-dimer levels in SED correlated positively with FEV₁ and blood monocyte counts.</p><p><strong>Conclusions: </strong>Direct sputum processing with DTT may be a useful procedure for assessing biomarkers of inflammation and fibrinolysis in CF.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148581736","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":"The Pathophysiological Mechanisms of Glia in Animal Models of Chronic Orofacial Pain: A Systematic Review.","authors":"Afonso Brito, Bruno Daniel Carneiro, Daniel Humberto Pozza","doi":"10.3390/pathophysiology33030054","DOIUrl":"10.3390/pathophysiology33030054","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Chronic orofacial pain represents a heterogeneous group of disorders affecting the trigeminal system and remains difficult to treat due to its complex pathophysiology, which involves glial cells in the development and maintenance of persistent pain states. This systematic review aimed to synthesize evidence from animal studies investigating the pathophysiological role of glial cells in chronic orofacial pain. <b>Methods</b>: After registering on PROSPERO, a systematic search of the literature, based on PRISMA guidelines, was conducted to identify experimental animal studies evaluating glial involvement in orofacial pain models. After screening and eligibility assessment, 10 studies met the inclusion criteria. Data regarding experimental models, glial populations investigated, and pain-related behavioral outcomes were extracted and qualitatively synthesized. <b>Results</b>: Activation of satellite glial cells, microglia, and astrocytes was consistently associated with increased neuroinflammatory signaling and enhanced neuronal excitability within trigeminal pathways, demonstrating that both peripheral and central nervous tissues were involved. Several studies reported that pharmacological modulation of glial activity may reduce pain-related behaviors. <b>Conclusions</b>: Glial cells are key modulators of chronic orofacial pain through neuroimmune interactions that contribute to peripheral and central sensitization. Although these findings highlight promising therapeutic targets, further translational research is required to clarify their relevance for human pain conditions.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148582081","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":"SHP-2 Expression Is a Positive Prognostic Biomarker in Non-Small-Cell Lung Carcinoma: Association with KRAS Mutation and Prolonged Survival.","authors":"Konstantinos Stamopoulos, Georgios Pilichos, Eleni Karatrasoglou, Penelope Korkolopoulou, Stratigoula Sakellariou","doi":"10.3390/pathophysiology33030052","DOIUrl":"10.3390/pathophysiology33030052","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Lung cancer tumors are the most frequent malignant tumors and the primary cause of cancer-related deaths. Despite the improvement in survival related to the implementation of immunotherapy, a significant proportion of patients fail to demonstrate satisfactory response. As a result, the need for new biomarkers, which will predict patient response, as well as for novel therapeutic targets, is urgent. SHP-2 is an intracellular signal transduction molecule, modifying signal transduction of numerous intracellular cascades, acting primarily as an oncogene. In this study we analyzed the expression pattern of SHP-2 in a cohort of non-small-cell lung cancer cases and attempted to correlate it with available clinicopathological parameters. <b>Methods</b>: We performed immunohistochemistry for SHP-2 detection in a cohort of 258 NSCLC cases. H-score was estimated and statistical analyses correlated it with survival and other clinicopathological and molecular parameters. <b>Results</b>: SHP-2 expression was observed in 60 cases (23.3%), with an H-score ranging from 150 to 300. Positive samples were distributed among the three major histological subtypes, without statistically significant differences. Statistical analysis revealed significant positive correlation of SHP-2 expression with smoking, PD-L1 levels, and <i>KRAS</i> mutations. Moreover, positive SHP-2 immunohistochemistry was associated with better clinical outcome in both the total cohort and in the group of patients who received immunotherapy. Finally, the simultaneous presence of SHP-2 expression and <i>KRAS</i> mutation was correlated with prolonged survival. <b>Conclusions</b>: Our findings indicate that SHP-2 could be a useful prognostic factor and a very reliable biomarker in predicting response to immune checkpoint inhibitors.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148581980","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":"Maternal Obesity Doubles the Risk of Preeclampsia and Eclampsia: Post-COVID Changes in a Brazilian Cohort of 2.3 Million Hospitalizations.","authors":"Priscilla Vogt Fernandes de Souza, Maria Clara Salgado-Ramos, Jhenifer de Paiva Quadros, Juliana Cardoso Moraes, Daniel Luiz Santos da Silva, Alex Oliveira da Camara, Rafaella de Carvalho Cardoso, Hércules Rezende Freitas","doi":"10.3390/pathophysiology33030051","DOIUrl":"10.3390/pathophysiology33030051","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Hypertensive disorders of pregnancy, particularly preeclampsia and eclampsia, are associated with high maternal and fetal morbidity and mortality, with maternal obesity representing a major, modifiable risk factor. This study aimed to estimate the association between obesity and preeclampsia/eclampsia (PEC) in obstetric hospitalizations in the state of São Paulo, Brazil, and to examine risk trends across maternal age groups and between two distinct temporal cohorts. <b>Methods:</b> This population-based observational study analyzed 2,338,934 obstetric hospitalizations using data from the Hospital Information System of the Unified Health System (SIH/SUS). PEC and obesity diagnoses were coded according to the International Classification of Diseases, 10th Revision (ICD-10). Logistic regression models were applied to estimate associations adjusted for maternal age, complemented by adjusted marginal predictions. <b>Results:</b> PEC occurred more than twice as often among women with obesity than without (5.4% vs. 2.2%; OR 2.13, 95% CI 1.84-2.47) and was associated with longer hospital stays (3.52 vs. 2.70 days) and higher costs (R$797.91 vs. R$602.69). The absolute risk difference between obese and non-obese women declined from 24.7% to 13.6% at age 20 between the 2017-2019 and 2023-2025 cohorts, while the relative risk gradient remained stable across all ages. <b>Conclusions:</b> Obesity is strongly associated with increased PEC risk, longer hospitalization, and higher costs. The observed attenuation in absolute risk differences in the most recent cohort reinforces the need for preventive interventions, nutritional surveillance, and public health policies aimed at reducing hypertensive complications during pregnancy for both obese and non-obese women.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148582001","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":"Prevalence of Overweight and Obesity and Their Impact on Lung Function in Healthy Bulgarian Children and Adolescents: A Cross-Sectional Study.","authors":"Meri Hristamyan, Stoilka Mandadzhieva, Plamena Stoimenova, Nikolay Mandadzhiev, Blagoi Marinov","doi":"10.3390/pathophysiology33030050","DOIUrl":"10.3390/pathophysiology33030050","url":null,"abstract":"<p><p><b>Background/Objectives</b>: There is increasing evidence on the effect of obesity on lung function in children with and without respiratory diseases. The aim of was to evaluate the prevalence of overweight and obesity and their impact on lung function parameters among healthy children. <b>Methods</b>: Six hundred and seventy-one healthy Bulgarian school children (339 males) aged 7-18 years were included in the study. All participants completed anthropometric measurements, including standing height, weight, and BMI. The studied group underwent comprehensive pulmonary function assessment. <b>Results</b>: The overweight and obese children group consisted of 131-overweight, 97, and obese, 34, children, accounting for 19.5% or every fifth child. The highest prevalence of overweight was at the ages of 10, 11, 12 and 17 years, and that of obesity was 7, 10 and 14 years, respectively. We compared normal weight, overweight and obese children in every age group and found that an increase in weight was associated with increased height and increased lung function parameters, such as FVC, FEV₁, PEF, and FEF₅₀. To overcome the effect of height, we compared normal weight and overweight obese children in height groups and found nonsignificant differences in the spirometric indices. Only in the 130-139 cm group the obese children had lower values of FEV₁(L): 1.78 ± 0.13 vs. 1.91 ± 0.19 (NS) in children with normal weight. <b>Conclusions</b>: The increase in weight is associated with height growth, and the same pattern is observed for the mean spirometry indices, with lowest values found only in obese 7-year-old children.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148582017","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":"Type 1 Diabetes Mellitus Pathogenesis: Mechanisms, Early Diagnostic Strategies, and Emerging Therapeutic Approaches.","authors":"Nokwanda N Ngcobo, Ntethelelo H Sibiya","doi":"10.3390/pathophysiology33030048","DOIUrl":"10.3390/pathophysiology33030048","url":null,"abstract":"<p><p>Type 1 diabetes mellitus (T1DM) is regarded as an autoimmune disorder characterized by a progressive loss of β-cells, culminating in insulin deficiency and hyperglycemia. Currently, T1DM is managed through exogenous insulin administration. Continued efforts to decipher T1DM pathogenesis have yielded significant progress, which can be harnessed to develop disease-modifying therapeutic modalities. Immunological and genetic studies have demonstrated pathogenetic mechanisms that underpin the sensitivity and risk of developing autoimmunity, ultimately leading to the destruction of β-cells. Genetic and immunological studies, therefore, suggest that certain individuals are at risk of developing T1DM; and that autoantibodies against β-cells develop and circulate years before the onset of symptomatic T1DM. Furthermore, the onset of autoimmunity has been associated with specific triggers in genetically susceptible individuals. Recent developments have revealed how viral infections, gut dysbiosis, dietary factors, and obesity trigger autoimmunity and β-cell damage. In this review, we present the current, consolidated understanding of T1DM pathogenesis, informed by recent research. We further identify opportunities for early-detection strategies and drug development targeting the asymptomatic phase of T1DM to slow disease progression. Currently, immunomodulatory strategies have yielded promising outcomes in clinical trials. These strategies seek to target immune cells and inflammatory mediators implicated in the pathogenesis of T1DM. Other strategies include tolerogenic strategies against autoimmune cells, whilst others employ β-cell protection. The emergence of regenerative therapies also offers promising avenues toward T1DM.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148582075","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}