ABSTRACT Restrictive right ventricular physiology (RRVP) occurs due to impaired right ventricular compliance and associated diastolic dysfunction. This results in reduced cardiac output and elevated central venous pressure with downstream consequences for the liver, kidneys, gut, and lymphatic system. RRVP is frequently seen after surgical repair of tetralogy of Fallot (TOF), though it occurs across a range of congenital heart defects with long‐standing RV pressure overload. This review provides a clinically oriented description of the pathophysiology, patients at risk, end‐organ consequences, and management of RRVP in the immediate post‐operative period after TOF repair.
In humans, hypersecretion of amyloidogenic amylin (islet amyloid polypeptide, IAPP) in the setting of insulin resistance and type 2 diabetes (T2D) promotes systemic oligomerization and tissue deposition, with deposits identified in failing human hearts and the cerebrovasculature of patients with Alzheimer's Disease. In the renal vasculature, amylin aggregation disrupts microvascular integrity, activating hypoxia signaling pathways and contributing to maladaptive erythropoietic responses, including excess erythrocytosis. We hypothesized that amyloid-forming amylin would activate hypoxia-inducible factor (HIF) signaling, leading to metabolic alterations in liver and heart during T2D pathogenesis. To investigate this, we used the HIP rat, which expresses human amylin specifically in pancreatic β-cells, comparing tissues from 14 to 16-month-old rats with those from age-matched wild-type, hyperglycemic UCD and amylin-knockout (AKO) rats. We found greater accumulation of HIF-1α and HIF-2α in HIP rat livers compared with those in other groups, alongside increased expression of HIF-1 target genes. Mitochondrial ETS capacity was elevated in HIP rat livers, in conjunction with the formation of mitochondrial supercomplexes. Amylin aggregates formed in the hearts of HIP rats, alongside HIF-1α and HIF-2α accumulation. This was associated with suppression of ETS capacity, and increased p-AMPK/AMPK, indicating possible cardiac energetic impairment. Pancreatic secretion of amyloidogenic amylin is thus associated with HIF activation in key metabolic organs beyond the renal vasculature, and occurs alongside mitochondrial alterations in liver and heart that are consistent with sustained hypoxic stress. Our results, alongside previous work, suggest that amylin dysregulation is an overlooked, human-relevant aspect of diabetes pathogenesis, and as such, a potential therapeutic target.
ABSTRACT Background Irritable bowel syndrome (IBS) is a disorder of gut–brain interaction frequently accompanied by anxiety, depression, and low‐grade systemic inflammation. Intestinal dysbiosis and vitamin D deficiency may contribute to disease severity. This study evaluated the effects of probiotic supplementation, vitamin D replacement, and their combination on inflammatory biomarkers, IBS symptom severity, and psychological outcomes. Methods In this single‐center retrospective cohort study, 120 adults with IBS diagnosed according to the Rome IV criteria (January 2023–December 2025) received probiotic monotherapy, vitamin D monotherapy, or combined therapy. Clinical characteristics, inflammatory biomarkers, serum 25‐hydroxyvitamin D levels, Hospital Anxiety and Depression Scale (HADS) scores, and IBS Severity Scoring System (IBS‐SSS) scores were assessed before and after treatment. Correlation and multivariable logistic regression analyses were performed. Results The mean age was 41.8 ± 12.6 years, and 62% of participants were female. Combined therapy achieved the greatest reductions in C‐reactive protein, neutrophil‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio, anxiety, depression, and IBS symptom severity. Serum 25‐hydroxyvitamin D levels were inversely correlated with depressive symptoms ( r = −0.31, p = 0.01). Combined therapy independently predicted psychological improvement after adjustment for age, sex, body mass index, and IBS subtype (OR 1.92, 95% CI 1.14–3.26, p = 0.01). Conclusions Combined probiotic and vitamin D supplementation was associated with greater improvements in psychological symptoms and inflammatory biomarkers than either monotherapy. These findings support targeting the gut–brain axis and vitamin D deficiency as complementary therapeutic strategies for IBS. Prospective randomized multicenter studies are warranted.
ABSTRACT Traditionally viewed as a static scaffold, bone is now unequivocally recognized as a dynamic, metabolically active organ intricately integrated into the systemic endocrine and metabolic landscape. Osteoblast homeostasis is central to this paradigm as an emergent property of systemic integration rather than being governed solely by local bone surface dynamics. Diverse systemic inputs—ranging from classical mineral metabolism and sex/stress hormones to energy metabolism and inter‐organ communication via the brain‐bone and gut‐bone axes—converge upon common intracellular effector modules within osteoblasts. Disruption of these delicate endocrine–metabolic networks is critical to the pathogenesis of postmenopausal osteoporosis, diabetic bone disease, obesity, aging, and chronic kidney disease‐mineral and bone disorder. Crucially, such systemic disruptions elucidate why bone fragility frequently reflects defective bone quality and profound osteoanabolic failure, rather than merely a reduction in bone mass. Therapeutic strategies are undergoing a critical shift away from purely antiresorptive strategies towards precision medicine aimed at actively restoring osteoblast function. This review synthesizes multi‐scale evidence to establish osteoblast homeostasis as a unifying framework for skeletal endocrinology, highlighting mechanism‐driven osteoanabolics, targeted metabolic interventions, multi‐omics stratification, and microbiota‐based therapeutics to advance the individualized management of metabolic bone diseases.
We hypothesized that vascular maladaptations resulting from chronic hypoxemia worsen end-organ function via insidious positive feedback. To test this hypothesis in the systemic circulation, we quantified brain perfusion and left heart function and then biomechanically phenotyped the left common carotid artery (LCCA) in adult female mice under normoxic (21% oxygen) and chronic hypoxic (10%) conditions. Functional MRI revealed that hypoxia impaired cerebrovascular reactivity during transient hypercapnia (pCO2 5%) while echocardiography revealed altered left ventricular diastolic, but not systolic, function. These end organ changes associated with an 18.8% decrease in distensibility of the LCCA due to a 34.4% increase in circumferential material stiffness without an increase in wall thickness. This finding suggested a change in the state (e.g., collagen microstructure), not amount, of the LCCA extracellular matrix. Active biaxial testing of the LCCA further revealed up to an 11% reduction of SMC contractility in response to vasoactive agents. Treatment with the mTOR inhibitor rapamycin improved LCCA properties in hypoxic mice, as reflected by a 53.37% increase in distensibility and a 43% improvement in contractility relative to the hypoxic group. We conclude that chronic hypoxia causes multiorgan effects: stiffer carotid arteries having impaired vascular reactivity associate with impaired cerebral and cardiac function. Maladaptive LCCA changes are prevented with mTOR inhibition during hypoxia, suggesting mTOR as a potential target to break the insidious feedback loop that leads to hypoxia-induced maladaptive remodeling and to mitigate associated end-organ dysfunction, with possible advantages to single ventricle patients who experience long periods of hypoxemia.
ABSTRACT Objective To investigate the therapeutic effects of short‐chain fatty acids (SCFAs) in endometriosis (EMs) and determine whether these effects are associated with NLRP3‐related macrophage pyroptosis and immune regulation. Methods Integrated GEO datasets were analyzed to identify pyroptosis‐ and metabolism‐related pathways. Network pharmacology and molecular docking were used as hypothesis‐generating approaches to prioritize candidate targets. An autologous rat model of EMs was established to evaluate the effects of acetate, propionate, and butyrate on lesion growth, inflammation, intestinal barrier integrity, Th17/Treg balance, and pyroptosis‐related proteins. Propionate was further investigated using an LPS+ATP‐induced THP‐1 macrophage model, together with GBP5 expression analysis, NLRP3 overexpression rescue, and comparison with the NLRP3 inhibitor MCC950. Results Bioinformatics analyses suggested activation of pyroptosis‐related pathways and metabolic dysregulation in EMs. Rats with EMs exhibited reduced SCFA levels and impaired intestinal barrier‐related protein expression. Propionate and butyrate suppressed lesion growth, while propionate consistently reduced inflammatory cytokines, restored Th17/Treg balance, and decreased NLRP3, ASC, cleaved caspase‐1, GSDMD‐N, IL‐1β, and IL‐18 expression. In vitro, propionate attenuated LPS+ATP‐induced GBP5 expression and macrophage pyroptosis, whereas NLRP3 overexpression partially reversed these effects. MCC950 produced comparable inhibitory effects, and combination treatment further enhanced the response. Molecular docking generated preliminary structural hypotheses but did not demonstrate direct target binding. Conclusion SCFA metabolic dysregulation is associated with EMs. Propionate supplementation attenuates inflammation, improves immune homeostasis, and suppresses NLRP3‐related macrophage pyroptosis, highlighting metabolic‐immune regulation as a potential therapeutic strategy for endometriosis.
ABSTRACT Hypertensive disorders of pregnancy (HDP), encompassing gestational hypertension, preeclampsia, and eclampsia, are leading causes of maternal and perinatal morbidity and mortality worldwide. These conditions are characterized by abnormal placentation, impaired uteroplacental perfusion, endothelial dysfunction, and chronic hypoxic stress. Erythropoietin (EPO), a key regulator of erythropoiesis, also exerts cytoprotective, angiogenic, and anti‐inflammatory effects that are essential for normal placental and fetal development. In normal pregnancy, EPO production increases in response to physiological hemodilution and heightened oxygen demand. However, in hypertensive disorders of pregnancy, erythropoietin regulation is frequently disrupted. Evidence indicates that circulating and placental EPO levels may be elevated as a compensatory response to placental hypoxia and maternal anemia, particularly in severe and early‐onset preeclampsia. Conversely, renal impairment and systemic inflammation may blunt erythropoietin synthesis or reduce erythropoietic responsiveness, resulting in functional anemia despite hypoxic stimuli. Altered placental expression of erythropoietin and its receptors further suggests dysregulated signaling pathways that may contribute to impaired angiogenesis and adverse pregnancy outcomes. This narrative review synthesizes current knowledge on erythropoietin physiology in pregnancy and critically examines the mechanisms, clinical significance, and potential biomarker role of altered erythropoietin production in hypertensive disorders of pregnancy. A clearer understanding of these alterations may enhance risk stratification and inform future research aimed at improving maternal and fetal outcomes.
Genetic variation in cytokine genes may influence cytokine-related signaling, metabolism, and exercise-related phenotypes, yet large-scale population data remain scarce. This study examined whether five polymorphisms in interleukin-6 (IL6; rs1800795; rs1800796; rs1800797), interleukin-15 (IL15; rs1589241), and tumor necrosis factor-alpha (TNF-α; rs1800629) associate with physiological, biochemical, and performance-related traits in healthy adults. For VO2max-stratified analyses, 501 healthy Polish adults underwent physiological, biochemical, and genomic assessments, classified by maximal oxygen uptake using sex-and age-adjusted reference categories. Whole-cohort analyses were performed for biochemical and hematological traits in up to 962 participants. IL6 rs1800795 CC genotype showed an exploratory higher serum-iron (p = 0.004) and hematocrit (p = 0.033). The IL6 C-G-G haplotype (rs1800795-rs1800796-rs1800797) was associated with higher serum-iron (p = 0.0012, within-phenotype FDR-adjusted p = 0.002). TNF-α rs1800629, showed a model-dependent association with lower aerobic fitness classification in grouped analyses (p = 0.006). A-allele carriers had lower odds of higher-fitness classification under the dominant model and AG heterozygotes showed the strongest association under overdominant model. Grouped analyses; AG heterozygotes (p = 0.037) had higher LDL cholesterol, was not retained in whole-cohort adjusted-analyses. IL15 showed no single-locus effects but an exploratory multi-locus genotype combination, IL15 CC/CT × TNF-α GG, associated with higher odds of aerobic fitness classification (p = 0.004). Whole-cohort analyses: IL6 rs1800795 was associated with serum-iron, hematocrit, hemoglobin, and RBC after adjustments. Findings provide preliminary evidence of modest, trait-specific associations between cytokine-related genetic variation and hematological, metabolic, and aerobic fitness-related phenotypes. IL6 rs1800795 mainly associated with iron-related and hematological traits; TNF-α rs1800629 findings were model-dependent and inconsistent. IL15 CC/CT × TNF-α GG combination is exploratory, requiring independent replication.
ABSTRACT Background The oral microbiota significantly influences systemic health and is linked to various oral and systemic diseases. Dental plaque, a complex biofilm harboring diverse microorganisms, acts as an essential reservoir for the lung microbiome. Pulmonary hypertension (PH), a progressive pulmonary vascular disorder, remains poorly understood in terms of its association with oral microbiota. Methods This study defined and compared oral microbiota composition in dental plaque between PH patients (PH = 46) and reference subjects (HC = 34). A total of 80 dental plaque and 80 pharyngeal swab samples were analyzed by sequencing the 16S rRNA V3‐V4 region to assess oral and respiratory microbiome. Another 23 participants (PH = 15, HC = 8) were enrolled. Dental plaque samples were collected from them solely to perform RT‐qPCR as an independent validation. Results Oral microbiome health index (Oral MHI) is markedly lower in patients with PH, compared to those of the reference subjects. The microbial profiles on dental plaque showed significant differences between the two groups by principal component analysis. Linear discriminant analysis effect size also revealed significantly higher proportions of Prevotella and Veillonella in PH patients than reference subjects, which was also confirmed in another independent cohort by using RT‐qPCR. The microbial dysbiosis index (MDI) was significantly higher for PH patients compared with the controls both in the oral and pharyngeal regions. Our β‐diversity assessment and Procrustes tests confirmed a significant ecological disparity between the oral and pharyngeal regions. Conclusions Our study provides a comprehensive characterization of the distinct dental plaque microbiota between PH patients and control subjects. The dental plaque ecology of patients with PH is dysregulated, lowering Oral MHI. Their oral‐pharyngeal microbial communities correlate more strongly than those of healthy individuals. This weakened ecological divergence may increase PH patients' vulnerability to external pathogen colonization.
ABSTRACT Obesity is a complex systems‐level disorder characterized by disrupted interorgan communication across the gut‐brain‐adipose‐liver axis. This study examines how hepatic lipid metabolism, adipose tissue remodeling, and central satiety pathways are modulated by incretin hormones (GLP‐1 and GIP), which function as master regulators of energy balance. Importantly, we emphasize how host genetics, oxysterol‐driven signaling pathways, and metabolites generated from the microbiome, like short‐chain fatty acids, interact to shape treatment responsiveness. The shift from organ‐specific management to next‐generation precision obesity therapies is made easier by incorporating these multi‐omics networks into a pharmacomicrobiomics framework, which maximizes clinical efficacy and reduces interindividual treatment variability.
ABSTRACT Introduction Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling. Pulmonary vascular impedance (PVZ) provides a comprehensive view of pulmonary arterial function. We hypothesized that functional vascular remodeling significantly alters pulsatile pulmonary hemodynamics and PVZ in severe PAH. Methods Participants with a right heart catheterization (RHC) and an echocardiogram including right ventricular outflow tract (RVOT) images (delay: 24 [5–76] days) were identified from the University of Arizona PH registry. Participants were split using the World Symposium PH classifications and PVR (mild: < 3.9WU, Moderate: 3.9–8.5WU and Severe: > 8.5WU). PVZ was calculated in the frequency domain using pulmonary artery (PA) pressure and RVOT‐PA flow profiles. Impedance measures of resistance ( Z 0 ), global stiffness ( Z 1 ) and proximal stiffness ( Z C , average Z 2‐4Hz ) were derived. To evaluate proximal arterial mechanics, we used the Z c‐mPAP relationship to distinguish pressure‐dependent from stiffness‐related changes on Z C . Data were presented as median [interquartile range]. Results Forty‐eight subjects were identified (Control (mPAP < 25 mmHg): n = 8 and WSPH1: n = 40). Z 0 and Z C were significantly increased in WSPH1 compared to Control ( p < 0.05). Z 0 , Z 1 , and Z C were increased in WSPH1‐severe compared WSPH1‐mild and WSPH1‐moderate ( p < 0.05). All impedance parameters correlated with end‐systolic elastance (Ees) and arterial elastance (Ea, p < 0.05) but only Z 0 correlated with Ees/Ea ( p < 0.05). Z C ‐mPAP relationships were modeled for Control and WSPH groups using estimated unstressed diameters (16.7–27.0 mm) and wall thickness/elastic modulus pairs. Conclusion PVZ analysis demonstrates increased resistance ( Z 0 ), global stiffness ( Z 1 ), and proximal stiffness ( Z C ) in severe PAH. The Z C ‐mPAP relationship suggests proximal vascular stiffening.
ABSTRACT Gut microbiome has emerged as a pivotal regulator of host physiology, extending its influence beyond gastrointestinal homeostasis to the coordinated regulation of multiple distant organs. This regulation is mediated through an intricate network of microbial metabolites, immune mediators, neuroactive compounds, and epigenetic modulators that collectively facilitate inter‐organ communication and systemic homeostasis. Among the key microbial‐derived molecules, short‐chain fatty acids (SCFAs), secondary bile acids, and tryptophan metabolites play fundamental roles in modulating host metabolic, immune, and neuroendocrine signaling pathways. In parallel, microbiota‐driven cytokine production and neurotransmitter synthesis contribute to bidirectional gut‐organ axes, including gut‐brain, gut‐liver, gut‐heart, and gut‐kidney axes. Disruption of these tightly regulated signaling networks leads to microbial dysbiosis, which is increasingly implicated in the pathogenesis of metabolic syndrome, neurodegenerative disorders, cardiovascular diseases, and immune‐mediated conditions. Recent advancements in multi‐omics technologies, including metagenomics, transcriptomics, metabolomics, and epigenomics, alongside systems biology and computational modeling, have enabled high‐resolution characterization of microbiome–host interactions and mechanistic insights into disease associations. This review consolidates current evidence on systems‐level microbiome signaling, highlighting molecular mediators, inter‐organ communication pathways, and disease relevance. Furthermore, it highlights emerging translational strategies such as microbiome‐based therapeutics, precision nutrition, and biomarker development. By synthesizing findings across microbiology, immunology, neuroscience, and systems biology, this work provides a comprehensive framework for understanding how gut microbial networks interface with host regulatory systems to influence health and disease trajectories.
ABSTRACT Chloroquine (CQ) and hydroxychloroquine (HCQ), originally developed as antimalarial agents, have demonstrated broad pharmacological activity across diverse diseases. As weak lipophilic bases, both compounds accumulate in acidic organelles such as lysosomes, interfering with their function and disrupting key cellular processes. This review explores the therapeutic applications of CQ and HCQ in gastrointestinal (GI) pathologies and beyond, with a focus on molecular and cellular mechanisms. In inflammatory bowel disease, CQ and HCQ modulate autophagy, suppress proinflammatory cytokines, and alter gut microbiota composition, contributing to barrier protection and immune regulation. In colitis‐associated colorectal cancer, both agents inhibit tumor development, enhance the efficacy of 5‐fluorouracil, and reverse drug resistance through autophagy blockade. CQ additionally potentiates PI3K/mTOR‐targeted therapies and natural product‐based treatments in gastric cancer. Moreover, CQ decreases GI motility, potentially delaying gastric emptying, and both agents modulate other GI disorders, including Cheilitis granulomatosa, Whipple's disease, Sjögren's syndrome, and dysphagia. Furthermore, the lysosomotropic properties of CQ may serve as a therapeutic adjunct to improve the efficacy of conventional antibiotics against Mycobacterium tuberculosis . The pharmacodynamic profiles of CQ and HCQ underscore their potential as modulators of immune, microbial, and intracellular signaling networks. While accumulating evidence supports their repositioning across inflammatory and neoplastic GI diseases, further mechanistic studies and clinical validation are required to refine their therapeutic applications.
ABSTRACT Parkinson's disease (PD) progression is closely linked to astrocyte senescence and mitochondrial dysfunction. Olfactory mucosa mesenchymal stem cells (OM‐MSCs)‐derived exosomes (OM‐MSC‐Exos) have emerged as promising therapeutic vectors for neurodegenerative disorders. However, it remains unclear whether OM‐MSC‐Exos can alleviate astrocyte senescence in PD by restoring mitochondrial function through the nuclear respiratory factor 1 (NRF1)‐mitochondrial transcription factor A (TFAM) pathway. We employed a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mouse model, a 1‐methyl‐4‐phenylpyridinium (MPP)‐induced astrocyte senescence model, molecular analysis, and targeted knockdown to investigate the mechanism of normoxia‐ or hypoxia‐preconditioned OM‐MSC‐Exos (N‐Exos/H‐Exos) against astrocyte senescence. The motor coordination ability of mice was evaluated using the rotarod, hanging, and pole tests. In the MPTP‐induced PD mouse model, both OM‐MSCs and OM‐MSC‐Exos increased the number of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta, delayed astrocyte senescence, and improved motor function. H‐Exos showed better efficacy than normoxia controls. In vitro experiments confirmed that H‐Exos reduced the number of senescence‐associated β‐galactosidase‐positive astrocytes, reversed mitochondrial membrane potential decline and mitochondrial reactive oxygen species upregulation, and mitigated mitochondrial DNA leakage in MPP‐induced senescent and naturally aged astrocytes. Venn analysis screened transglutaminase 2 (TGM2) as the key exosomal cargo linking PD, senescence, and NRF1. TGM2 was enriched in H‐Exos, and H‐Exos treatment restored the down‐regulated TGM2 levels in astrocytes and up‐regulated NRF1/TFAM. Knocking down TGM2 significantly weakened the neuroprotective and anti‐senescence effects of H‐Exos. In conclusion, H‐Exos could mitigate senescence‐dependent PD pathology, an effect associated with the TGM2 enrichment in exosomes and activation of the NRF1‐TFAM axis in astrocytes.
ABSTRACT This review examines the neurobiological mechanisms governing circadian rhythm regulation and their disruption in sleep–wake disorders. Endogenous circadian clocks, coordinated by the suprachiasmatic nucleus, synchronize physiological and behavioral functions across a 24‐h cycle. Modern lifestyle factors such as artificial lighting, shift work, and irregular sleep schedules increasingly disrupt this synchronization, leading to chronic circadian misalignment. Such disruption is strongly associated with metabolic disorders, cardiovascular disease, and neuropsychiatric conditions. The review focuses on the role of key neurotransmitters, including serotonin, dopamine, GABA, glutamate, and melatonin, in maintaining circadian stability and sleep–wake regulation. Serotonin and dopamine contribute to photic and non‐photic entrainment, while GABA and glutamate regulate inhibitory‐excitatory balance and phase resetting within the suprachiasmatic nucleus. Melatonin functions as the primary hormonal signal of darkness, reinforcing circadian phase and modulating clock gene expression. Dysregulation of these neurochemical systems contributes to disorders such as insomnia, delayed sleep phase disorder, shift work disorder, and jet lag, often influenced by genetic predisposition and environmental stressors. Therapeutic approaches now target orexin signaling, melatonin pathways, and circadian timing through pharmacological, behavioral, and neuromodulatory strategies. Advances in wearable technologies and digital phenotyping enable individualized assessment and chronotherapy‐based interventions. These developments highlight the importance of integrating neurotransmitter dynamics with circadian biology to improve diagnosis and treatment strategies in sleep medicine. Precision‐based circadian interventions offer a promising direction for restoring sleep health and biological synchrony in modern populations.
ABSTRACT Post‐acute depressive disorders associated with COVID‐19 can persist for years after infection. However, the neurobiological mechanisms underlying their pathogenesis remain poorly understood. In this study, using a well‐established hACE2 transgenic mouse model, we observed persistent depression‐like behaviors. We detected direct SARS‐CoV‐2 infection in the olfactory bulb, which relayed acute inflammation to the prefrontal cortex (PFC), and indirectly, the systemic influence of SARS‐CoV‐2 infection on the brain, leading to long‐term dysregulation of serum corticosterone levels. While inflammatory or stress reactions caused no neuronal deficits in the acute phase, we found post‐acute synaptic plasticity impairment and increased apoptosis of PFC neurons, where severe mitochondrial injuries resulted from excessive aerobic respiration and reactive oxygen species (ROS) production. Our findings indicate that the PFC glutamatergic and GABAergic systems, which regulate brain excitatory and inhibitory balance, rather than monoaminergic systems, were most affected in post‐acute COVID‐19. Importantly, these behavioral abnormalities and neuronal damage were ameliorated with sertraline. Together, our findings support the hypothesis that post‐COVID depression involves sertraline‐reversible cortical hyperexcitability, providing a practical platform for mechanistic and translational research into post‐acute neuropsychiatric sequelae.
ABSTRACT Background Interleukin‐17A (IL‐17A) is a key pro‐inflammatory cytokine implicated in acute myocardial infarction, but its upstream regulatory mechanisms remain unclear. Emerging evidence reveals the role of the gut–heart axis in cardiovascular diseases, suggesting that the gut microbiota influences inflammatory responses following myocardial ischemia. Methods and Results By performing Mendelian randomization analysis on human genomic data, we identified four gut bacterial genera with a potential causal relationship to elevated IL‐17A levels, including Barnesiella . Integrated multi‐omics network analysis reveals that Barnesiella regulates IL‐17A‐related inflammatory gene expression through its metabolite succinate. In a myocardial infarction (MI) mouse model, inoculating Barnesiella intestinihominis significantly elevated succinate concentrations in both serum and myocardial tissue, exacerbated cardiac injury, and amplified inflammatory responses in Pseudo‐Germ‐free (pGF) mice. Flow cytometry analysis demonstrated that within the CD3 + T cell population of the ischemic myocardium, IL‐17A + γδ T cells consistently outnumbered IL‐17A + CD4 + T cells across all experimental groups. Co‐immunoprecipitation (Co‐IP) assays further demonstrated that Barnesiella ‐derived succinate promotes MAPK3 lysine succinylation in the ischemic myocardium. In vitro Transwell co‐culture of HL‐1 cardiomyocytes and γδ T cells confirmed that succinate directly promotes IL‐17A expression in γδ T cells and upregulates MAPK3 and NLRP3/caspase‐1 pathways, effects that were abrogated by MAPK3 inhibition. Conclusion Barnesiella intestinihominis exacerbates myocardial injury and inflammatory responses following MI by promoting IL‐17A expression in γδ T cells through succinate‐mediated MAPK3 lysine succinylation and downstream NLRP3 inflammasome activation. This study reveals a novel “gut–metabolite–immune–heart” regulatory pathway linking a specific gut bacterium to localized myocardial immune pathology.
Persistent hyperglycemia is a hallmark of diabetes mellitus (DM), a chronic metabolic disease that can lead to peripheral artery disease, retinopathy, nephropathy and other systemic vascular complications. Impaired angiogenesis and compromised vascular integrity are fundamental features of diabetic vascular complications to pathophysiological conditions. Emerging evidence highlights the SLIT/ROBO signaling pathway, which was first identified for its function in axonal guidance and is now recognized as a crucial regulator of angiogenesis and vascular development. In this review, the dualistic role of SLIT/ROBO signaling is discussed with particular emphasis on its context-dependent regulation of angiogenesis, vascular endothelial permeability, and vascular homeostasis. The classical signaling cascade involving SRGAPs/Rho GTPases, as well as its non-classical crosstalk with VEGF, PI3K/Akt, and TGF-β1, illustrate its potential for the regulation of these vascular processes. Evidence from the retina, kidney, brain, and skin will highlight the tissue-specific expression dynamics of SLITs and ROBOs, particularly in the context of hyperglycemic stress. This review discusses the dual role of its member, ROBO4, which has the potential to act as a protective or pathologic factor depending on the vascular microenvironment. In addition, the epigenetic regulation of SLIT2/ROBO signaling through microRNAs, including miR-15a, miR-125b-5p, miR-146a-5p, and miR-411, provide a new perspective, especially with respect to diabetic retinopathy. A deeper understanding of the intricacies of the SLIT/ROBO signaling axis paves the way for further research into SLIT2 mimetics, agonists of its member, ROBO4, as well as microRNA-based therapeutic targets.
Sensory neurons innervating the heart transmit chemical and mechanical cues to the central nervous system via the dorsal root ganglion (DRG) and nodose ganglion (NG). Despite their importance in cardiac pain and cardiovascular reflexes, the molecular and functional properties of heart-specific sensory (HS) neurons remain elusive. Here, DRGHS and NGHS neurons innervating the heart were FACS purified using a retrograde labeling strategy with Di-8-ANEPPQ, then characterized molecularly by bulk RNA sequencing or evaluated functionally in cocultures with neonatal cardiomyocytes. DRGHS and NGHS neurons formed functional connections with neonatal cardiomyocytes as demonstrated by immunolabeling, electron microscopy, and optogenetic manipulation. Functionally coupled DRGHS neurons exhibited enhanced spontaneous and evoked Ca2+ activity in response to optogenetic and chemical stimulation, indicating dynamic neuro-cardiac communication. Global RNA sequencing analysis revealed that DRGHS and NGHS neurons exhibited distinct transcriptomic profiles, including enrichment of transcripts encoding ion channels and G protein-coupled receptors, compared with their respective total populations. In DRGHS tissue, these included Scn10a, P2xr2, and Mrgprd, whereas NGHS neurons preferentially expressed P2xr2, Ptgdr, and Cckar, collectively supporting a combination of molecular signatures including nociceptors. Collectively, these findings define molecularly distinct sensory pathways connecting the heart and the sensory nervous system, providing mechanistic insights and highlighting potential targets for modulation of cardiovascular reflexes and hemostasis.
The diagnostic landscape of obesity is transitioning from weight centric metrics toward a functional "clinical obesity" framework. This review explores the pathophysiology of adiposopathy ("sick fat"), where hypertrophic adipose tissue triggers systemic metabolic failure via the adipose-hepatic axis. Impaired subcutaneous adipose tissue (SAT) expandability, ectopic lipid accumulation, chronic inflammation, and maladaptive endocrine signaling are the hallmarks of adiposopathy ("sick fat"), a worldwide adipose tissue dysfunction. Through integrated adipose-organ communication networks, these changes support systemic cardiometabolic illness, MASLD, and hepatic insulin resistance. The molecular roles of DJ-1, Nrf2, and inflammatory kinases (JNK/IKKβ) in mediating this metabolic hit were examined in this study.
