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Sinomenine hydrochloride alleviates autoimmune myocarditis via suppressing Th1 cell induced-M1 macrophage pyroptosis.
Int Immunopharmacol
Zhenhao Zhang, Yulong Xiong, Shangyu Liu +11 more
CD4+ T cells are crucial to the cardiac autoimmunity of myocarditis, with the underlying pathogenesis remaining unclear. Sinomenine hydrochloride, a natural compound from Sinomenium acutum, is reported to protect against some autoimmune diseases. This study aimed to elucidate the role of CD4+ T-helper 1 (Th1) cells in regulating inflammatory cell death and investigate the effect of sinomenine hydrochloride on Th1 cells and myocarditis.
Linking clinical and imaging diagnostic assessments of the feline hypertrophic cardiomyopathy phenotype.
Front Vet Sci
Felipe Gaia de Sousa, Ruthnea Aparecida Lazaro Muzzi, Roberto Baracat de Araújo +3 more
Hypertrophic cardiomyopathy (HCM) phenotype represents the most commonly diagnosed cardiac disorder in felines, characterized by heterogeneous clinical presentations and a well-established genetic basis. This study aims to integrate clinical, laboratory, and imaging diagnostic assessments of the feline HCM phenotype, providing a comprehensive perspective on how complementary diagnostic approaches enhance disease understanding and precision. The HCM phenotype is defined by concentric hypertrophy of the left ventricular free wall and/or interventricular septum, often accompanied by secondary left atrial remodeling due to chronic pressure and volume overload. Clinical signs typically emerge with disease progression, frequently culminating in congestive heart failure (CHF) and respiratory signs; however, some cats may remain asymptomatic. Accurate diagnosis of the HCM phenotype requires an integrative approach combining thorough clinical evaluation and advanced imaging modalities to avoid misdiagnosis, which may negatively impact prognosis and quality of life. Detailed clinical history and physical examination are essential for diagnostic orientation, particularly in symptomatic patients. Routine laboratory tests support systemic assessment, although no pathognomonic biomarker has been identified to date. Cardiac biomarkers such as atrial natriuretic peptide (ANP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and cardiac troponin I (cTnI) provide complementary diagnostic information, albeit with lower sensitivity than imaging techniques. While electrocardiography may reveal conduction disturbances suggestive of HCM, transthoracic echocardiography remains the diagnostic gold standard. In addition to confirming the diagnosis, echocardiographic evaluation allows for disease staging, longitudinal monitoring, and evidence-based therapeutic decision-making. Our study reinforces the need for an integrated diagnostic framework that combines clinical examination, laboratory testing, and imaging evaluation. By promoting a multidimensional diagnostic perspective, this study contributes to refining the understanding of the feline HCM phenotype and supports the development of more precise diagnostic and therapeutic strategies, ultimately improving clinical outcomes in affected cats.
GnRH-driven FSH synthesis and secretion are modulated through circ-ptpn4 ceRNA sequestration of let-7b-5p miRNA, which negatively controls ELK1 expression.
Theriogenology
Yu-Xin Zhang, Ling-Ling Qiu, Zhe Zhang +8 more
During animal growth and development, the reproductive system is tightly controlled by the central nervous system through a highly conserved, self-feedback loop-the hypothalamic-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH), which is produced in the hypothalamus and secreted into the hypophyseal portal circulation, serves as a master regulator of pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis and secretion, thereby orchestrating growth and reproductive functions. We identified circ-ptpn4 as a GnRH-responsive circular RNA (circRNA) that sequesters let-7b-5p, thereby attenuating its suppression of ELK1. This decrease in let-7b-5p availability thus allows enhanced ELK1 expression, which ultimately stimulates FSH production. In summary, we revealed a novel competing endogenous RNA (ceRNA)-dependent pathway (circ-ptpn4/let-7b-5p/ELK1) underlying GnRH-induced FSH regulation.
A Cluster of Potential Molecular Contributors in Myocardial-Tissue-Derived In Situ Proteomic Profiling Mediate Myocardial Hypertrophy Linked to Right Heart Dysfunction.
J Proteome Res
Shengjie Liao, Xing Zhou, Yichen Xiong +4 more
Myocardial hypertrophy is an adaptive response in the initial stage of heart failure (HF), which exacerbates HF by causing cardiac decompensation and impaired contractility. In proteomic analysis, 216 differentially expressed proteins were obtained in the RHD patients relative to normal controls, including 141 upregulated and 75 downregulated proteins. Among these candidate proteins, protein phosphatase 3 catalytic subunit alpha (PPP3CA), indolethylamine N-methyltransferase (INMT), a disintegrin and metalloproteinase 9 (ADAM9), and myosin light chain-2 (MYL2) exhibited significantly higher expression in the myocardial tissues from patients compared with controls. Moreover, bioinformatic analysis demonstrated that dysregulation of PPP3CA, INMT, ADAM9, and MYL2 may alter the expression of proteins involved in cell adhesion, gap junction coupling, and tight junction stability, weakening cell-cell contacts and disrupting intercellular homeostasis, ultimately facilitating myocardial hypertrophy. In the Angiotensin (Ang) II-induced myocardial hypertrophy model in AC16 cardiomyocytes, the protein expression of PPP3CA, ADAM9, and INMT was elevated. Furthermore, PPP3CA, ADAM9, and INMT were involved in Ang II-induced myocardial hypertrophy by upregulating the expression of smooth muscle α-actin, atrial natriuretic factor, and connective tissue growth factor. Our study identifies molecular alterations associated with the development of myocardial hypertrophy, which may provide insights into potential therapeutic strategies for RHD and subsequent heart failure.
Diurnal and Daily Variations in Growth Hormone and Growth Hormone Stimulation Test in Male Cynomolgus Monkeys.
In Vivo
Yasunori Taniguchi, Tetsuya Yoshikawa, Tomonobu Yamada +1 more
Growth hormone (GH) secretion patterns differ across species. Humans exhibit a nocturnal surge, while rodents exhibit ultradian pulses. In cynomolgus monkeys, diurnal and daily variations and responsiveness to exogenous GH-releasing hormone (GHRH) remain insufficiently defined in non-clinical studies. This study aimed to characterize GH secretion patterns and evaluate responsiveness to exogenous GHRH in adult male cynomolgus monkeys for pituitary toxicity studies.
Injectable Peptide Therapy: A Primer for Orthopaedic and Sports Medicine Physicians.
Am J Sports Med
Cory K Mayfield, Ioanna K Bolia, Cailan L Feingold +5 more
Therapeutic peptides are short-chain amino acids that regulate cellular functions and facilitate biochemical processes. In recent years, there has been significant growth in the global market for therapeutic peptides and thus its popularity among patients. Given the increase in the development of peptides and increased marketing to patients for orthopaedic injuries, it is critical for orthopaedic surgeons to understand the current evidence behind these therapeutic peptides.
New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective.
Orphanet J Rare Dis
Cornelia Dechant, Sebastian Wäscher, Francesca Granata +6 more
The erythropoietic protoporphyrias (EPP) are a group of ultra-rare (1:100.000) inborn errors of the heme biosynthesis characterised by painful phototoxic reactions in tissue exposed to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents phototoxic reactions and improves the quality of life of the patients. In the past years, several new potential treatment options for EPP have been identified, some of which are currently under investigation in clinical trials. While these developments could improve patient care, it is important to know how safety and efficacy of drug candidates compare to the existing treatment, i.e. afamelanotide.
PVN AVP neurons projecting to MeA modulate social recognition and anxiety-like behavior in female mice.
Behav Brain Res
Weizheng Zhang, Caihong Huang, Jing Liu +9 more
Arginine vasopressin (AVP) is well established in regulating social cognition and emotional responses in males. However, its roles in these processes in females and the underlying circuit mechanisms, remain poorly understood. In this study, female mice spent significantly more time sniffing the anogenital region of unfamiliar conspecifics compared to familiar individuals. Fiber photometry recordings revealed that the calcium activity in paraventricular nucleus of the hypothalamus (PVN) AVP neurons was elevated when sniffing unfamiliar mice relative to familiar ones. No significant differences were observed during non-social exploratory behaviors such as bedding sniffing or self-grooming, indicating a specific involvement of these neurons in social investigation. Retrograde tracing using cholera toxin B (CTB) confirmed direct projections from AVP neurons in the PVN to the medial amygdala (MeA). Chemogenetic inhibition of the PVN-MeA AVPergic pathway impaired social recognition and reduced anxiety-like behaviors. Furthermore, bilateral microinjection of the V1a receptor (V1aR) antagonist into the MeA decreased both anxiety-like behaviors and social investigation toward unfamiliar mice. These findings demonstrate that the AVPergic projection from the PVN to the MeA modulates social cognition and emotional state in female mice, providing a circuit mechanism for social and affective dysregulation and offering potential targets for the treatment of related neuropsychiatric disorders.
The effect of chronic stress on sensitivity to dexamethasone treatment of HPA axis gene expression in C57Bl/6 mice.
Behav Brain Res
Rasha Salman, Polina Ritter, Yuliya Ryabushkina +2 more
Chronic social stress is a major risk for psychopathologies such as depression, often leading to altered hypothalamic-pituitary-adrenal (HPA) axis function and glucocorticoid resistance. This study examines how chronic social defeat stress (CSDS) affects sensitivity to dexamethasone by analyzing HPA axis genes expression in C57Bl/6 mice. Adult male mice were subjected to 30 days of stress, followed by dexamethasone or saline administration. Genes expression was analyzed in the hypothalamus, prefrontal cortex (PFC; Nr3c1 only), and adrenal glands at multiple time points post-treatment. CSDS induced marked dysregulation of HPA axis-related genes, including a decrease in hypothalamic Crh and Crhbp, and adrenal Mc2r, Nr3c1, alongside an upregulation of steroidogenic enzymes Cyp11a1 and Cyp11b1, which may account for the elevated corticosterone levels observed under chronic stress conditions. CSDS alters the genes expression response to dexamethasone, indicating a delayed recovery of glucocorticoid receptor signaling in the brain and adrenal glands. Our findings reveal significant stress-induced alterations in the expression of key HPA axis genes, suggesting impaired glucocorticoid receptor signaling and potential glucocorticoid resistance in stressed mice.
Exploring the Prospective Insights Into the Prognostics of N-terminal Pro-B-Type Natriuretic Peptide in Predicting Heart Failure Readmissions in a Tertiary Healthcare Setting.
Cureus
Ghulam Muhammad Shoaib, Uday Shree Akkala Shetty, Muhammad Zaman Baloch +1 more
Heart failure (HF) is a significant cause of morbidity and hospital readmission despite improvements in treatment. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a sensitive biomarker of ventricular wall stress and could be able to give prognostic insight into the post-discharge outcome. The aim of the study was to evaluate the prognostics of NT-proBNP in predicting heart failure readmissions in a tertiary healthcare setting.
A Case of Atrial Septal Defect Unveiled by the Treatment for Pulmonary Arterial Hypertension.
Clin Case Rep
Takaaki Fujii, Sayuri Yamabe, Yoshiro Tsuruta +10 more
We present a case of a 51-year-old woman with atrial septal defect (ASD) masked by pulmonary arterial hypertension (PAH). Three months after PAH treatment with a combination of endothelin receptor antagonist and phosphodiesterase five inhibitor, the transthoracic echocardiography revealed left-to-right shunting through a secundum ASD. The pulmonary vascular resistance decreased from 7.4 to 2.6 Wood units. Subsequent transcatheter closure of ASD using Occlutech Figulla Flex II device was successfully performed as a treat-and-repair strategy. Five months later, hemodynamics had normalized. Due to reduced shunt flow caused by PAH, ASD may not be detectable before treatment, so care must be taken not to overlook PAH associated with intracardiac defects.
Challenge of Corneal Ulcer Healing: A Novel Conceptual Framework, the "Triad" of Corneal Ulcer Healing/Corneal Neovascularization/Intraocular Pressure, and Avascular Tendon Healing, for Evaluation of Corneal Ulcer Therapy, Therapy of Neovascularization, Glaucoma Therapy, and Pentadecapeptide BPC 157 Efficacy.
Pharmaceuticals (Basel)
Sanja Masnec, Antonio Kokot, Tamara Kralj +16 more
To better address the challenge of corneal ulcer healing, with already available standard agents, and those recently introduced, such as stable gastric pentadecapeptide BPC 157, we introduced a novel conceptual framework-the "triad" of corneal ulcer healing↔corneal neovascularization↔intraocular pressure-and extended it to avascular tissues such as tendon. Within this framework, cytoprotection serves as the unifying principle, underscoring that therapeutic effects are not isolated but interconnected. Preclinical studies with BPC 157 therapy, as a cytoprotection agent, illustrate this integration. BPC 157 rapidly normalizes elevated intraocular pressure in glaucomatous rats, preserves retinal integrity, restores pupil function, maintains corneal transparency during ulcer or abrasion healing, and counteracts both corneal neovascularization and dry eye. In parallel, its consistent efficacy in tendon injury models highlights a cytoprotective specificity across avascular tissues. The cornea's "angiogenic privilege," preserved during healing and tendon recovery together, provides strong proof of concept. Furthermore, mapping standard therapeutic agents used for corneal ulcers, neovascularization, or glaucoma onto this triad, and linking them with tendon healing, reveals both shared pathways and inconsistencies across existing drug classes. Analyzed were the ascorbate, fibronectin, hyaluronic acid, metalloproteinase inhibitors, EGF, FGF, NGF, insulin, and IGF-1 (corneal ulcer healing), the antiangiogenic agents (endostatin, PAI-1, PEDF, angiostatin, TSP-1, TSP-2, IFN-α), corticosteroids, NSAIDs, cyclosporine A, anti-VEGF drops (treatment of corneal neovascularization), and alpha 2-agonists, beta-blockers, carboanhydrase inhibitors, muscarinic agonists, Rho-kinase inhibitors, and prostaglandin analogs (glaucoma). Taken together, these findings advance cytoprotection as a unifying therapeutic paradigm, with BPC 157 emerging as its first exemplar, and encourage further translational research toward clinical application.
Recombinant human thymosin beta 4 improves ischemic cardiac dysfunction in mice and patients with acute ST-segment elevation myocardial infarction after reperfusion.
Cardiovasc Res
Yuze Zhang, Qiuting Dong, Xiaohui Bian +22 more
Despite advancements in primary percutaneous coronary intervention (PCI), cardiac dysfunction remains a challenge in patients with ST-segment elevation myocardial infarction (STEMI). Although thymosin beta 4 has shown cardioprotective effects in preclinical MI models, its impact on chronic cardiac functional recovery post ischemia/reperfusion (I/R), especially in STEMI, warrants further investigation. This study aims to explore the therapeutic potential of recombinant human thymosin beta 4 (rhTB4) in both murine models subjected to I/R and in subjects with STEMI post-PCI.
Thymosin β4 stabilizes hypoxia induced brain microvascular endothelial cell dysfunction through S1PR1 dependent mechanisms.
Sci Rep
William G Stewart, Christina D Hejl, Rakeshwar S Guleria +1 more
Acute ischemic injury causes impairment of blood brain barrier (BBB) permeability and is considered as secondary insult in the brain after traumatic brain injury (TBI). The mechanisms underlying these events are incomprehensible and therefore therapeutic opportunities are limited. Although drugs have been showing some promise in TBI outcome, the restoration of BBB damage remain elusive. Thymosin β4 (Tβ4) is a secreted 43 amino acid peptide showed beneficial outcome in cerebral ischemia or TBI, however, it's role in hypoxia-induced BBB damage remains elusive. We hypothesize that Tβ4 protect hypoxia-induced BBB disruption via Sphingosine 1-phosphate receptor 1 (S1PR1) modulation. In the current study, we investigated the beneficial effects of Tβ4 in hypoxia induced gene expression of several tight junction proteins, S1PR1, endothelial cell permeability and tight junction dynamics in human brain microvascular endothelial cells (hBMVECs), one of the important cell types in the BBB integrity. The data suggests that pretreatment with Tβ4 reversed the hypoxia-induced damage of BBB components in hBMVECs. Furthermore, results identify S1PR1, a possible target for Tβ4. Inhibition of S1PR1 showed that Tβ4 failed to offer protection. Together, data provided evidence that S1PR1 is pivotal and Tβ4 can serve as a protective agent in BBB integrity and may offer a promising therapeutic target. In conclusion, we propose that depletion of S1PR1signaling is vital in hypoxia-induced BBB pathophysiology and Tβ4 may be tested as a potential treatment modality and warrant further investigation.
Food-specific IgG-based elimination diet decreased IL-6, TNF-α, and CGRP and improved symptoms in adults with migraine.
Front Nutr
Zhiming Zhao, Meimei Yang, Fujun Wan +4 more
Food-specific IgG antibodies have been proposed to be biomarkers to identify food that triggers an inflammation response. We aimed to evaluate the effect of a food-specific IgG-based elimination diet by assessing the changes in the symptoms of migraine and its comorbidities, inflammatory cytokines, neuropeptides, and neurotransmitters, and their correlation.
Effect of carperitide on clinical outcomes among patients with acute heart failure: a meta-analysis of randomized and propensity‑matched studies.
BMC Cardiovasc Disord
Tsuyoshi Shiga, Atsushi Suzuki, Sachie Inoue +1 more
Carperitide, which is an α-human A-type natriuretic peptide, is used intravenously for the treatment of acute heart failure (AHF) primarily in Japan. However, its clinical effectiveness has not been established. The aim of this meta-analysis was to assess the effect of carperitide on the clinical outcomes of patients with AHF.
Metabolic-Associated Steatotic Liver Disease and FGF21 Dysregulation in Seipin-Deficient and BSCL2-Associated Celia's Encephalopathy Murine Models.
Int J Mol Sci
Silvia Cobelo-Gómez, Lía García-Formoso, Antía Fernández-Pombo +7 more
Seipin, a protein encoded by the BSCL2 gene, plays a crucial role in lipid metabolism, and some pathogenic biallelic variants cause lipodystrophy and associated metabolic disorders. This study investigates liver pathology and dysregulation of the FGF21 signalling pathway in two mouse models: Bscl2-/- (knock-out) and Bscl2Celia/Celia (knock-in). We evaluated liver histopathology using H&E and Oil red O staining, assessed hepatic triglyceride levels via enzymatic assays, and analyzed gene expression of key FGF21-related components (Fgf21, Ppargc1a, Fgfr1, and Klb) using quantitative real-time PCR. The liver histology was scored using the NAFLD activity score (NAS) system. Both models exhibited hepatic steatosis and inflammatory features. The Bscl2-/- mice showed more pronounced liver damage, including ballooning degeneration and fibrosis. Gene expression analysis revealed a significant increase in Fgf21 in both models, suggesting an adaptive response to liver injury. Notably, Fgfr1 and Ppargc1a expression was moderately elevated in severe neurologically affected mice showing less hepatic involvement, suggesting a potential adaptive or protective association of these genes with reduced steatosis. Seipin deficiency leads to metabolic-associated steatotic liver disease and dysregulated FGF21 signalling. These findings provide insight into the pathophysiological mechanisms of lipodystrophy and liver disease and suggest that the FGF21 pathway could be a therapeutic target for treating seipin-related metabolic disorders.
Apelin-13 Attenuates Blood-Brain Barrier Dysfunction Following Intracerebral Hemorrhage via Targeting the Keap1/Nrf2 Signaling.
CNS Neurosci Ther
Pingping Guo, Rabeea Siddique, Juanfeng Qian +3 more
Blood-brain barrier (BBB) dysfunction serves as a critical driver of the secondary brain injury following intracerebral hemorrhage (ICH). Previous research has indicated that Apelin-13 demonstrates the potential to alleviate BBB dysfunction in various cerebrovascular disorders. However, the precise mechanisms through which Apelin-13 preserves BBB integrity remain elusive. This study investigated whether Apelin-13 exerted neuroprotective effects by targeting the Keap1/Nrf2 signaling.
The Neuropsychological Dimensions to Pathogenesis of Chronic Spontaneous Urticaria Beyond Autoallergy - A Brief Narrative Review.
Indian Dermatol Online J
M Sendhil Kumaran, Sahibpreet Kaur, Davinder Parsad +1 more
Chronic spontaneous urticaria (CSU) is a burdensome dermatological condition with a complex, multifactorial pathogenesis involving intricate immune, neurological, and psychological interactions. While traditional models primarily emphasize auto-allergic mechanisms, evidence highlights the critical role of neuroimmune interaction in the chronicity and exacerbation of disease. This review examines the neuroimmune contributions to CSU pathogenesis, focusing on mast cell (MC)-sensory neuron interactions, autonomic nervous system dysregulation, neuroinflammatory pathways, and psychological comorbidities that perpetuate disease activity. A comprehensive narrative review of the literature was undertaken, evaluating mechanisms such as MC activation through immunoglobulin-E (IgE)-independent pathways, neuropeptide-mediated inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and psychiatric associations with CSU. Findings indicate that beyond the classical IgE-mediated MC degranulation, neurogenic inflammation via Mas-Related G-Protein Coupled Receptor X2 (MRGPRX2) receptors-triggered by neuropeptides such as substance P and vasoactive intestinal peptide-plays a pivotal role. Chronic psychological stress activates the HPA axis, contributing to MC hyperactivity and reinforcing the pruritus-stress cycle. Furthermore, a high prevalence of psychiatric comorbidities, including anxiety and depression, contributes to central sensitization and worsens disease severity. The interplay of T cells, basophils, eosinophils, and endothelial cells further amplifies the neuroimmune-inflammatory network. These insights suggest that optimal CSU management requires an integrated approach encompassing dermatological, immunological, and psychological interventions. Emerging therapies targeting neuroimmune pathways, such as MRGPRX2 antagonists, beta-adrenergic blockers, and cognitive-behavioral strategies, show promise. Future research should prioritize the development of personalized neuroimmune-directed therapies to enhance disease control in CSU.
Collagen supplementation and regenerative health: advances in biomarker detection and smart material integration.
Front Nutr
Tatjana Ivaskiene, Jonas Viskelis, Paulina Streimikyte +3 more
Collagen, the most abundant structural protein in the human body, plays a key role in skin integrity, tissue repair, and extracellular matrix organization. With increasing consumer and clinical interest, collagen supplementation has expanded rapidly, yet scientific evidence supporting its efficacy in anti-aging and regenerative applications remains inconsistent. This review critically evaluates current evidence on oral collagen supplementation, integrating insights from over 60 clinical studies assessing its effects on skin aging, musculoskeletal health, and hair disorders. Emerging data suggest that hydrolyzed collagen peptides may improve skin elasticity, joint function, and recovery after exercise, particularly when co-supplemented with vitamin C, silica, or resveratrol. Beyond supplementation, recent advances in biosensing and material science have enabled novel approaches to collagen detection and targeted delivery. Electrochemical, optical, and molecularly imprinted polymer (MIP)-based biosensors facilitate real-time monitoring of collagen biomarkers such as CTX-I, MMPs, and hydroxyproline, supporting precision assessment of collagen metabolism. In parallel, collagen-based hydrogels, nanoparticles, and electroresponsive scaffolds have shown promise as biocompatible carriers for controlled drug release and regenerative therapy. Collectively, these developments outline a translational framework connecting collagen supplementation, detection, and delivery. Continued integration of biosensing and smart material technologies may enhance clinical monitoring and therapeutic efficacy, advancing collagen-based interventions toward precision dermatology and regenerative medicine.