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Prospective cohort study of TIMP-1 and myocardial fibrosis in Chagas disease at a reference clinic in Pernambuco, Brazil: PTICH trial protocol.

BMJ Open

Sílvia Marinho Martins, Carolina The Macedo, Cassio Santana Meira +7 more

Chagas disease affects millions of individuals across Latin America and imposes a substantial economic burden on healthcare systems, particularly in rural and underserved regions. Chronic Chagasic cardiomyopathy remains one of the leading causes of heart failure-related mortality in endemic countries. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has emerged as a potential biomarker of myocardial fibrosis in cardiomyopathies. This study was designed to investigate the association between TIMP-1 and myocardial fibrosis in chronic Chagas disease and to assess its potential as an early biomarker of fibrotic remodelling.

Tirzepatide and metformin effects on hunger and BMI in an adolescent with hyperphagia and severe obesity due to MC4R Deficiency: a case report.

Obes Facts

Eline E P L van der Walle, Mariëtte R Boon, Elisabeth F C van Rossum +1 more

Tirzepatide, a dual GLP-1/GIP receptor agonist, is recently approved for the treatment of type 2 diabetes and obesity in adults. Melanocortin-4-receptor (MC4R) deficiency is the most common monogenic cause of obesity and presents with hyperphagia and early onset obesity. While tirzepatide seems to be effective in inducing weight loss in adults with MC4R deficiency, its effects on hyperphagia and weight loss in pediatric patients are unexplored.

Endocrine Modulation of Inflammation: The Role of Adrenocorticotropic Hormone and Cortisol.

Endocr Pract

Maritza Vidal, Nancy E Lane

The melanocortin system, derived from pro-opiomelanocortin processing, represents a crucial neuroendocrine-immune interface that regulates inflammatory and metabolic pathways. Through its 5 melanocortin receptors (MCRs), MCR1 to MCR5, this system exerts widespread endocrine, paracrine, and autocrine functions across the central nervous system, skin, adipose tissue, bone, and immune cells. Activation of melanocortin signaling produces potent anti-inflammatory effects by modulating cytokine release, leukocyte trafficking, and transcriptional control of proinflammatory mediators. Adrenocorticotropic hormone (ACTH), via the hypothalamic-pituitary-adrenal axis and direct interaction with MCR2, stimulates both cortisol synthesis and mediates steroid-independent immunomodulation in extra-adrenal tissues. It should be taken into account that ACTH is the only ligand for MCR2 inducing steroidogenesis, cell proliferation and anti-inflammatory effects. Synthetic and natural ACTH formulations, such as repository corticotropin injection (Acthar® Gel) and Purified Cortrophin Gel, have demonstrated clinical benefit in refractory inflammatory diseases, as their efficacy may extend beyond classic glucocorticoid pathways. Recent preclinical studies of selective MCR agonists, including MCR1-targeted compounds like dersimelagon, highlight novel therapeutic possibilities for autoimmune and fibrotic disorders. Understanding the dual steroidogenic and nonsteroidogenic actions of melanocortins provides a framework for developing targeted therapies with improved safety profiles compared with conventional glucocorticoids.

Symptom management with osilodrostat in multiple endocrine neoplasia type 1 with a Cushing syndrome presentation.

JCEM Case Rep

Hasan Frookh Jamal

Multiple endocrine neoplasia type 1 (MEN1) syndrome is a rare autosomal dominant disorder characterized by predisposition to a multitude of endocrine neoplasms. Cushing syndrome (CS) within MEN1 presents complex diagnostic and therapeutic challenges. We report a case of a 36-year-old male with adrenocorticotropic hormone (ACTH)-dependent Cushing disease and MEN1 syndrome with thymic and pancreatic neuroendocrine tumors. The patient presented with weight gain, weakness and proximal myopathy. Biochemical testing confirmed ACTH-dependent hypercortisolism. Imaging revealed a pituitary microadenoma, a large anterior mediastinal mass, and pancreatic lesions. Genetic analysis confirmed a pathogenic heterozygous MEN1 frameshift variant. After thymectomy, he declined further surgery. Treatment with thymectomy and octreotide long-acting release (LAR) was ineffective. Initiation of osilodrostat (titrated to 5 mg twice daily) resulted in a 76% reduction in urinary cortisol levels and a 47 kg weight loss, with significant functional improvement. Pancreatic and pituitary lesions remained stable. This is the first reported case of successful symptom management of MEN1-associated Cushing disease with osilodrostat, establishing it as an effective therapeutic option for medically complex MEN1 cases where surgery is not feasible or is declined.

The AMP-antibiotic-microbiota triad in IBD: a mechanistic framework for dysregulated antimicrobial defense.

Front Immunol

Yuyuan Hu, Yan Li, Qiang Zhang +7 more

Inflammatory bowel disease (IBD) represents a chronic relapsing disorder driven by a loss of homeostatic balance between the host immune system and the intestinal microbiota. Endogenous antimicrobial peptides (AMPs), produced primarily by epithelial and immune cells, function in concert with commensal microorganisms to preserve mucosal integrity and barrier function. Disruption of this antimicrobial equilibrium-through genetic susceptibility such as NOD2 mutations or environmental perturbations including antibiotic overuse-can impair antimicrobial defense, distort microbial composition, and initiate chronic inflammation. Recent investigations have revealed distinct alterations in AMP expression across IBD subtypes. In Crohn's disease, Paneth cell-derived α-defensins (HD5 and HD6) are markedly diminished in the ileal mucosa, whereas colonic, segmental IBD exhibits inadequate induction of β-defensins and LL-37. Conversely, in actively inflamed regions, certain AMPs such as human β-defensin-2 (HBD2) and lysozyme are strongly upregulated, reflecting a compensatory response to inflammatory cell infiltration and microbial invasion. Beyond host-derived peptides, broad-spectrum antibiotic exposure profoundly reshapes commensal communities, attenuates basal pattern-recognition receptor signaling, and secondarily perturbs AMP regulation-creating a feedback loop that amplifies dysbiosis. Here, we conceptualize these interactions as an integrated AMP-antibiotic-microbiota triad, in which endogenous antimicrobial regulation, exogenous antimicrobial pressure, and microbial ecological resilience dynamically co-determine mucosal stability. By positioning AMPs within this tripartite regulatory framework, this review delineates how antimicrobial imbalance arises across IBD subtypes, compares emerging therapeutic strategies-including AMP enhancement, microbiota-sparing antibiotic regimens, fecal microbiota transplantation, and metabolite-guided interventions-and highlights implications for precision recalibration of antimicrobial homeostasis in IBD.

[Consensus statement of the Austrian Society for Rheumatology and Rehabilitation on the management of increased cardiovascular risk in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis].

Wien Klin Wochenschr

Boris Lindner, Mathias Ausserwinkler, Christina Siess +14 more

Chronic inflammatory rheumatic diseases are associated with an increased risk of cardiovascular diseases (CVD), which significantly contribute to an increased morbidity and mortality. Although international recommendations exist, disease-specific and pragmatic guidance for the routine clinical practice are lacking due to heterogeneous evidence and incompletely understood pathophysiological mechanisms of cardiovascular events.

Activin A-Endothelin-1 Axis Governs Pulmonary Vascular Remodeling: Mechanistic Basis for Emerging Therapies in PAH.

Arterioscler Thromb Vasc Biol

Novia Nurul Faizah, Gusty Rizky Teguh Ryanto, Sagita Mega Sekar Kencana +4 more

Pulmonary arterial hypertension remains a life-threatening disease despite advances in vasodilator therapy. Vascular remodeling, partly driven by pulmonary artery endothelial cell dysfunction, is accompanied by vasoactive mediators imbalance such as ET-1 (endothelin-1). Although endothelin receptor antagonists alleviate vasoconstriction, they incompletely address the remodeling process. We previously reported how endothelial-derived activin A promotes vascular remodeling, leading to the clinical development of the activin signaling inhibitor sotatercept, which improves outcomes when added to endothelin receptor antagonists. As both activin A and ET-1 originate from endothelial cells and promote remodeling, we investigated whether activin A regulates ET-1 production and activity in pulmonary arterial hypertension.

Deconstructing senescence phenotypes in cells of the bone and bone marrow.

J Clin Invest

Lorenz C Hofbauer, Martina Rauner

Cellular senescence in osteogenic mesenchymal cells contributes to age-related bone loss. The bone marrow hosts myeloid cells, the precursors of immune cells, as well as mesenchymal cells, which give rise to osteoblasts and osteocytes. The senotype and senolytic response of bone marrow cells, particularly hematopoietic cells, in age-related bone loss is unclear. In this issue, Doolittle et al. showed that of all immune cells, myeloid cells had the strongest senescence profile, yet the relative level of senescence remained lower than that of mesenchymal stromal cells. Mesenchymal cells displayed a profound senotype, rendering them susceptible to senolytic clearance protecting against bone loss. By contrast, selective clearance of p16+ myeloid cells was not long-lasting and, hence, did not fully protect against age-related bone loss. These findings underscore the challenges of developing senolytic strategies for tissues with mixed senotypes, such as bone.

TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade.

Nat Commun

Yan Xiong, Jaiprakash Sharma, Meggie N Young +9 more

Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and cellular clearance pathways. TFEB activity is tightly controlled by multiple post-translational mechanisms, but the exact molecular mechanism controlling its stability has remained elusive. Here, we identify the IκB kinase (IKK) complex as a key regulator of TFEB protein stability through a phosphorylation-ubiquitination cascade. A high-content kinase inhibitor screen reveals that IKK inhibition increases TFEB protein levels, and genetic ablation of IKK components increases TFEB stability, upregulates lysosomal genes, and enhances lysosomal biogenesis and degradative capacity. Mechanistically, we show that IKK phosphorylates TFEB on a cluster of serine residues (423SPFPSLS429), generating a phosphodegron recognized by the E3 ligase β-TrCP2, which in turn targets TFEB for proteasomal degradation via ubiquitination of adjacent lysine residues (K430 and K431). Mutation of either the phosphosites or the ubiquitination sites stabilizes TFEB without impairing its ability to translocate to the nucleus, activate target gene expression, or promote tau clearance in a cell model of tauopathy. These findings establish IKK-β-TrCP2 as a core regulatory axis controlling TFEB protein turnover and levels and reveal a mechanistically distinct layer of TFEB regulation that may be leveraged to enhance lysosomal function in disease contexts.

Human Umbilical Cord Blood Mesenchymal Stem Cells Ameliorate Autism-Like Behaviors in a Valproic Acid-Induced Mouse Model via the IGF-1/Akt Signaling Pathway.

Brain Behav

Jie Tian, Hujing Deng, Zhoujing Hu +9 more

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that significantly impacts children's physical and mental health, yet effective pharmacological treatments remain limited. The primary objective of this study was to investigate the therapeutic effects of human umbilical cord blood mesenchymal stem cells (hUC-MSCs) on ASD, evaluate the safety profile of hUC-MSCs, and elucidate their underlying mechanisms and functional roles.

The Crucial Role of Exercise in Promoting Adolescent Muscle Development.

Adv Exp Med Biol

Xilong Hu, Haiwang Shi, Rui Duan

Skeletal muscle, as one of the largest organ system in the human body, exerts a determining influence on adolescents' mastery of motor skills and their lifelong health. Puberty represents a critical window for muscle development, during which the quality of myogenesis not only shapes athletic potential but also profoundly influences long-term health outcomes in adulthood. Under pathological conditions, such as obesity, an aberrant metabolic environment can compromise muscle function in youth, impede the progression of motor abilities, and increase susceptibility to metabolic disorders. It is well established that scientifically prescribed exercise interventions effectively unlock adolescents' muscle-building potential, thereby laying a solid foundation for enduring physical performance and overall well-being.This chapter offers a systematic overview of the key biological principles that regulate skeletal muscle development during puberty and provides an in-depth analysis of the mechanisms and signaling pathways by which structured exercise drives muscle growth and functional adaptation. In addition, it examines the challenges posed by muscle structural and functional impairments under pathological states and evaluates how targeted exercise regimens can restore and enhance muscle health. By mastering the conceptual framework presented here, coaches and parents will be better equipped to identify early warning signs of impaired muscle development, support individualized training plans that optimize motor skill acquisition while minimizing injury risk, and implement proactive interventions to prevent metabolic dysregulation and age-related muscle decline.

Telocytes in skeletal muscle: Emerging players in homeostasis and repair/regeneration.

Histol Histopathol

Irene Rosa, Eloisa Romano, Mirko Manetti

Telocytes (TCs) have recently emerged as novel components of the skeletal muscle interstitium. They are distinguished from other stromal cells by their immunophenotypic profiles and, especially, unique ultrastructural traits. Specifically, TCs feature a small cell body and very long, thin telopodes with a moniliform appearance conferred by the alternation of slender segments (podomers) and small dilated portions (podoms). Experimental evidence suggests that, as part of the skeletal muscle stem cell niche, TCs may be involved in orchestrating satellite cell activation and myogenic differentiation through both direct physical interactions and paracrine signaling. Yet, further in-depth research is needed to uncover specific immunophenotypic signatures for skeletal muscle TCs within the niche, as well as to identify the signaling pathways by which they influence neighboring satellite cells and, possibly, other cellular components of the niche. In the present review, particular emphasis is placed on the putative strategic role of TCs in maintaining skeletal muscle tissue homeostasis, their involvement in muscle pathological alterations, and, most importantly, their possible role in the coordination of the regenerative response following injury. In perspective, the promising therapeutic potential of TC-based strategies to enhance skeletal muscle tissue repair/regeneration and restrain post-injury fibrosis is also discussed.

snRNA sequencing-based skeletal muscle analysis of Jiangquan black pigs with different average daily growth rates.

Sci Rep

Hongzhen Cao, Jing Wang, Yunzhou Wang +7 more

The Jiangquan black pigs, a new breed of swine obtained by introducing traits from Duroc pigs into Yimeng black pigs, exhibits fast growth rates and high meat quality. To understand how daily weight gain influences muscle development in this breed, we analyzed longissimus dorsi muscle cell subpopulations from Jiangquan black pigs using snRNA and bulk RNA sequencing. Thirteen distinct cell types (e.g., muscle stem cells, satellite cells, fibroblasts) were identified, and marker genes (PAX7, MYOD, MYOG) were found to exhibit stage-specific expression during differentiation. Pseudotime analysis revealed the differentiation trajectories of these cell populations, while cell cycle analysis uncovered the higher mitotic activity in satellite cells of the fast-growth versus slow-growth groups. Furthermore, cell communication analysis highlighted the interactions between muscle cells and other cell types. Finally, intergroup analysis revealed that 2,466 and 2,597 genes were differentially expressed in muscle stem cells and muscle satellite cells, respectively. These genes were enriched in disease-related pathways. This study provides a single-cell resolution atlas of porcine muscle development, offering insights into the genetic regulation of growth and potential targets for breeding optimization.

Appetite, Obesity, Metabolism, and Malignancy: Do Incretin-Mimetic Drugs Reduce Cancer Risk?

Cancer Prev Res (Phila)

Andrew G Renehan, Michael N Pollak

Obesity is associated with increased risk of at least 13 adult cancer types and is the second most common cause of cancer (after tobacco) in many populations. Uncertainty about the extent to which intentional weight loss leads to reduced cancer risk represents a gap in knowledge. Evidence from bariatric surgery studies shows that sustained weight reduction of 20% to 30% in individuals with severe obesity is associated with reduced risk of obesity-related cancers over 10 years. However, in terms of population health, this is not a viable cancer prevention strategy. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RA), known to be effective antidiabetes drugs, have been shown in randomized trials to cause substantial weight loss (in the order of 15%) in obese individuals with or without diabetes. This is a rapidly evolving field, which has revolutionized the modern management of obesity. Much clinical experience has been with semaglutide (a GLP-1RA) and tirzepatide (a dual agonist of the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide receptor), but newer drugs in the class are being developed. We review available data that provide a strong rationale for evaluating incretin-mimetic drugs in a cancer prevention trial but show that the feasibility of such a trial is questionable.

Responses to GLP-1RA in White and Black Adults With Obesity: Insights From Generalized Additive Mixed Models of EHR Data.

Obesity (Silver Spring)

Jordan H Mallette, Joshua S Speed, Seth T Lirette +2 more

This study examined racial differences in weight loss and clinical response to glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy among adults with obesity using real-world data.

Efficacy of tirzepatide, lanifibranor, and resmetirom in metabolic dysfunction-associated steatotic liver disease: a meta-analysis of high-quality randomized controlled trials.

Intern Emerg Med

Shuai Zhao, Fei Tian, Lan Yu +6 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent condition and a leading cause of chronic liver disease worldwide. Several pharmacological agents are currently used in its clinical management. This meta-analysis assesses the comparative efficacy and safety profiles of three novel therapeutic agents-tirzepatide (a dual GIP/GLP-1 receptor agonist), lanifibranor (a pan-PPAR agonist), and resmetirom (a thyroid hormone receptor-β agonist)-in patients with MASLD/MASH.We systematically searched PubMed, Scopus, Web of Science, the Cochrane Library, and Embase from inception to December 31, 2024. Eligible randomized controlled trials (RCTs) were those that enrolled adults with MASLD/MASH and compared tirzepatide, lanifibranor, or resmetirom with placebo. Non-randomized trials, animal studies, trials using only imaging or biomarkers for diagnosis, studies without a placebo arm, and those including subjects aged < 18 years were excluded. Methodological quality was assessed using the Cochrane Risk of Bias 2.0 tool. Data synthesis was performed using RevMan 5.3. The protocol was registered with PROSPERO (CRD 42025637054). Five placebo-controlled trials met the inclusion criteria: one for tirzepatide (NCT04166773), one for lanifibranor (NCT04849728), and three for resmetirom (NCT03900429, NCT04197479, NCT04951219). The analysis included 2497 individuals (1112 [45%] male, mean age 55.6 years [SD 11.6], mean BMI 35.3 kg/m2 [SD 6.3], and 1385 [55%] with diabetes). All agents led to MASH resolution without worsening of fibrosis in a proportion of patients, with significant effects observed for tirzepatide and resmetirom. Tirzepatide (mean difference [MD] - 34.90% [95% CI: - 53.31 to - 16.49]) and resmetirom (MD - 31.45% [95% CI: - 35.93 to - 26.97]) significantly reduced hepatic steatosis as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF). Tirzepatide significantly reduced serum aminotransferase levels (ALT: MD - 30.90%, p < 0.00001; AST: MD - 20.71%, p < 0.00001). Although lanifibranor demonstrated improvements in lipid profiles (HDL-C + 9.87%, triglycerides - 26.90%), it did not achieve a statistically significant improvement in fibrosis (OR 1.26, p = 0.08). Gastrointestinal adverse events were frequently reported across all treatment arms. Tirzepatide and resmetirom significantly improved MASH resolution without worsening of fibrosis and reduced hepatic steatosis. All three agents lowered serum aminotransferase levels, while lanifibranor and resmetirom improved lipid profiles. Gastrointestinal adverse events were common, which may affect tolerability. Due to the limited number of trials for tirzepatide and lanifibranor, further large-scale studies are warranted to confirm their role in MASLD/MASH management.

The Role of GLP1 Receptor Agonists and Multi-agonist Incretin Therapies for Specific Obesity-related Health Conditions: Evidence and Rationale for Prioritisation.

Curr Obes Rep

Christo Albor, Oluwaseun Anyiam, Luke D Boyle +17 more

Study on chitosan/carrageenan core-shell nanoparticles for oral co-administration of insulin/exenatide enhance insulin secretion in type 2 diabetes.

Int J Biol Macromol

Tuong-Vy Nguyen, Ngoc-Hanh Cao-Luu, Thi-Bao-Tran Nguyen +2 more

This study developed and evaluated the feasibility of using core-shell chitosan and carrageenan nanoparticles for insulin and exenatide dual-delivery to control blood glucose levels in type 2 diabetes model. Core-shell nanoparticles were fabricated using the coaxial electrospraying technique, exploiting the electrostatic interactions between components to achieve controlled drug release in physicological media. Experimental results indicated that the prepared nanoparticles demonstrated proper physicochemical properties of an oral delivery system, including a hydrodynamic diameter around 300 nm, fitting well through the digestive wall and remaining somewhat stable in the physiologic milieu throughout time, and exhibited non-toxicity to multiple cell lines. The in vitro drug release approximately 80% from the nanoparticles was triggered by pH-sensitive behavior and controlled in spatiotemporal manners in simulated intestinal fluids with digestive enzymes, resulting in inhibition of premature release and self-sustained drug delivery. In type 2 diabetic mice, a single dose (100 IU kg-1) of nanoparticle generated a pronounced hypoglycemic response, achieving approximately a 45% reduction in blood glucose levels following 4 h oral administration and maintaining insulin plasma at a low level within 12 h owing to insulin and exenatide synergic stimulation effects. Remarkably, treatment with this nanoparticle significantly preserved pancreatic islets and averted type 2 diabetes complications within major organs such as the heart, liver, and kidneys, while maintaining an excellent systemic safety profile. This study evidenced that the nanoparticle-loaded insulin and exenatide were an encouraging long-acting formulation and validated a novel strategy to overcome multiple absorption barriers using polyelectrolyte complex nanoparticles from chitosan and carrageenan.

Bifunctional Peptide Amphiphile Hydrogel Orchestrates Concerted Antioxidant and Anti-Inflammatory Actions to Counter Myocardial Ischemia/Reperfusion Injury.

Adv Healthc Mater

Yuanyuan Wu, Siman Luo, Guanghui Xu +8 more

Myocardial ischaemia/reperfusion injury presents significant clinical challenges driven by a self-perpetuating cycle of oxidative stress and inflammation. Current therapeutic strategies fail to simultaneously address these interconnected pathological events. Here, we present T&A-Gel, a supramolecular peptide amphiphile hydrogel integrating α-tocopherol and Angiotensin-(1-7) (Ang-(1-7)) through covalent conjugation to enable localized co-delivery and synergistically disrupt this oxidative-inflammatory feed-forward circuit. Upon hierarchical self-assembly into filamentous nanofibres, T&A-Gel forms a sustained-release depot that exposes Ang-(1-7) moieties while sequestering hydrophobic α-tocopherol. This design enables α-tocopherol to scavenge excess reactive oxygen species, ameliorating oxidative mitochondrial dysfunction and reducing cardiomyocyte apoptosis, while exposed Ang-(1-7) acts as a selective Mas receptor (MasR) agonist, activating the protective MasR/PI3K/Akt signaling axis. This dual-action mechanism suppresses NF-κB nuclear translocation and inhibits pro-inflammatory cytokine cascades. In vitro, T&A-Gel significantly enhanced hypoxia/reoxygenation-injured cardiomyocyte viability. In vivo, T&A-Gel demonstrated prolonged retention with substantial reduction in infarct size and cardiac necrosis biomarkers. Quantitative analysis confirmed substantial attenuation of interstitial fibrosis and cardiomyocyte hypertrophy, translating into restored ejection fraction and reduced ventricular dilation with excellent biocompatibility. These findings establish injectable supramolecular hydrogels as a powerful strategy for disrupting the interconnected injury cascade via mechanistically complementary payloads, offering a paradigm for precision cardioprotection.

Cardiac biomarkers response under angiotensin receptor-neprilysin inhibitor: a sub-analysis of the NATRIUM-HF study.

ESC Heart Fail

Jolie Bruno, Aziz Daghmouri, Malha Sadoune +13 more

Natriuretic peptides (NPs) are central to the diagnostic and therapeutic management of heart failure (HF), yet their short-term dynamics under sacubitril/valsartan (S/V) therapy and during acute volume changes remain incompletely characterized. We aimed to assess changes in circulating biomarkers and response to standardized acute intravascular volume expansion and diuretic treatment before and after S/V initiation.