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Ectopic Cushing Syndrome due to an Adrenocorticotropic Hormone-Producing Pheochromocytoma.
AACE Endocrinol Diabetes
George A Stamatiades, Athanasios Bikas, Hina J Shah +4 more
Pheochromocytomas are rare catecholamine-secreting tumors arising from adrenomedullary chromaffin cells. Very rarely, they cosecrete adrenocorticotropic hormone (ACTH), causing ectopic Cushing syndrome. Because of its rarity, clinicians may not consider this etiology, despite the high morbidity associated with simultaneous catecholamine and cortisol excess. We present a case in which a systematic and methodical diagnostic approach led to identification and successful treatment of an ACTH-producing pheochromocytoma.
Cartilage calcification of the ears secondary to adrenal insufficiency.
Skin Health Dis
Luis Escalante, Carmen Santamaria, Astrid Maldonado +2 more
Calcification of the auricular cartilage is a rare condition, associated with either local or systemic causes. Among systemic causes, endocrine disorders, particularly adrenal insufficiency, are the most frequently reported. A 41-year-old man presented with a 1-year history of stiffness and pain in both ears. The ears became swollen and erythematous and, over time, they became painful to touch or move. Physical examination revealed rigid, immobile auricles. Biopsy, X-ray and computed tomography (CT) confirmed cartilage calcification. Laboratory tests showed markedly low cortisol and adrenocorticotropic hormone levels, leading to the diagnosis of secondary adrenal insufficiency. Auricular cartilage calcification is a rare but significant manifestation of adrenal insufficiency. Skull X-rays, noncontrast CT and laboratory tests are essential for diagnosis. No effective treatment currently exists to reverse calcification. Early recognition and hormone replacement therapy can prevent further progression.
Prognostic significance of atrial functional mitral regurgitation in patients with HFpEF and end-stage renal disease.
Front Cardiovasc Med
Yuanyuan Wang, Bingya Lv, Yangyang Chen +8 more
Atrial functional mitral regurgitation (AFMR) is common in patients with heart failure with preserved ejection fraction (HFpEF) and end-stage renal disease (ESRD) undergoing hemodialysis, but its prognostic value and potential diagnostic biomarkers remain unclear.
Paradigm shift: from pulmonary vasodilation to cardiopulmonary dual-track therapy-a comprehensive review of pathophysiology and advances in pulmonary hypertension-associated right heart failure.
Respir Res
Rongtao Chen, Chang Liu, Jiange Han +2 more
Pulmonary arterial hypertension (PAH)-induced right heart failure (RHF) remains a major determinant of poor patient outcomes, driven by multifaceted pathophysiological mechanisms including impaired right ventricle-pulmonary artery coupling, metabolic reprogramming, mitochondrial dysfunction, chronic inflammation, and gut–lung axis disruption. Traditional therapies focusing solely on pulmonary vasodilation provide symptomatic relief but often fail to halt progressive right heart deterioration. Recent advances underscore a paradigm shift toward cardiopulmonary dual-track strategies that simultaneously reduce right ventricular afterload and directly protect or enhance right heart function. Novel agents such as Sotatercept—an activin signaling inhibitor—significantly reverse vascular remodeling and improve hemodynamics. Metabolic modulators (e.g., metformin), mitochondrial-targeted antioxidants (e.g., Elamipretide), and immunomodulators (e.g., tocilizumab) show promise in correcting bioenergetic deficits and inflammatory activation. Interventional approaches like percutaneous pulmonary artery denervation (PADN) and atrial septostomy serve as effective bridging options, while percutaneous right ventricular assist devices (pRVADs) and extracorporeal membrane oxygenation (ECMO) offer critical circulatory support in end-stage disease. Emerging therapies—including gene editing, cell-based treatments, and exosome technology—hold potential for targeted, personalized intervention. Despite these innovations, challenges persist such as variable treatment responses, long-term safety concerns, and translational inefficiencies. Future efforts should prioritize multi-omics-guided precision medicine, multidisciplinary care integration, and novel technologies like CRISPR/Cas9 to advance disease-modifying therapies and improve quality of life.
Evaluation of the Safety, Efficacy and Pharmacokinetics of BGM0504 in Chinese Adults With Type 2 Diabetes: A Multicentre, Randomised, Controlled and Double-Blind Phase II Trial.
Diabetes Obes Metab
Ping Jin, Linong Ji, Yangqing Huang +7 more
This study aimed to evaluate its safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy in Chinese adults with T2DM and to preliminarily compare its efficacy and safety with semaglutide through multiple subcutaneous injections.
Semaglutide Injection in Indian Patients With Type 2 Diabetes Mellitus: A Randomised, Phase III, Active-Controlled Study.
Diabetes Obes Metab
Unnikrishnan Ambika Gopalakrishnan, Ameya Sudhakar Joshi, Richa Giri +31 more
To evaluate the efficacy, safety and immunogenicity of semaglutide injection (synthetic) (Test group) compared with the Reference semaglutide injection [Ozempic, (Reference group)] in Indian patients with Type 2 diabetes mellitus (T2DM).
The Impact of GLP-1-Based Therapies on Cardiovascular Outcomes in Type 2 Diabetes: A Comprehensive Systematic Review and Network Meta-Analysis.
Diabetes Obes Metab
Shih-Ming Chuang, Sung-Chen Liu, Kuo-Liong Chien +3 more
To provide updated agent-level comparative estimates of GLP-1-based therapies for cardiovascular outcomes in adults with Type 2 diabetes mellitus (T2DM) using a hazard ratio (HR)-based systematic review and network meta-analysis (NMA).
Do GLP-1 Receptor Agonists Sabotage Fat Grafts? : A Scoping Review of GLP-1 Receptor Agonist Effects on Adipocyte Biology and Implications for Autologous Fat Transfer.
Aesthet Surg J
Xavier Chalhoub, Zhi Yang Ng
The rapid adoption of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for weight management has created an unprecedented overlap with aesthetic surgery. Millions of patients experiencing GLP-1-mediated weight loss now present with facial volume depletion, soft tissue deflation, and contour irregularities; conditions for which autologous fat grafting remains the gold-standard solution. However, the fundamental biology of GLP-1 receptor agonism may be inherently antagonistic to the mechanisms upon which fat graft survival depends. This scoping review, conducted in accordance with the PRISMA extension for Scoping Reviews (PRISMA-ScR), synthesizes current preclinical and clinical evidence on the effects of semaglutide, liraglutide, tirzepatide, and the emerging triple agonist retatrutide on adipocyte metabolism, adipose-derived stem cell (ASC) function, and tissue revascularization, and maps these effects onto established models of fat graft take. We identify multiple potential interference points, including GLP-1-mediated adipocyte browning and thermogenic activation with upregulation of UCP1 and mitochondrial uncoupling, enhanced lipolysis through ATGL and HSL upregulation, suppression of white adipogenic differentiation in ASCs with preferential commitment toward thermogenic beige lineages, and modulation of inflammatory and angiogenic signaling during the critical revascularization window. The growing off-label use of retatrutide in bodybuilding communities introduces additional concerns through glucagon receptor-mediated lipolysis and thermogenesis. Despite the strong mechanistic rationale, no clinical or preclinical studies have directly examined fat graft outcomes in patients receiving incretin-based therapies. We propose a framework for future investigation and offer preliminary, mechanism-based clinical considerations regarding perioperative GLP-1 RA management in fat transfer patients. These recommendations should be understood as hypothesis-generating rather than evidence-based guidelines.
[Pulmonary Arterial Hypertension Impairs Duodenal Barrier Integrity in Rats].
Yakugaku Zasshi
Shouei Ishimaru, Satoshi Mizuno, Tomoya Tanada +4 more
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease that leads to right heart failure and systemic venous congestion. Such congestion can impair multiple organs, including the gastrointestinal tract. Recent clinical studies have reported elevated circulating endotoxin levels in patients with PAH, suggesting a potential disruption of intestinal barrier function. However, whether PAH affects duodenal permeability remains unclear. This study aimed to elucidate the impact of PAH on duodenal barrier integrity. PAH was induced in rats through two subcutaneous injections of monocrotaline (20 mg/kg). Histological analysis was performed, and the mRNA expression levels of duodenal tight junction proteins were quantified using real-time PCR. Duodenal permeability was assessed by performing in situ and ex vivo experiments with paracellular probes. PAH rats exhibited characteristic signs of right heart failure, including reduced weight gain, elevated brain natriuretic peptide levels, and thickening of the right ventricular wall. Histological examination revealed duodenal villous atrophy and thickened muscularis mucosa. Claudin-1 mRNA expression in the duodenum of PAH rats was 70% lower than that in control rats. In situ permeability assays revealed 2.0- and 1.5-fold increases in the portal vein concentrations of polyethylene glycol 400 and 600, respectively. In addition, ex vivo experiments showed a 1.9-fold increase in the cumulative lactulose permeation from the luminal to the vascular side over 120 min. To the best of our knowledge, this is the first report to describe decreased duodenal barrier integrity caused by monocrotaline-induced PAH in rats.
Melanocortin-4 Receptor Agonist Treatment of Hypothalamic Obesity in ROHHAD Syndrome.
Pediatrics
Anna Grünewald, Emma Steidel, Carsten Müntjes +4 more
ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) syndrome is a rare and complex pediatric condition marked by severe, early-onset hyperphagia and life-threatening obesity. For the past 2 years, we have been treating a boy, now aged 12 years, with ROHHAD syndrome. In light of the patient's progressive weight gain, intractable appetite, ventilator dependence, metabolic dysfunction-associated steatotic liver disease and behavioral dysregulation, including aggressive outbursts posing significant risk to self and others, we initiated off-label treatment with setmelanotide, a melanocortin-4 receptor (MC4R) agonist. Setmelanotide induced meaningful improvements, including substantial weight loss (28%, from 97 to 70 kg), measurable regression of hepatic steatosis as quantified by ultrasonography-based attenuation imaging, reduced ventilatory support, and a marked improvement in behavioral disorders that permitted the tapering of antipsychotic medication. After 18 months of therapy, insurance coverage for the off-label use was refused, and treatment was discontinued, which resulted in significant weight gain within 3 months (10%, from 70 to 77 kg). This treatment of hyperphagia-associated obesity in ROHHAD syndrome with setmelanotide suggests a potential pathophysiological origin in the MC4R pathway.
Liver Aging Index: A Noninvasive Score for Liver Biological Aging and Liver-Related Outcomes in Multicohorts.
Aging Cell
Zhiyu Wu, Shanshan Wu, Shuyao Song +35 more
Biological aging is a key determinant of liver disease and mortality, but there is little evidence on noninvasive index for assessment of liver biological aging. We developed the Liver Aging Index (LAI) in the China Kadoorie Biobank (CKB, N = 21,629) using Cox-Gompertz proportional hazards model. The LAI incorporated three clinical factors (body mass index, systolic and diastolic blood pressure), eight plasma biomarkers (glucose, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase), and two imaging biomarkers (fat attenuation parameter and liver stiffness measurement). External validation was conducted in the National Health and Nutrition Examination Survey (NHANES; N = 3412) and the VCTE-Prognosis cohort (N = 12,170, 16 global centers). Across all cohorts, the LAI demonstrated strong discrimination for all-cause mortality (AUROC: 0.764 in NHANES; 0.759 in VCTE-Prognosis), outperforming chronological age (p < 0.05). Liver aging acceleration (LAA), defined as the difference between LAI and chronological age, was associated with substantially elevated risks: each 1-SD increase in LAA conferred a 22%-85% higher risk of all-cause mortality and a 34%-170% higher risk of liver-related event or mortality. Using genetic instruments identified in CKB, we found genetic predisposition to accelerated liver aging was associated with higher risks of cirrhosis and liver cancer (HR = 3.94 [3.20-4.86] and 7.82 [2.05-29.80]), further validated in Biobank Japan. Integrating genetics and proteomics revealed novel pathophysiological involvement of amyloid-beta clearance pathway and amyloid precursor protein in liver aging. These findings demonstrate the feasibility of a noninvasive, liver-specific biological aging index and provide new insights into mechanisms underlying liver aging.
Acute liver injury associated with tirzepatide: An unexpected adverse event warranting clinical attention.
Ann Endocrinol (Paris)
Bayan Alqarni, Shaher Aldadi, Awatef Alotaibi
Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type-2 diabetes and for weight management. While generally well-tolerated, common adverse effects include gastrointestinal symptoms such as nausea and vomiting. Hepatotoxicity is not a widely recognized complication of tirzepatide, and reported cases of liver injury are exceedingly rare. As its use expands beyond diabetic populations, emerging safety concerns are increasingly relevant to clinical practice. We report a case of a young, previously healthy female who developed acute hepatocellular liver injury several months after initiating tirzepatide therapy for weight loss. Following dose escalation, she experienced recurrent episodes of abdominal pain radiating to the back. Workup revealed a hepatocellular pattern of injury, with exclusion of viral, autoimmune, biliary or structural causes. Symptoms resolved and liver enzymes normalized within 3weeks of presentation. This case adds to the limited but growing body of literature on tirzepatide-associated hepatotoxicity and emphasizes the importance of considering drug-induced liver injury even with newer agents believed to have favorable safety profiles.
IgG Fc-Binding Motif-Conjugated Exendin-4: A Long-Acting Hypoglycemic Agent via Broad-Spectrum Antibody Engagement for Type 2 Diabetes Therapy.
Bioconjug Chem
Baojing Mi, Shengjie Ding, Ziyu Tian +6 more
Type 2 diabetes mellitus requires therapies that optimize both efficacy and durability. Although incretin mimetics such as exendin-4 (Ex4) enhance glycemic control, their short half-life restricts their clinical utility. Current extension strategies (e.g., Fc fusion) encounter challenges including immunogenicity and manufacturing complexity. Here, we engineered a series of site-specific IgG Fc-binding motif-modified Ex4 analogues using two orthogonal conjugation methods, leveraging Fc-III-4C-mediated IgG binding (human IgG: KD = 20.1 nM) to achieve a significantly extended plasma half-life. Structure-activity relationship studies revealed that the lead candidate, conjugate 7, retained robust GLP-1R activation and acute glucose-lowering efficacy. In human IgG-preconditioned db/db mice, conjugate 7 achieved a hypoglycemic duration comparable to that of semaglutide. Chronic once-daily dosing of the lead conjugate rivaled semaglutide in reducing HbA1c and protecting pancreatic islets, without toxicity. This strategy leverages >80% of endogenous circulating IgG as a biological reservoir to overcome peptide therapy limitations, offering a translatable platform for long-acting antidiabetic agents.
Real-World Effectiveness of Tirzepatide in Japanese Patients with Type 2 Diabetes: A Multicenter Retrospective Observational Study.
Diabetes Ther
Noriyuki Takahashi, Makoto Ohara, Hiroki Yokoyama +14 more
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, significantly affects glucose and body weight-lowering effects in randomized controlled trials. However, real-world clinical evidence in Japan remains limited. This study aimed to evaluate the real-world effectiveness of tirzepatide on glycemic and metabolic factors in Japanese patients with type 2 diabetes mellitus (T2DM).
An Edible Biohybrid Platform Accomplishes In Situ Fenton-Mediated Enteral Nanoplastics Aging and Excretion.
Adv Sci (Weinh)
Su Zhou, Anran Yan, Haowei Guo +2 more
Ingested nanoplastics (NPs) readily translocate across the intestinal barrier due to their small size, posing a pervasive threat to human health. Current mitigation approaches, constrained to environmental water purification or postexposure injury alleviation, entail unavoidable NPs ingestion or organism damage. Effective strategies to impede NPs internalization at the lumen stage and promote safe elimination remain limited. Here, an edible biohybrid platform, composed of a natural polyphenol reductant, redox-active ferric ions, and H2O2-generating Enterococcus faecalis, is developed to trap NPs within the intestine. The platform enables persistent in situ generation of hydroxyl radicals in the intestine through Fenton reactions, accelerating the oxidative aging and subsequent NP agglomeration into micrometer-scale clusters that exceed the physiological pore-size limit of intestinal barrier. In an in vitro intestinal barrier model, the platform achieved a 96.02% NPs clearance efficiency within 24 h. Daily oral co‑administration effectively blocked NP penetration into lamina propria, alleviated intestinal inflammation, tight‑junction disruption, and mucosal damage in mice, as well as a protective effect further corroborated by the diminished NP fluorescence in C. elegans. Validated with both polystyrene and polypropylene NPs, this strategy of directed regulation of intestinal NP behaviors offers a green and generalizable approach to combat the NP exposure hazards.
Two contrasting cases of adrenal insufficiency in adults: a case report.
J Med Case Rep
Yingqi Guo
Adrenal insufficiency (AI) is a clinical syndrome characterized by insufficient secretion of glucocorticoids and/or mineralocorticoids. The incidence of AI is low, and its clinical manifestations are non-specific, including fatigue, generalized weakness, nausea, and weight loss. Consequently, the condition can easily be misdiagnosed or overlooked. If not treated promptly, it may progress to a life-threatening adrenal crisis. This paper reports one case of primary and one case of secondary adrenal insufficiency, aiming to enhance clinical vigilance regarding this disease through a comparative case analysis.
The clinical efficacy of Astragalus-containing Chinese patent medicines in the effective treatment of heart failure: A systematic review and network meta-analysis.
Medicine (Baltimore)
Fangfang Rui, Yunfeng Di, Chun Li +2 more
The incidence of cardiovascular diseases, particularly heart failure, has been rising year by year. Traditional Chinese medicines containing Astragalus have been widely used in clinical research. However, there is no definitive research on the efficacy of proprietary Chinese medicines containing Astragalus. A network meta-analysis was conducted to investigate the efficacy and safety of oral traditional Chinese medicines containing Astragalus for the treatment of heart failure.
Precision Management of Autoimmune Ocular Complications: Th17 Mechanisms and Therapeutic Innovations.
Exp Eye Res
Hongyu Li, Ting Wang, Chuyao Wang +3 more
Precision management of ocular complications in systemic autoimmune diseases, such as Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), Behçet's disease, and thyroid-associated ophthalmopathy (TAO), requires integration of immune mechanisms with clinical translation. These disorders manifest as dry eye, uveitis, retinal vasculitis, optic neuritis, and orbital fibroinflammatory disease, posing a substantial risk of irreversible visual loss. Recent studies highlight the T-helper 17 (Th17)/interleukin-17 (IL-17) axis, tumor necrosis factor-alpha (TNF-α), complement component 5a (C5a), and TAO-related immunostromal remodeling as pivotal inflammatory drivers. Specifically, TAO is increasingly recognized as an immunostromal disorder in which fibroblast-immune crosstalk connects thyrotropin receptor antibody/insulin-like growth factor-1 receptor signaling with orbital edema, adipogenesis, and fibrosis. Disease-specific pathways, including anti-Sjögren's-syndrome-related antigen A (anti-SSA)-mediated lacrimal damage and the human leukocyte antigen B27 (HLA-B27) gut-eye axis, further enrich etiological insights. Diagnostically, aqueous IL-17, C-X-C motif chemokine ligand 10 (CXCL10), tear biomarkers, and optical coherence tomography angiography (OCTA) enable more precise phenotyping, whereas invasive ocular-fluid testing requires careful risk-benefit evaluation. Therapeutically, anti-TNF-α monoclonal antibodies, teprotumumab, and avacopan target critical pathways and improve refractory cases, while Janus kinase inhibitors, B-cell-directed combinations, and engineered regulatory T-cell therapies show promise but require rigorous safety and translational validation. This review discusses major advances in immunopathogenesis, diagnostics, and therapeutics, comparing disease commonalities and distinctions to propose a framework for precision management. It envisions multi-omics phenotyping, artificial intelligence-assisted diagnostics, and pathway-directed immunomodulation to reduce blindness and enhance quality of life, bridging rheumatology and ophthalmology.
Hypericin Alleviates High Glucose-Induced Ferroptosis in Cultured Rat Satellite Glial Cells via Targeting P2X7R to Activate the Akt/GSK3β/Nrf2 Axis.
Neuropharmacology
Qixing Hu, Congfa Zhou, Hongmin Guo +6 more
Hyperglycemia is a major risk factor for diabetic cardiovascular autonomic neuropathy (DCAN), but the underlying cellular mechanisms remain incompletely understood. To address this gap, this in vitro study aimed to determine whether high glucose induces ferroptosis in primary satellite glial cells (SGCs) isolated from rat stellate ganglia (SG) and to evaluate the protective mechanism of hypericin. Our results showed that high glucose markedly upregulates P2X7 receptor (P2X7R) expression in SGCs, leading to reduced cell viability and characteristic ferroptotic events, including increased levels of reactive oxygen species (ROS), abnormal iron accumulation, enhanced lipid peroxidation, and a marked decline in both glutathione (GSH) content and the activity of glutathione peroxidase 4 (GPX4). Hypericin at 0.1 μmol/L exhibited strong protective effects against high glucose-induced injury. Mechanistically, hypericin directly binds to the K110 site of P2X7R, inhibiting its function and subsequently activating the Akt/GSK3β pathway. This activation stabilizes Nrf2 by suppressing its ubiquitin-mediated degradation, promotes Nrf2 nuclear translocation, and upregulates the GPX4/SLC7A11 antioxidant axis. Genetic knockdown of P2X7R or Nrf2 confirmed their essential roles in this pathway. These findings reveal a previously unrecognized mechanism by which hypericin alleviates SGCs ferroptosis under high glucose conditions through the P2X7R/Akt/GSK3β/Nrf2 axis, highlighting its potential relevance to DCAN.
GLP-1 receptor agonists for weight management and potential thromboembolic risk reduction in high risk population with cancer, diabetes, cardiovascular disease: A systematic review.
Dis Mon
Rushin S Parekh, Pugazhendi Inban, Andy Thai +3 more
Thromboembolic risk is increased in obesity and cardiometabolic disorders. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) also facilitate weight loss and cardiovascular benefits, yet their effects on thromboembolic events risk reduction in high-risk populations are not completely understood.