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Currently Approved and Future Regimens for Metabolic Dysfunction-Associated Steatohepatitis.
Clin Liver Dis
Eliabe S Abreu, Mazen Noureddin, Hirokazu Takahashi +2 more
Metabolic dysfunction-associated steatohepatitis (MASH), the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), has historically been treated with lifestyle modification (dietary changes, exercise and weight loss). While lifestyle modification remains foundational in the treatment of MASLD/MASH, resmetirom (a thyroid hormone β-receptor agonist) and semaglutide (a glucagon-like-peptide-1 receptor agonist) are now Food and Drug Administration-approved for patients with MASH and clinically significant hepatic fibrosis (ie, F2-F3 fibrosis). Emerging therapies will allow for future opportunities at a personalized approach to treatment of MASH. This article reviews currently approved and future regimens for the treatment of MASH and MASH-related cirrhosis.
Prognostic value of pretest probability of heart failure with preserved ejection fraction in patients with coronary artery disease: an insight from the CLIDAS-PCI database.
Cardiovasc Interv Ther
Tomoaki Nishikawa, Shunsuke Tamaki, Kazuhisa Nishimura +17 more
Coronary artery disease (CAD) is a major risk factor for the development of heart failure (HF) with preserved ejection fraction (HFpEF) and is associated with increased mortality. However, an optimal strategy to screen for HFpEF among patients with CAD has not yet been established. The HFpEF-ABA score was introduced to estimate the pretest probability of HFpEF and was shown to predict adverse HF events. This retrospective multicenter cohort study included patients registered in the Clinical Deep Data Accumulation System database who underwent percutaneous coronary intervention from April 2013 to March 2019. Patients with a left ventricular (LV) ejection fraction ≥ 50% and no known history of HF were included. Age, body mass index, and a history of atrial fibrillation were used to calculate the HFpEF-ABA score, and patients were dichotomized at a 50% threshold for descriptive risk stratification. The primary endpoint was a composite of all-cause death and unplanned HF hospitalization. Among 3307 patients, those with high HFpEF-ABA scores were more likely to have hypertension, renal dysfunction, anemia, larger left atrial size, higher LV mass index, and elevated brain natriuretic peptide levels, consistent with an HFpEF phenotype. Over a median follow-up of 721 days, 275 patients experienced the primary endpoint. The HFpEF-ABA score was independently associated with the primary endpoint as both a continuous and a categorical variable (hazard ratio: 1.07 [95% confidence interval: 1.00-1.14], P = 0.043, and 1.37 [1.07-1.76], P = 0.015, respectively). The HFpEF-ABA score identifies CAD patients with an HFpEF phenotype and predicts adverse outcomes.
Phenotypic and genotypic analysis of pediatric patients with congenital isolated growth hormone deficiency resulting from biallelic variants in the GHRHR gene: a Belgian registry study.
Eur J Pediatr
Simone Van de Velde, Emese Boros, Chloë Brunelle +6 more
Pathogenic variants in the growth hormone releasing hormone receptor (GHRHR) gene cause severe isolated growth hormone deficiency (IGHD). Over 82 distinct variants have been described, mostly in South and East Asia and Northern Brazil. This study characterizes the phenotypic and genotypic variability of children harboring (likely) pathogenic GHRHR variants, included in the Belgian and Luxembourg Registry for Growth Hormone Treated Children. We retrospectively reviewed clinical, biochemical, genetic and neuroimaging data from seven children with severe IGHD carrying biallelic GHRHR variants. Peak growth hormone (GH) concentrations were measured following insulin and glucagon-induced hypoglycemia. Auxological parameters at diagnosis and pituitary magnetic resonance imaging (MRI) findings were obtained from medical records. Three children of Syrian origin from two consanguineous families carried a novel likely pathogenic c.367G > T, p.(Glu123*) variant in a homozygous state. Among the four Belgian-origin patients, one was homozygous for a pathogenic c.674_677delinsGCTGTTGGCAGAAG, p.(Val225Gly*fs165) variant, while two siblings were compound heterozygous including this particular variant and an additional pathogenic c.271dupG, p.(Ala91Glyfs*13) frameshift variant. The other Belgian patient was compound heterozygous for the well described likely pathogenic c.431 T > A, p.(Leu144His) variant and a previously undescribed c.150C > A, p.(Asn50Lys) variant. IGHD was diagnosed between 7 months and 7 years. Height SDS at presentation ranged from - 4.6 to - 3.4. Peak GH levels after stimulation were markedly reduced (0.35-3.4 ng/ml), confirming severe growth hormone deficiency (GHD). No dysmorphic features were observed. Anterior pituitary hypoplasia at MRI was seen in six patients.
Optimization and verification of high-fat diet formulation for establishing a rat model of obesity-related precocious puberty.
Animal Model Exp Med
Jiayi Gong, Wei Qian, Deji Song +3 more
Childhood obesity is closely linked to the rising incidence of precocious puberty (PP), yet valid preclinical models of obesity-related PP remain lacking. High-fat diets (HFD) are widely used for obesity models, but the suitability of different HFD formulations for inducing PP is unknown. Female Sprague-Dawley (SD) rats were randomized to control, 45% HFD, or 60% HFD groups at postnatal day (PND) 21. Body weight and daily caloric intake were monitored; vaginal opening (VO) was recorded from PND 35. At study termination, serum levels of estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), leptin, and adiponectin were measured. Ovarian histology and vaginal cytology were assessed. In vitro, GT1-7 cells were treated with recombinant mouse leptin for 24 h, and GnRH secretion was quantified. Compared to controls and the 60% HFD group, rats fed 45% HFD exhibited significantly increased body weight, earlier VO onset, and elevated weights of organs. The 45% HFD group also had higher serum E2, LH, FSH, GnRH, and leptin levels, alongside reduced adiponectin; ovarian histology showed advanced follicular development, and vaginal smears displayed estrus-stage cytology. In contrast, the 60% HFD group had no significant changes in body weight or hormonal parameters, and limited ovarian development. In vitro, leptin treatment significantly upregulated GnRH secretion in GT1-7 cells. The 45% HFD formulation is optimal for constructing a juvenile rat model of obesity-related PP, as it recapitulates key phenotypic, histological, and endocrine features of the disease.
Stereoselective Targeting with Chiral Nanomaterials: A Strategy for Precision Therapy in Neurodegenerative Diseases.
Acta Biomater
Ruhui Luo, Yaqing Zhang, Xiner Tan +1 more
The challenge in treating neurodegenerative diseases (NDs) lies in the complexity of their pathological mechanisms. Strategies capable of synergistically regulating multiple pathological features are crucial for treating NDs. Chiral nanomaterials (CNMs), including chiral nanoparticles (CNPs) and chiral nanoassemblies (CAMs), offer a unique platform for achieving such precise multitarget regulation because of their stereoselective interactions. Strategies for synthesizing CNMs are outlined in this review, and an in-depth analysis of their core biological mechanisms for treating NDs-inhibiting and clearing pathological proteins, enhancing synaptic plasticity, alleviating neuroinflammation, selectively eliminating senescent cells and promoting the differentiation of neural stem cells-is provided. Optimization of these functions through internal chiral design and external physical field modulation is explored. Finally, we propose forward-looking concepts such as "stage-optimized chiral nanomedicines" and "intelligently responsive chiral nanomaterials" to provide guidance for next-generation precision nanomedicine for NDs. STATEMENT OF SIGNIFICANCE: The key challenge in treating neurodegenerative diseases (NDs) lies in the precise identification and coordinated regulation of multi-target pathological processes. In recent years, chiral nanomaterials (CNMs), including chiral nanoparticles (CNPs) and chiral nanoassemblies (CAMs), have emerged as innovative tools for NDs intervention owing to their unique stereoselective recognition capabilities. This review systematically categorizes CNMs and their synthesis strategies, and focuses on elucidating their core biological mechanisms, including the inhibition and clearance of pathological proteins, enhancement of synaptic plasticity, alleviation of neuroinflammation, selective elimination of senescent cells, and promotion of neural stem cell differentiation. Furthermore, strategies to optimize their functionality through internal chiral structure design and external physical field modulation are explored. Collectively, this review aims to systematically elucidate the biological mechanisms and material properties of CNMs in NDs therapy, providing a theoretical foundation and guidance for the rational design and construction of next-generation neurorepair materials.
Eugenol from Syzygium aromaticum enhances longevity and proteostasis in aged yeast.
Biogerontology
Suchanya Suesattayapirom, Tachaporn Kanhachai, Anjana Puttapong +5 more
Clove (Syzygium aromaticum) extracts promote longevity in several model systems, yet the underlying molecular mechanisms responsible for the pro-longevity remain poorly defined. This study utilized a Saccharomyces cerevisiae model to investigate how clove extracts modulate two primary hallmarks of cellular aging: oxidative damage and the decline of protein quality control systems. Clove extracts promoted increased chronological lifespan (CLS) of yeast cells. The change in longevity was associated with a reduction in both reactive oxygen species (ROS) levels and increased resistance to oxidant and thermal challenges. The appearance of protein aggregates was also limited with treatment with clove extract and is likely linked to induction of the autophagy pathway. Deletion of RAS2 abrogated the enhanced CLS from clove extracts. This observation suggests that the ability of clove extracts to extend the lifespan of S. cerevisiae is dependent on the Ras/PKA (Protein Kinase A) signaling pathway.These results indicate that the enhanced CLS from clove extracts are mediated through improving the maintenance of proteostasis rather than general antioxidant activity. Chemical profiling and comparative bioassays of major constituents identified eugenol as the principal bioactive compound, which successfully replicated the anti-aging and stress-reducing properties of clove extract. Our findings demonstrate that clove extracts, through the bioactive compound eugenol, promote survival in aged cells through reducing oxidative stress and damage and improving the clearance of aggregated proteins to limit proteotoxicity.
Differing Presentations of Excess Visceral Abdominal Fat in People Living With HIV: Two Clinical Cases Highlighting Distinct Therapeutic Pathways With Tesamorelin and Glucagon-Like Peptide-1 Receptor Agonists.
Clin Infect Dis
Robin Beach, Zandraetta Tims-Cook, Colleen S McGary +1 more
Excess visceral abdominal fat (EVAF) is a prevalent metabolic complication among people living with HIV-1 (PLWH), occurring even in individuals with normal or mildly elevated body mass index (BMI). This pattern of fat accumulation is associated with metabolic dysfunction, cardiovascular risk, and reduced quality of life. Since EVAF can present without generalized obesity, weight-based assessments may fail to identify it; moreover, addressing EVAF warrants distinct approaches based on a patient's presentation. Two therapeutic classes have been studied in this setting: growth hormone-releasing hormone analog (tesamorelin), which selectively reduces visceral fat, and glucagon-like peptide (GLP-1) receptor agonists, which induces generalized weight loss in a nonspecific way.
FAS-controlled T cells drive lymphoproliferation through glycolysis without effector differentiation.
J Hum Immun
Maria Elena Maccari, Christoph König, Geoffroy Andrieux +38 more
Lymphoproliferation in autoimmune lymphoproliferative syndrome (ALPS) due to FAS deficiency is driven by highly proliferative FAS-controlled T cells (FCT) with a distinct molecular signature. Activating signals and metabolic fuels of their proliferation are poorly understood. Lymphoproliferation caused by proliferative T cells is also a hallmark of acute EBV infection. In these antiviral T cells, a metabolic switch to glycolysis underpins effector differentiation and IFNγ translation. Here, we used EBV-induced CD8 effector T cells as a benchmark to characterize FCT metabolism. Metabolic assays, RNA sequencing, and in silico computational analysis revealed that FCT are as highly glycolytic as EBV-induced effector T cells, but this metabolic program is uncoupled from T-BET expression and IFNγ production. In contrast to virus-activated T cells, FCT showed mitochondrial hyperpolarization and elevated reactive oxygen species production. These findings support a model of FCT lymphoproliferation, in which activating signals strongly enhance glycolysis but do not induce classical effector differentiation.
Unmasking counterfeit semaglutide: analysis of real-world safety data from EudraVigilance.
Front Pharmacol
Alessia Zinzi, Mario Gaio, Rosanna Ruggiero +7 more
The spread of counterfeit drugs represents a serious threat to public health because they may be ineffective or cause the onset of severe suspected adverse drug reactions (ADRs). To date, the traceability of semaglutide-based products, widely used off-label for weight loss, is not a well-studied area.
Liraglutide Causing Pancreatitis in an Indian Obese Female: A Case Report and Review of the Literature.
Curr Drug Saf
Jitendra Singh, Anju Dinkar, Rajeev Verma +3 more
Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is commonly prescribed for obesity and type 2 diabetes mellitus (T2DM). While its metabolic benefits are well-established, rare cases of acute pancreatitis (AP) have raised concerns about drug safety. Despite regulatory warnings from the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), causality remains debated due to confounding factors and limited human data.
Six-month effects of liraglutide and dapagliflozin on lipid profile, cardiovascular risk, and NT-proBNP levels in patients with metabolic dysfunction-associated steatotic liver disease.
Wiad Lek
Volodymyr Cherniavskyi, Artem Akimov, Luiza Parunian +2 more
Aim: This study assessed and compared changes in lipid profile and cardiovascular risk in patients with metabolic dysfunction-associated steatotic liver disease after six months of liraglutide or dapagliflozin treatment. We also evaluated changes in N-terminal pro-B-type natriuretic peptide levels.
Efferocytosis: Signaling Pathways and New Therapeutic Strategies for Diseases.
MedComm (2020)
Lei Wang, Jingjing Ge, Zehua Wang +4 more
Efferocytosis-the phagocytic clearance of apoptotic cells (ACs)-is essential for maintaining tissue homeostasis, immune tolerance, and inflammation resolution. Beyond classic receptor-mediated recognition, this process drives phagocyte metabolic reprogramming to actively facilitate tissue repair. Consequently, defective efferocytosis serves as a core pathogenic mechanism across major human diseases. This review outlines the molecular and metabolic foundations of efferocytosis and defines four universal hallmarks of its dysfunction: senescence-driven impairment, unresolved inflammation, loss of immune tolerance, and fibrotic tissue repair. Subsequent sections explore how these defects manifest in cardiovascular, autoimmune, and neurodegenerative conditions, as well as cancer. Because efferocytosis exhibits a dual pathophysiological nature, therapeutic interventions must be highly disease-specific. Enhancing apoptotic clearance can effectively resolve chronic inflammatory and fibrotic conditions. Conversely, because tumors hijack these same pathways to build immunosuppressive microenvironments, inhibiting efferocytosis remains a critical strategy in oncology. The synthesis of these divergent roles informs a "context-dependent directionality" framework to guide the clinical translation of efferocytosis-targeted precision therapies.
Improving Pulmonary Edema Assessment in Pediatric Congenital Heart Disease: The Role of Lung Ultrasonography.
Arq Bras Cardiol
Yasemin Nuran Donmez, Derya Bako, Safak Alpat +2 more
Pulmonary edema is a clinically significant complication in children with congenital heart disease (CHD). It occurs more frequently in complex cases and is associated with prolonged hospital stays. Early identification is essential because of its direct impact on clinical outcomes.
GLP-1/GIP dual agonist tirzepatide in obstructive sleep apnea syndrome: mechanisms, evidence, and clinical perspectives.
Front Med (Lausanne)
Qiujie Fang, Yipeng Zhu, Mei Rao +1 more
Obstructive sleep apnea syndrome (OSAS) is closely associated with obesity and metabolic dysfunction. Tirzepatide, a dual GLP-1 and GIP receptor agonist, has demonstrated superior efficacy for weight reduction and improved metabolic health compared with single GLP-1 agonists. Emerging evidence indicates that tirzepatide may alleviate OSAS through its multifaceted effects on adiposity, inflammation, and neuromuscular regulation. This review synthesizes the pharmacological mechanisms, clinical findings, and safety data of tirzepatide in OSAS management. Preliminary studies show promising reductions in body weight, apnea-hypopnea index (AHI), and systemic inflammation, although long-term trials remain warranted. Further exploration into its integration with existing OSAS therapies could redefine the pharmacologic management of obesity-related OSAS.
Developments in Pharmacotherapy for Acromegaly: Current and Emerging Approaches.
Drugs
Nicholas A Tritos, Beverly M K Biller
Pituitary surgery is the primary therapy for most patients with acromegaly. Medical therapy has an important, albeit adjunctive role in the management of patients with persistent disease after surgery. However, primary medical therapy can be appropriate as an option in select patients. Medical therapies in current use for acromegaly are somatostatin receptor ligands (SRLs) (octreotide long-acting release [LAR], octreotide acetate, lanreotide depot, octreotide subcutaneous (SC) depot, pasireotide LAR, oral octreotide, paltusotine), dopamine agonists (cabergoline) and growth hormone receptor antagonists (pegvisomant). These are often efficacious and generally well tolerated. However, a particular pharmaceutical agent may not meet the needs of individual patients because of intolerance, contraindications to their use, lack of sustained efficacy, or decreased quality of life. Several investigational drugs are in development towards addressing unmet needs of patients with acromegaly, including new formulations of SRLs (lanreotide prolonged-release formulation, Debio 4126, pasireotide SC depot), novel SRLs (somatoprim, HTL0030310), monoclonal antibodies against growth hormone, and new growth hormone receptor antagonists. Current and emerging therapies are offering renewed hope for disease control. More studies including comparator agents, identification of accurate biomarkers and models predictive of clinical effectiveness may further improve the care of patients with acromegaly.
Comprehensive assessment of novel cardiovascular biomarkers in AF.
Europace
Amelie H Ohlrogge, Daniel Engler, Patricia Schlieker +10 more
Biomarkers have the potential to improve risk prediction beyond clinical characteristics. We examined the association of four emerging cardiovascular biomarkers (angiopoietin 2 [Angpt2], bone morphogenetic protein 10 [BMP10], fibroblast growth factor 23 [FGF23], insulin-like growth factor binding protein 7 [IGFBP7]) in comparison with N-terminal pro B-type natriuretic peptide (NTproBNP) across the disease course of atrial fibrillation (AF).
Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
Nat Aging
David E Lee, Lauren K McKay, Akshay Bareja +8 more
Sarcopenia and the age-related decline in muscular strength and regenerative capacity contribute directly to loss of autonomy, greater risk for hospitalization and healthcare utilization. One contributing cellular phenotype associated with skeletal muscle aging is a loss in the function and number of resident muscle stem cells (MuSCs) or satellite cells. MuSC activation leads to dramatic changes in cellular architecture and metabolic reprogramming, including both mitochondrial biogenesis and increased glycolysis. Despite these changes to increase energy production, high energy demands may not be fully met during periods of MuSC activation. Here we used in vitro and in vivo approaches in mice to demonstrate the function of glutaminase for age-related changes in MuSC function. By combining fluorescence-activated cell sorting (FACS) isolation with metabolomics and stable isotope tracing, we show an age-related decline in reductive (counterclockwise) flux of glutamine through the tricarboxylic acid (TCA) cycle, a pathway by which MuSCs build cellular fatty acid stores as necessary biomass for MuSC function.
The effects of time constraints on electrocortical dynamics underlying obstacle avoidance while walking.
Cortex
Marco A Bühler, Sylvain Baillet, Bradford J McFadyen +2 more
A growing body of literature has characterized the extensive and widespread engagement of cortical resources during the execution of locomotor adaptations. However, evidence suggests that the extent of cortical regulation involved in such adaptations is modulated by the available time to respond. In this study, a treadmill-based virtual reality paradigm was used to examine the electrocortical oscillations associated with obstacle avoidance under short versus long available response times (ARTs). Electroencephalography data were recorded from healthy young adults as they stepped over virtual obstacles. These obstacles were presented in far space, allowing either a short (1.5 sec) or long (4 sec) ART between their presentation and clearance. Data were parsed with independent component analysis and clustered within the prefrontal, sensorimotor, parietal and occipital regions. Distinct spectral signatures were observed across all cortical regions, characterized by transient synchronizations shortly after obstacle presentation and immediately prior to clearance. Compared to the long ART condition, the short ART condition elicited stronger prefrontal theta, alpha, and beta synchronizations. During clearance, long ARTs were associated with a sensorimotor alpha desynchronization during obstacle clearance; however, such desynchronization was largely absent under short ART. Taken together, these findings suggest that tighter temporal constraints during obstacle avoidance enhance prefrontal involvement and decrease sensorimotor network activation. Such time-dependent cortical dynamics offer new insights into the neural mechanisms underlying locomotor adjustments that can inform our understanding of locomotor deficits in aging and neurological disorders.
Antibodies targeting amyloid-β and Tau oligomers in Alzheimer's disease.
Adv Protein Chem Struct Biol
Subashchandrabose Chinnathambi, Nagaraj Rangappa, Madhura Chandrashekar
Alzheimer's disease is a leading neurodegenerative disorder, is characterized by cognitive decline linked to amyloid-beta plaques and Tau tangles. These pathological aggregates disrupt the neuronal communication, induce neuroinflammation, and contribute to synaptic dysfunction. Genetic mutations, aging, environmental and lifestyle factors exacerbate these mechanisms, promoting neurotoxicity. Advances in immunotherapy have targeted Aβ and Tau oligomers using several monoclonal antibodies and Tau-specific antibodies. These therapies aim to neutralize toxic aggregates, facilitate clearance, and slow cognitive decline. Dual-targeting approaches, such as bispecific antibodies, address both Aβ and Tau, enhancing therapeutic efficacy. Despite challenges-like limited blood-brain barrier penetration, off-target effects, and high production costs, innovations in nanobody technology and personalized medicine are the key players. Artificial intelligence-driven antibody design further accelerates development, offering hope for transformative Alzheimer's disease treatments. Future research focuses on optimizing safety and efficacy, paving the way for comprehensive management of this devastating disease.
Objective Assessment of Functional Capacity Improvement Following Transcatheter Tricuspid Valve Interventions.
Am J Cardiol
Luca Cumitini, Ailia Giubertoni, Marco Mennuni +2 more
Transcatheter tricuspid valve interventions have recently emerged as effective therapeutic options for patients with severe tricuspid regurgitation (TR) and heart failure at high surgical risk. Despite evidence of post-procedural clinical improvement, data regarding changes in functional capacity remain limited. In this prospective, observational study we enrolled high-risk patients with at least severe TR and heart failure undergoing transcatheter tricuspid valve repair by the PASCAL® device or replacement with the EVOQUE® system. Functional capacity was evaluated by cardiopulmonary exercise testing (CPET), in addition to clinical, laboratory, and echocardiographic parameters, at baseline and 3 months post-procedure. The primary endpoint was the change in peak oxygen consumption (VO₂) by CPET at 3 months versus baseline. Secondary endpoints included changes in other CPET parameters, TR severity by transthoracic echocardiography, New York Heart Association (NYHA) class, daily furosemide dose, and pro-brain natriuretic peptide (pro-BNP) levels. A total of 10 patients were enrolled, with successful device implantation obtained in all cases. Peak VO₂ improved significantly from 14.7±3.7 at baseline to 16.4±2.9 ml/kg/min at 3 months (p=0.009). Peak oxygen pulse increased from 85.1±20.2% to 103.7±23.3% (p=0.022), and ventilation maximum rose from 39.9±10.3 L/min to 45.7±10.9 L/min (p=0.035). TR severity was reduced (p=0.002), NYHA class improved (p=0.016), and daily furosemide dose decreased (p=0.016). Although pro-BNP levels declined, this reduction was not statistically significant. No adverse event occurred during follow-up. In conclusion, among patients with severe TR and heart failure, TR reduction by transcatheter tricuspid valve interventions was associated with improved CPET-derived functional capacity, better functional class and reduced diuretic requirement during short-term follow-up.