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The Effects of Exercise Combined with Pharmacotherapy on Body Composition and Metabolic Parameters in Overweight/Obese Adults: A Meta-Analysis and Network Pharmacology Study.
Diabetes Metab Syndr Obes
Tianhang Peng, Wanyuan Liang, Ju Wei +3 more
Overweight and obesity are major global health issues. Traditional interventions have limited efficacy, while pharmacological treatments are hindered by side effects and weight rebound. This study evaluates the effects of combined exercise and medication on body composition and metabolic health in overweight/obese adults, using network pharmacology to explore potential synergistic mechanisms.
The emerging role and therapeutic targeting of autophagy-lysosome pathway in the pathogenesis of Parkinson's disease.
Transl Neurodegener
Takahiro Shimizu, Sanem Isik, Nitika Kamath +1 more
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and the accumulation of misfolded α-synuclein, yet the underlying mechanisms remain incompletely understood. Over the past two decades, genetic discoveries have highlighted the convergence of multiple familial PD genes on the autophagy-lysosome pathway (ALP), a key cellular system responsible for the degradation and recycling of intracellular components. Recent studies have further revealed that components of the ALP not only mediate the clearance of α-synuclein aggregates but also, under certain pathological conditions, contribute to their propagation via lysosomal exocytosis or secretory autophagy. The precise functions of autophagy are highly context-dependent, with neuronal and glial cells exhibiting distinct ALP dynamics that shift with development, stress, and aging. In this review, we summarize current knowledge on the physiological regulation of autophagy in the brain and critically examine its involvement in PD pathogenesis, incorporating mechanistic insights from familial models and emerging evidence from sporadic PD. We also explore translational implications, focusing on efforts to identify ALP-related biomarkers in cerebrospinal fluid and urine, and on the therapeutic potential of modulating ALP activity. Although the causality between ALP dysfunction and PD remains elusive, mounting evidence supports its contribution to disease progression, particularly through impaired lysosomal homeostasis and disrupted intracellular trafficking. Future research should aim to define cell type-specific ALP alterations, clarify the bidirectional interactions between α-synuclein and autophagic machinery, and develop in vivo tools to monitor autophagy activity and secretory signatures. A deeper understanding of these processes will be crucial for refining PD models, discovering robust fluid biomarkers, and designing targeted therapies capable of modifying disease trajectory.
Mapping cardiac and respiratory pulsations simultaneously with functional connectivity in the rat brain using zero echo time fMRI.
J Cereb Blood Flow Metab
Ekaterina Paasonen, Petteri Stenroos, Antonio Caulin Atienzar +8 more
Vascular pulsations are increasingly recognized as key contributors to cerebral perfusion and brain clearance mechanisms, with alterations linked to aging and neurodegenerative diseases. However, capturing fast physiological dynamics in preclinical models remains technically challenging due to high cardiac frequencies and small brain size. Here, we investigated the feasibility of zero echo time (ZTE) functional MRI (fMRI) to capture cardiac- and respiration-related pulsations across multiple temporal scales in the rat brain under isoflurane anesthesia. We used retrospective binning to assess cardiac- and respiration-related pulsations. Cardiovascular state was modulated with medetomidine, and functional connectivity analyses were performed to evaluate slower neural dynamics. ZTE fMRI robustly detected physiological pulsations across the brain, achieving effective temporal resolution of 8 ms, with the strongest signals observed in large arteries, consistent with an inflow‑based contrast mechanism. Cardiac pulsation amplitudes increased significantly under combined medetomidine-isoflurane anesthesia, whereas respiration‑related pulsations remained stable. Functional connectivity decreased under combined anesthesia, confirming ZTE fMRI sensitivity to slower neural dynamics. ZTE fMRI enables simultaneous assessment of cerebrovascular pulsatility and functional connectivity, providing a powerful tool for studying physiological brain dynamics in vivo.
Engulfment by brain macrophages in a short-lived vertebrate.
bioRxiv
Rahul Nagvekar, Angela N Pogson, Prateek R Kalakuntla +20 more
Engulfment by macrophages is critical for waste clearance in the vertebrate brain. Understanding clearance mechanisms may open new therapeutic possibilities to counter brain aging and neurodegenerative diseases. However, few in vivo models exist to study engulfment in the brain and characterize this process during aging and across species. Here we present a genetic model for secretion of a fluorescent protein by neurons in the brain of the African turquoise killifish, the shortest-lived vertebrate that can be bred in captivity. We use this model to identify a population of brain macrophages in the killifish responsible for engulfment of material from the brain extracellular space. Intriguingly, many of these cells bear similarities to mammalian border-associated and monocyte-derived macrophages, rare subsets of macrophages in mouse and human brains noted for their engulfment capabilities. We also find that in our model, killifish brain macrophages decline in engulfment capacity with age. This work highlights how vertebrate brain macrophages, particularly those at brain border regions, can play a critical role in clearance and provides an opportunity to test interventions that can boost engulfment by these macrophages to promote brain resilience in old age and disease.
Host immunosenescence compromises Mycobacterium tuberculosis clearance.
Aging (Albany NY)
Falak Pahwa, Shweta Chaudhary, Ashish Gupta +2 more
Immunosenescence increases susceptibility to infectious diseases like tuberculosis (TB) in older adults (≥60 years) and hinder effective containment of Mycobacterium tuberculosis (Mtb) during therapeutic intervention. A comprehensive understanding of the cellular and molecular changes underlying age-associated immune alterations may inform development of strategies to improve treatment outcomes. Here, we monitored the immunopathology, frequency, and functionality of immune cells across extreme age groups of C57BL/6 mice following low aerosol dose infection (100-120 cfu) with Mtb H37Rv and treatment with rifampicin and isoniazid (RIF-INH). Up to 6 weeks post infection, mycobacterial load in tissues (lung, spleen, and liver) of old (17-19 months; M) and aged (31M) C57BL/6 mice was similar to that of young (2-4M) mice. However, at two weeks post-treatment, older mice showed a slower rate of Mtb clearance in the lungs. Mtb-infected old mice had higher splenic T-follicular cytotoxic (TFC)-like cells, and proteomic analysis of flow-sorted CD4+CD44+ T cells revealed deregulated mitochondrial proteins (4-hydroxy-2-oxoglutarate aldolase, aspartate aminotransferase, and prostaglandin E synthase), suggesting impaired mitochondrial function. Collectively, these findings suggest that age-associated immune alterations may disrupt immunometabolic pathways, thereby contributing to the delayed Mtb clearance. Targeting immunometabolic dysfunction therefore represents a promising strategy to enhance TB treatment efficacy and reduce disease burden in older populations.
Cellular senescence: from pathogenic mechanisms to precision anti-aging interventions.
Aging (Albany NY)
Jian Deng, Ruipu Sun, Zhiyong Bai +3 more
For decades, research on cellular senescence has predominantly focused on the static identification of senescent cells using markers such as p16 and β-galactosidase, largely overlooking their functional heterogeneity across spatiotemporal dimensions. Accumulating evidence reveals that senescent cells are not merely deleterious pathological byproducts; rather, a subset plays indispensable physiological roles in embryonic development, wound healing, and the maintenance of tissue homeostasis. Based on these insights, this review summarizes the induction mechanisms of cellular senescence and the subsequent evolution of their functional phenotypes across diverse tissues. Consequently, we propose a novel paradigm for senescence management centered on "prevention first, followed by precision intervention." This strategy involves, on one hand, mitigating environmental stressors and optimizing metabolism to intercept the onset of detrimental senescence at its source. On the other hand, it advocates for the functional profiling of existing senescent populations via single-cell omics and lineage tracing, enabling the targeted clearance of "maladaptive" components that drive pathological phenotypes while preserving "beneficial" elements essential for physiological stability. Such a systematic intervention, grounded in the classification of induction factors and functional subtypes, offers a safer and more efficacious trajectory for the prevention of age-related diseases and the extension of healthspan.
Early mortality in multiple myeloma patients with renal impairment: a nested case-control study.
BMC Nephrol
Yan Li, Wenjiao Tang, Bing Xiang +4 more
Renal impairment (RI) in multiple myeloma (MM) patients significantly impacts outcomes, yet the prevalence and causes of early mortality within 12 months of diagnosis in newly diagnosed MM (NDMM) with RI are understudied in the novel agent era.
An experimental study of early cardiovascular disease and risk factors in a collagen-induced arthritis rat model.
Front Immunol
Chun Yun Jiang, Da Li, Quan Jiang +2 more
This study investigated the pathological characteristics and risk factors of early cardiovascular disease (CVD) associated with rheumatoid arthritis (RA) using a collagen-induced arthritis (CIA) rat model.
Concurrent Assessment of Neurotrophic Factors and HPA-Axis Hormones in Early Childhood Autism Spectrum Disorder.
J Autism Dev Disord
Hurşit Ferahkaya, Ayşegül Tuğba Hira Selen, Şeyma Tezer +4 more
Neurotrophic pathways and hypothalamic-pituitary-adrenal (HPA) axis regulation have been implicated in autism spectrum disorder (ASD), yet peripheral findings-particularly in early childhood-remain inconsistent. We examined peripheral neurotrophic factors and HPA-axis hormones in medication-naïve young children with ASD and evaluated their associations with clinical severity.
[The physiological roles of primary ciliary resorption and its potential as therapeutic targets].
Nihon Yakurigaku Zasshi
Masaki Saito, Gen-Ichi Atsumi
Primary cilia are cellular antennae protruding from the surface of nearly all cell types during the G0 phase. They control the organization and maturation of systemic tissues and organs by receiving selective signals. Ciliopathies are heritable disorders that cause dysplasia of various tissues and organs, as well as the progression of obesity. In contrast, recent studies using cultured cells have revealed that cilia were resorbed upon receiving selective proliferative stimuli, thereby reentering the cell cycle into the G1/S phase. However, the physiological significance and molecular mechanisms of ciliary resorption were unclear, as no diseases caused by abnormal ciliary resorption had been identified in humans or experimental animals. To address this problem, we focused on the role of the cytoplasmic dynein light chain Tctex-1. We found that activating the insulin-like growth factor-1 receptor at cilia results in the phosphorylation of threonine 94 in Tctex-1 and subsequent endocytosis of the ciliary pocket membrane surrounding the ciliary basal region. This mechanism is responsible for ciliary resorption and reentry into the G1/S phases of the cell cycle. Additionally, we found that phospho-(T94)Tctex-1 localizes to the ciliary transition zone of neural progenitor cells in the fetal cerebral cortex, where it regulates cell cycle reentry and neurogenesis. Recent reports indicate that mice with abnormal ciliary resorption develop microcephaly-like symptoms. Our study and these reports shed light on the physiological significance of ciliary resorption. Finally, this review discusses new directions in ciliary resorption research and its potential therapeutic applications.
Should Incretin Agonist-Based Brugs be Considered for First Line Antihypertensive Therapy?
Curr Hypertens Rep
Dominik Kylies, Leonie Dreher, Ulrich O Wenzel
This review evaluates the antihypertensive potential of next-generation incretin-based therapies, including GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists. It examines their effects on blood pressure reduction, underlying mechanisms, clinical benefits, and implications for future guidelines.
Cellular senescence in skeletal muscle regeneration.
Cell Regen
Xingyuan Liu, Huating Wang
Skeletal muscle possesses a remarkable capacity for regeneration, driven by the activation and proliferation of Pax7-positive muscle stem cells within a dynamic niche that includes immune cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and neural elements. Cellular senescence, a stress-induced program featuring stable cell-cycle arrest and the senescence-associated secretory phenotype (SASP), has emerged as a critical yet paradoxical regulator of this process. Accumulating evidence indicates that transient senescence, particularly in FAPs, macrophages, and other niche cells during acute muscle injury, plays a beneficial role in supporting muscle regeneration. These senescent cells promote cellular plasticity, enhance myoblast differentiation, facilitate phagocytic clearance of debris, and modulate inflammation and repair via timely SASP factor secretion. However, conflicting findings suggest that senescent cells exert detrimental effects, impairing regeneration by establishing a sustained pro-inflammatory and pro-fibrotic niche, especially when senescence persists in aged or dystrophic muscle. This review synthesizes the complex and contradictory roles of cellular senescence in skeletal muscle regeneration, underscores the distinction between transient pro-regenerative and persistent deleterious senescence, highlights the importance of cell-type-specific contributions, and emphasizes the need for precise characterization of senescent cell dynamics and fate. Resolving these discrepancies will be critical for developing targeted senotherapeutic strategies to enhance muscle regeneration in aging and degenerative diseases.
The molecular mechanisms of incretin resistance in Type 2 Diabetes Mellitus (T2DM).
Nutr Diabetes
Rawayh Muslim Albaghlany, Abbas Ali Mansour
Incretin hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), serve as crucial mediators of postprandial glucose homeostasis by primarily enhancing glucose-stimulated insulin secretion. Research indicates that the incretin effect accounts for approximately 50% of insulin secretion in individuals without diabetes, which is significantly reduced to 30% or less in those with Type 2 Diabetes Mellitus (T2DM). The mechanisms underlying this incretin resistance have emerged as critical causes of postprandial hyperglycemia. Incretin-based therapies, including GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors, have demonstrated efficacy in managing T2DM; however, intrinsic resistance mechanisms may limit their effectiveness. Understanding the processes by which T2DM affects incretin action, from hormone secretion to the modulation of signal transduction, is essential for optimizing current therapies and developing new interventions to enhance β-cell responsiveness and improve glycemic control. The concept of incretin resistance has a well-established history in literature, dating back to at least the early 1990 s. It is used to describe a reduced insulinotropic responsiveness to incretin hormones in individuals diagnosed with T2DM. This review examines how hyperglycemia, chronic inflammation, and genetic susceptibility collectively inhibit incretin signaling through distinct yet interconnected molecular pathways. This impairment exacerbates postprandial hyperglycemia and accelerates β-cell dysfunction. We propose novel hypotheses regarding selective β-arrestin signaling, enhancers, epigenetic regulation, interactions between gut microbiota and incretins, inflammation-induced endoplasmic reticulum (ER) stress, and genotype-specific therapeutic responses. The hypotheses presented in this review serve as a framework for future research and therapeutic development to combat the phenomenon of incretin resistance and improve the clinical management of T2DM.
Chondrolectin regulates the sublaminar localization and regenerative function of muscle satellite cells in mice.
iScience
Lijie Gu, Kun Ho Kim, Xiyue Chen +5 more
Skeletal muscle satellite cells (SCs) reside between the myofiber sarcolemma and basal lamina, where extracellular matrix (ECM) interactions maintain stemness and regenerative function. Here, we identify chondrolectin (CHODL), a type I transmembrane protein with a C-type lectin domain, as a critical regulator of SC biology. Single-cell RNA-seq analysis reveals that Chodl is highly enriched in quiescent SCs but downregulated in proliferating myoblasts. The conditional deletion of Chodl in embryonic myoblasts (Chodl MKO ) or adult SCs (Chodl PKO ) leaves muscle development intact yet delays injury-induced regeneration in young and aged mice. Chodl-deficient SCs exhibit reduced self-renewal and diminished proliferation, leading to defective myofiber repair. In silico network perturbation further predicts disrupted ECM-ligand interactions and Notch signaling, consistent with SC mislocalization outside the basal lamina and precocious activation in Chodl PKO muscle. Together, these findings establish CHODL as a determinant of SC niche localization and function, linking ECM interactions to muscle stem cell maintenance and repair.
Identifying Quiescent Satellite Cells: A Scoping Review of Transcriptomic Markers and Limitations.
Am J Physiol Cell Physiol
Anika L Syroid, Alexandra P Steele, Kevin A Murach +1 more
Skeletal muscle regeneration relies on the resident stem cell population, termed satellite cells. Mechanistically, understanding the quiescence and activation dynamics of muscle satellite cells are essential for regenerative therapies and emerging applications such as cellular agriculture. Quiescent satellite cells (QSCs) are typically identified by expression of PAX7 and functional characteristics including a lack of proliferation. However, with the rapidly growing body of transcriptomic data, there is a lack of consensus regarding what markers can be used to identify quiescent satellite cells across transcriptomic studies. The purpose of this review was to evaluate the transcripts currently used to identify QSCs using transcriptomics and to establish an evidence-based foundation that could be used for future analyses. After surveying published single-cell transcriptomic studies, we identified Pax7 and/or Myf5 as the most used markers of general satellite cell identity, while Spry1, Cd34, and Calcr, together with the absence of Myod1, Mki67, and Cdk1 were most commonly used to identify QSC clusters in murine studies. In contrast, there is currently insufficient literature to make a confident conclusion on quiescence markers in larger mammals, including humans, pigs, and cattle. We also highlight the conceptual and technical challenges associated with transcriptomic analysis of satellite cell subpopulations, including continuum-based cell states, isolation induced transcriptional changes, and inconsistent terminology. As a field, greater consistency in language, standardized analyses, and cross-species validation will be required to progress the study of satellite cell quiescence and its translational utility.
One half of the sprinting coin: The oxygen transport cascade of a 91-year-old female world-record sprinter.
J Appl Physiol (1985)
Marta Colosio, Andrea M Pilotto, Massimiliano Ansaldo +8 more
A 91-year-old female set the W90+ world record in the 200m sprint in 2024 surpassing her previous record by 1.13s. This study characterized her cardiorespiratory fitness, skeletal muscle oxidative capacity, fiber type distribution, capillarization, and satellite cells and compared these outcomes, where possible, to published reference data. Cardiorespiratory responses were assessed during a ramp cycling test to exhaustion, and muscle oxidative capacity (mV ̇O₂) was determined using near-infrared spectroscopy during repetitive arterial occlusions. Fiber type distribution, cross-sectional area, capillarization, satellite cell content and localization, and mitochondrial respiratory capacity were analyzed in a vastus lateralis biopsy. Peak oxygen uptake (V ̇O₂peak) was 23ml·kg⁻¹·min⁻¹ at 98W, with a maximal heart rate of 141beats·min⁻¹ and cardiac output of 13.6L·min⁻¹. The mV ̇O₂ recovery rate constant (k) was 1.83min⁻¹. Fiber composition was 57% fast MyHC II fibers (50%IIa, 5%IIa-IIx, 2%IIx), 38% slow MyHC I fibers and 5% hybrid I-IIa fibers. MyHC I fibers were larger, more vascularized and had satellite cells located closer to capillaries (4267±2181μm²; 1.67 individual capillary-to-fiber ratio (C/Fi), 5.58 capillaries×1000μm-1 capillary-to-fiber perimeter exchange index (CFPE), 1.8µm satellite cell-to-capillary distance) than MyHC II fibers (2752±1608μm²; 1.03 C/Fi, 4.00capillaries×1000μm-1 CFPE and 10.4µm, respectively). Mitochondrial O₂ flux was 58 and 68pmol·(s·mg)⁻¹ during coupled and uncoupled respiration, respectively. The athlete's cardiorespiratory and oxidative capacity resembled those of females' in their 50s or younger. Collectively, her large, well-vascularized slow fibers, high proportion of fast fibers, and preserved muscle oxidative capacity likely contributed to her world record performance, illustrating the remarkable plasticity of skeletal muscle even in very advanced age.
Dulaglutide-associated body odor with dechallenge and rechallenge in a patient with type 2 diabetes.
Int J Clin Pharmacol Ther
Srecko Marusic, Matea Staresinic, Maja Cigrovski Berkovic
Although uncommon, medications may induce unpleasant body odor, potentially leading to psychosocial distress and reduced treatment adherence. To date, unpleasant body odor has not been recognized as an adverse effect of dulaglutide. We report a novel case of dulaglutide-associated body odor, confirmed by dechallenge and rechallenge.
Effect of Semaglutide Combined With Conventional Insulin Therapy on Blood Glucose Control and Renal Function in Elderly Patients With Type 2 Diabetes.
Int J Endocrinol
Lan Ye, Ying Yín
Poor glycemic control in elderly diabetes patients leads to complications like nephropathy. Semaglutide (SEM), a GLP-1 receptor agonist, may improve both blood glucose (BG) control and renal function (RF). This study evaluates the effects of SEM combined with insulin therapy on BG and RF.
Semaglutide vs. Bariatric Surgery: Comparing Costs and Clinical Outcomes in Patients With Diabetes and Obesity.
Obesity (Silver Spring)
Karan R Chhabra, Nihan Gencerliler, Babak J Orandi +9 more
We compared health care spending and utilization associated with semaglutide relative to bariatric surgery in patients with obesity and type 2 diabetes (T2D).
Physical Therapy Intervention With Hippotherapy (HPOT) Affects Balance Control in the Elderly: A Randomized Controlled Trial.
Health Sci Rep
Bita Bahrami Gholami, Ali Fatahi, Neda Boroushak +1 more
Aging is characterized by a decline in functional abilities, strength, balance, flexibility, agility, and coordination due to neurological and muscular changes. Hippotherapy (HPOT) has been recognized for its physical and psychological benefits for older adults. Hence, this study aimed to investigate the effects of hippotherapy on balance in elderly individuals. The novelty lies in using the Biodex Balance System SD for dynamic balance assessment in healthy elderly without neurological disorders.