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Tirzepatide in Metabolically Dysfunctional-Associated Steatohepatitis (MASH): A Bibliometric and Evidence-Based Review.

J Diabetes Res

Ileana Pantea, Angela Repanovici

Metabolically-dysfunction-associated steatohepatitis (MASH) is the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD) and is strongly linked to obesity and type 2 diabetes mellitus (T2D). Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a promising therapeutic option due to its profound metabolic effects and potential hepatic benefits. This study integrates bibliometric mapping with current clinical evidence to evaluate tirzepatide's role in MASLD/MASH.

Real-world weight impact upon tirzepatide discontinuation at a single-center endocrinology clinic in patients with overweight or obesity.

J Am Pharm Assoc (2003)

Lily Huang, Angla Lee, Dahye Kim +3 more

Overweight and obesity are major contributors to cardiovascular-kidney-metabolic (CKM) disease. Tirzepatide (TZP-MJ), originally approved for type 2 diabetes (T2D), has demonstrated significant weight loss beyond glycemic improvement. Despite these benefits, real-world medication access barriers may lead to abrupt therapy discontinuation. Currently, there is a lack of real-world data of TZP-MJ discontinuation in outpatient settings.

Senescence-like cells recruit γδ T cells to drive prolonged hyposmia after SARS-CoV-2 infection in mice.

EMBO Rep

Shunya Tsuji, Sosuke Nakano, Koyu Ito +19 more

Persistent hyposmia is a hallmark of post COVID-19 conditions, yet the mechanisms sustaining olfactory dysfunction after viral clearance remain poorly understood. Here, using mouse models of SARS-CoV-2 infection, we show that virus-induced senescence-like changes in uninfected olfactory mucosal fibroblasts persist long after viral clearance and drive prolonged olfactory dysfunction. These senescence-like cells secrete SASP factors, including IFNγ, CXCL9, and CXCL11, thereby recruiting γδ T cells to the olfactory mucosa. The accumulated γδ T cells produce excessive IL-17A, which acts on IL-17 receptor A expressed on olfactory sensory neurons, leading to sustained impairment of their function. Genetic ablation of senescence pathways (p16/p21 double knockout), pharmacological elimination of senescent cells with the senolytic drug ABT263, or olfactory neuron-specific deletion of IL-17 receptor A each significantly alleviate prolonged olfactory dysfunction. These findings identify a senescence-γδ T cell-IL-17A axis as a key driver of prolonged hyposmia following SARS-CoV-2 infection in mice.

Bridging loneliness and mobility: an integrated community-based rehabilitation model for older adults.

BMC Geriatr

Hatice Cecen-Celik, Gülnihal Deniz

As populations age, older adults increasingly experience challenges that extend beyond physical changes to include loneliness, reduced social connections, and lower life satisfaction. Although physical rehabilitation and social participation initiatives have been widely examined, they are commonly addressed as separate domains. Consequently, evidence on integrated community-based rehabilitation (CBR) programmes that simultaneously support physical functioning and psychosocial well-being remains limited. This study examined the effects of a structured, multidimensional CBR programme delivered within a university-based lifelong learning initiative for older adults in Türkiye.

A Practical Strategy for Primary Aldosteronism Subtyping: Leveraging the Unilateral Adrenal Vein Sampling Index When Bilateral Cannulation Fails.

Endocr Pract

Qing-Rong Deng, Xiang Cao, Jun Deng +9 more

Adrenal vein sampling (AVS) is the standard procedure for identifying unilateral primary aldosteronism (uPA) in surgical candidates. However, many patients undergo non-diagnostic or partially successful AVS, which may preclude them from curative surgery. This study aimed to evaluate the diagnostic utility of the unilateral AVS index for identifying uPA.

In brief: Rybelsus R2 rebranded as Ozempic.

Med Lett Drugs Ther

ACE2 Mediated Cardiac Fibrosis Alleviation Through Angiotensin-(1-7)/Mas Axis Regulation of the Renin-Angiotensin System/Rac Signaling Pathway.

J Biochem Mol Toxicol

Lili Zou, He Zhang, Jinqi Fan +3 more

This study aimed at investigating whether Angiotensin-(1-7) [Ang-(1-7)] could alleviate cardiac fibrosis by modulating the expression of Rac1 and Rad GTPase and evaluating the specific mechanism in rat cardiac fibroblasts (CFs) and in canine atrial rapid pacing models. Fresh CFs were isolated from ventricles of 1 ~ 3 day-old Sprague-Dawley rats, and were randomly divided into control group, LPS group, Ang-(1-7) group and LPS+Ang-(1-7) group. CCK8 was used to detect cell proliferation. qRT-PCR was to detect the mRNA expression of ACE2. Mongrel dogs were randomized into four groups: Sham-operated (Sham), AF-Control, AF-EGFP and AF-ACE2 groups. Immunoperoxidase staining was used to test Rac1 and Gem expression. Collagen fibers in heart were stained a red color and extent of cardiac fibrosis was evaluated. Histopathology was to observe actin,α-smooth. Enzyme-Linked Immunosorbent Assay was to detect Ang II and Ang-(1-7) expression in canine atrial tissue. And western blot analysis was to detect the protein expression of iNOS, COX2, α-SMA, Rac1, ACE, and AT1R in cells and tissues. Cellular experiments showed LPS promoted proliferation of fibroblasts, which could be inhibited by Ang-(1-7) (p < 0.05). Compared with control group, LPS-induced CFs showed a significant increase in protein expression of iNOS, COX2, and α-SMA, which promoted cell proliferation. However, the application of Ang-(1-7) reversed these effects and suppressed the ACE/AT1R signaling pathway in LPS-induced CFs. In animal experiments, ACE2 over-expression would up-regulate atrial Ang-(1-7) and AT2R and reduce atrial angiotensin II (Ang II) and AT1R expressions (p < 0.05). In AF-ACE2 group, Rac1 was down-regulated and Rad GTPase was up-regulated, in comparison with AF-Control and AF-EGFP groups, associated with reductions of CTGF, fibrosis-related factors α-SMA and N-cadherin. ACE2 was found to alleviate cardiac fibrosis through the Ang(1-7)/Mas signaling pathway in animal experiments.

Albumin-Bilirubin Score and Subclinical Right Ventricular Dysfunction After Repair of Tetralogy of Fallot.

Echocardiography

Erhan Sönmez, Özge Pamukçu Akay, Yunus Emre Kum +3 more

Right ventricular (RV) dysfunction is a key determinant of long-term morbidity in patients following surgical repair of tetralogy of Fallot (TOF). Identifying practical biomarkers for early detection of right-sided heart failure remains clinically relevant, particularly in pediatric populations with subclinical disease. The albumin-bilirubin (ALBI) score, a simple and objective marker of hepatic function, has emerged as a potential surrogate of systemic congestion in heart failure. This study aimed to evaluate whether the ALBI score reflects right ventricular dysfunction in pediatric patients after TOF repair and to examine its relationship with N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic indices.

The GPCR Connection: Linking Alzheimer's Disease and Glioblastoma.

J Cell Mol Med

Ana B Caniceiro, Sofia P Agostinho, Luiz F Piochi +2 more

Alzheimer's disease (AD) and glioblastoma multiforme (GBM) are biologically distinct age-related brain disorders with opposing clinical phenotypes. AD is characterised by progressive neurodegeneration and cognitive decline, whereas GBM is characterised by aggressive cellular proliferation and a poor prognosis. Despite these differences, converging evidence indicates that both conditions share molecular pathways and network-level dysfunction that emerge during brain ageing. Central to this convergence are G protein-coupled receptors (GPCRs), which act as integrative signalling hubs that regulate inflammation, metabolism, calcium (CA2+) homeostasis, and cell survival. In AD, GPCR signalling modulates amyloid-β production and clearance, Tau phosphorylation, intracellular CA2+ dynamics, and glial-driven neuroinflammation. In contrast, the same receptor families promote tumour growth, angiogenesis, immune evasion, and therapeutic resistance in patients with GBM. Core intracellular cascades, such as PI3K-AKT-mTOR and MAPK-ERK, are dysregulated in both diseases and function as shared signalling backbones, with outcomes dictated by cellular context rather than receptor identity. CXCR4, LPA₁, and FPR1 exemplify this duality, driving either oncogenic proliferation or neuronal dysfunction, depending on the biological environment. Recent advances in integrative multiomics, computational modelling, artificial intelligence, and organoid systems have revealed GPCR-centred regulatory nodes and accelerated the identification of druggable targets. Collectively, these findings suggest that AD and GBM, although pathologically antithetical, share a molecular fingerprint shaped by ageing-associated inflammation, metabolic disruption, cellular senescence and dysregulated GPCR networks. Deciphering this context-dependent duality may enable precision therapeutic strategies to either restore neuronal integrity in AD or suppress malignant programmes in GBM while fostering cross-fertilisation between neurodegeneration and neuro-oncology research.

Cerebral small vessel disease burden relates to cognitive decline via impaired amyloid clearance in the general population.

J Cereb Blood Flow Metab

Chi-Heng Zhou, Fei Han, Feng Gao +10 more

Our aim is to examine the interplay between cerebral small vessel disease (CSVD) pathology, Alzheimer's disease (AD) related amyloid-β (Aβ) clearance, and cognition in general population. Cross-sectional structural equation modeling (SEM) was conducted to evaluate CSVD burden, cognition, and plasma Aβ42/40 ratios in 1026 participants without dementia from a prospective community-based cohort. CSVD burden was quantified using five established MRI markers, while cognition was assessed with the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), verbal fluency test, and reverse digit span. Models were adjusted for age, sex, education, body mass index, vascular risk factors (hypertension, diabetes mellitus, hyperlipidemia, and smoking), antihypertensive medication use, and APOE4 carrier status. Greater CSVD burden was significantly associated with poorer cognition (B = -2.607 ± 1.016, β = -0.167, p = 0.010), with white matter hyperintensity volume (∆R2 = 0.3%, p = 0.016) and brain parenchymal fraction (∆R2 = 0.4%, p = 0.019) contributing most strongly. CSVD burden was also negatively correlated with plasma Aβ42/40 ratios (B = -0.280 ± 0.074, β = -0.140, p < 0.001), which partially mediated the CSVD-cognition association (B = -0.241 ± 0.087, β = -0.015, p = 0.006). These findings underscore potential CSVD involvement in AD-related pathology across aging.

Preoperative systemic inflammation and muscle fatty infiltration are prognostic factors for quadriceps atrophy following anterior cruciate ligament reconstruction.

Front Immunol

Hanyi Wang, Yuqi Li, Hao Zheng +5 more

Muscle atrophy following anterior cruciate ligament reconstruction (ACLR) significantly impedes functional recovery, yet its underlying prognostic factors and potential cellular mechanisms remain poorly understood.

Haplotype-resolved centromeric chromatin organization from a complete diploid human genome.

bioRxiv

Yuan Xu, Hailey Loucks, Julian Menendez +23 more

Centromeres ensure proper chromosome segregation during cell division, yet the organization and regulation of centromeric chromatin within satellite DNA arrays remain incompletely understood. Here, we leverage the complete diploid human genome benchmark (T2T-HG002) to provide a detailed study of centromeric sequence and chromatin architecture on individual haplotypes. Using adaptive-sampling-enriched, ultra-long-read DiMeLo-seq, we achieve single-molecule chromatin profiling across all centromeres, revealing that along single chromatin fibers, CENP-A, the histone variant specifying centromere identity, forms multiple discrete subdomains within hypomethylated centromere dip regions (CDRs) that are flanked by H3K9me3-enriched heterochromatin. Despite underlying sequence variation, CDRs localize to sequence-homogeneous domains and maintain relatively balanced CENP-A dosage and aggregate length across all chromosomes and between haplotypes. Further, we show that bidirectional changes to centromeric and pericentromeric DNA methylation are accompanied by changes to centromeric chromatin architecture. In passaged cells with centromeric hypomethylation, subdomain boundaries are eroded, and adjacent CENP-A domains tend to merge and expand. Conversely, in pluripotent stem cells with centromeric hypermethylation, CDRs are fundamentally reorganized, such that discrete hypomethylated domains are frequently consolidated into broader contiguous tracts. These methylation-associated CDR restructuring events suggest that DNA methylation acts as a principal regulator of human centromere organization, with implications for understanding centromere plasticity, epigenetic inheritance, and chromosomal instability in development and disease.

Defective transcription of AAGAG satellite DNA causes sex-ratio meiotic drive in Drosophila.

bioRxiv

Tomohiro Kumon, Mami Nakamizo-Dojo, Amelie A Raz +3 more

Male germ cells have complex transcriptomes, with a large fraction of the genome being transcribed. This includes protein-coding genes (often not translated), non-coding DNA, and repetitive DNA, such as transposons and satellite DNA, which are normally silenced as heterochromatin. The significance of such widespread transcription remains unknown. Here, we show that a heterochromatin protein, HP2, is required for the transcription of AAGAG satellite DNA in Drosophila spermatocytes. HP2 depletion leads to abnormal retention of heterochromatin histone marks (H3K9me3) and spermatid death during sperm DNA packaging, leading to a model that transcription of AAGAG satellite DNA facilitates the remodeling of its heterochromatic nature in preparation for sperm DNA packaging. Strikingly, the severity of the spermatid death correlates with the amount of AAGAG satellite DNA carried by the spermatids, leading to preferential death of Y chromosome-containing spermatids over X-containing spermatids, and hence sex-ratio meiotic drive phenotype. We propose that widespread spermatocyte transcription may reflect the process of chromatin remodeling to allow sperm DNA packaging. We further propose that differential composition and amount of satellite DNA on chromosomes may underlie naturally occurring male meiotic drive.

Mitochondrial and Cardiolipin Adaptations to Ventricular Assist Device Support in Pediatric Versus Adult Failing Myocardium.

bioRxiv

Caitlyn S Conard, Mariana Casa de Vito, Obed O Nyarko +11 more

Ventricular assist devices (VADs) are used as treatment for end-stage heart failure in children and adults. We previously demonstrated decreased mitochondrial function and changes in cardiolipin, a mitochondrial phospholipid, in explanted pediatric and adult failing hearts. In this study, we tested the hypothesis that VAD unloading of failing hearts leads to positive changes in myocardial cardiolipin in both pediatric and adult hearts.

Comparing fourteen consensus biomarkers of aging: epigenetic pace of aging as the strongest predictor of mortality in BASE-II.

Biomark Res

Valentin Max Vetter, Marit Philine Junge, Christian A Drevon +8 more

In many countries, lifespan has been increasing faster than healthspan, leading to more years spent with late-life disease and highlighting the need for reliable biomarkers to measure biological aging.

Pathophysiology of chronic subdural hematoma-new insights.

Ther Adv Neurol Disord

Misa Trieu, Ajith J Thomas

Chronic subdural hematoma (CSDH) is an increasingly common disorder characterized by persistent accumulation of blood products and inflammatory exudate within the dural border cell (DBC) layer. Its pathogenesis represents a self-sustaining cycle of inflammation, pathological angiogenesis, and impaired resolution. Injury of the head, which may be traumatic or nontraumatic, initiates cleavage of the DBC layer, leading to fibroproliferative membrane formation mediated by collagen synthesis and TGF-β1/SMAD signaling. The resulting outer membrane develops fragile neovasculature, driven primarily by vascular endothelial growth factor, facilitating recurrent microhemorrhage and fibrinolysis perpetuating hematoma expansion. Chronic inflammation sustains disease progression through macrophage polarization, cytokine release, and increased vascular permeability, processes amplified by age-related immune dysregulation and hypoxia-induced factor-1alpha signaling. Impaired tissue repair due to metabolic deficits further limits resolution. Concurrent dysfunction of meningeal lymphatic drainage and fibrotic arachnoid granulations compromises clearance of blood degradation products and inflammatory mediators, while matrix remodeling and cerebrospinal fluid ingress contribute to hematoma persistence. This narrative review presents a pathophysiologic framework highlighting CSDH as a dynamic inflammatory-angiogenic disorder. Pharmacological strategies targeting inflammation, angiogenesis, fibrinolysis, hypoxia, and matrix remodeling hold potential as complements or alternatives to established treatments, including surgical drainage and middle meningeal artery embolization. As the burden of CSDH on healthcare systems rises, translational research and controlled clinical trials will be critical to developing mechanism-driven, multimodal management paradigms.

Brimonidine Therapy for Protection From Noise-Induced Hearing Loss.

Aging Cell

Jing Cai, Na Zhang, Yongdong Song +8 more

Noise exposure is a known cause of hearing loss, and only a few effective preventive drugs are available. Therefore, in this study, we aimed to investigate the protective effects of brimonidine on noise-induced inner ear hearing impairment in mice and explore its underlying mechanisms and long-term outcomes. Mice were randomly divided into control, noise exposure, and brimonidine groups. A 62-week follow-up was conducted after noise exposure. Brimonidine inhibited the noise-induced increase in inner ear glutamate concentration and downregulated inflammatory factors and immunoglobulins. Brimonidine decreased glutaminase and VGLUT2/3 expression and reduced glutamate synthesis and vesicle transport without affecting its clearance, thereby decreasing glutamate excitotoxicity and protecting synapses and spiral ganglion neurons long term. Mice exposed to noise could temporarily restore their hearing thresholds; however, their auditory function in old age remained significantly worse than those that received brimonidine-mediated cochlear protection in youth. These findings highlight the importance of enhancing noise protection from an early age.

Mitochondrial Quality Control as a Central Pharmacological Target in Aging.

Pharmacol Res

Kuan-Hao Tsui, Shih-Hsuan Cheng, Boyang Wang +7 more

Mitochondrial dysfunction is a convergent hallmark of biological aging and a mechanistically attractive target for gerotherapeutic development. Yet translation of mitochondria-focused interventions has been limited by pathway complexity, tissue heterogeneity, and insufficiently harmonized endpoints. This review synthesizes recent original evidence through a unifying mitochondrial quality control (MQC) framework comprising four interdependent modules: removal (mitophagy and mitochondrial-derived vesicles), repair (mitochondrial proteostasis and UPRmt/ISR signaling), remodeling (fission-fusion control and cristae architecture), and renewal (biogenesis coupled to turnover). We map druggable nodes across these modules and organize therapeutic efforts into five pharmacological classes: autophagy/mitophagy enhancers (including pathway-brake inhibitors and emerging mitophagy-targeting chimeras), NAD+/sirtuin-AMPK-mTOR axis modulators, mitochondria-targeted redox modulators, cristae/mPTP/cardiolipin-directed stabilizers, and mitochondria-targeted delivery platforms. Drawing on recent human studies and late-stage mitochondrial therapeutic programs, we highlight practical lessons on dosing schedules, baseline vulnerability, and the importance of pairing molecular engagement with performance endpoints. We then outline a translational strategy that prioritizes flux-aware readouts and triangulates mechanism with function using in vivo bioenergetics (31P-MRS), blood-based cellular respiration (PBMC/platelet assays and composite indices), and circulating stress/damage signals (cell-free mtDNA species and mitokines). Finally, we discuss key bottlenecks including tissue selective exposure, long term safety for maintenance therapies, and inconsistency in clinical endpoints, and we propose actionable directions such as biomarker guided precision geroscience, intermittent or sequential combination strategies that balance clearance with renewal, and next generation chemical biology approaches to improve target specificity. Collectively, this framework seeks to accelerate the development of pharmacotherapies targeting mitochondrial quality control with clinically interpretable endpoints in aging.

Elimination of senescent cells fails to attenuate disease progression in an ALS mouse model.

Neurol Sci

Lisha Fang, Zhiyong Bai, Dong Yang +3 more

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving progressive motor neuron degeneration, resulting in muscle weakness and paralysis. Current therapeutic options provide only modest benefit, and the etiology of ALS remains incompletely understood. Emerging evidence implicates cellular senescence in the central nervous system (CNS) of ALS pathogenesis, with senescent astrocytes identified in both animal models and patients.

IGF-1 and insulin receptors in LepRb neurons jointly regulate body growth, bone mass, reproduction, and metabolism.

Mol Metab

Mengjie Wang, Piotr J Czernik, Beata Lecka-Czernik +1 more

Leptin receptor (LepRb)-expressing neurons integrate metabolic and reproductive signals, yet the role of insulin-like growth factor 1 receptor (IGF1R) signaling within these neurons remains unclear. Because IGF-1 and insulin can partially activate each other's receptors, we generated mice lacking IGF1R selectively in LepRb neurons (IGF1RLepRb) as well as mice lacking both IGF1R and insulin receptor (IR) in LepRb neurons (IGF1R/IRLepRb). These models were used to assess body growth, skeletal development, reproductive function, energy balance, and metabolic homeostasis. Deletion of IGF1R alone in LepRb neurons delayed pubertal onset, impaired adult fertility, and accelerated reproductive aging, accompanied by transient postnatal growth retardation. IGF1R deficiency also altered trabecular and cortical bone structural parameters in both sexes, supporting a role for IGF1R signaling in coordinating growth, skeletal physiology, and reproductive function. Despite reduced food intake and increased energy expenditure in females after adjusting for lean mass, IGF1R deletion caused only modest metabolic alterations, with transient decreases in body weight and largely unchanged body composition and locomotor activity. In contrast, combined deletion of IGF1R and IR in LepRb neurons resulted in marked metabolic disturbances, including increased adiposity, reduced lean mass, lower energy expenditure, decreased locomotor activity, and impaired insulin sensitivity in males. These findings indicate cooperative roles of IGF1R and IR signaling within LepRb neurons in regulating body composition, energy balance, and glucose homeostasis. Together, our results demonstrate that IGF1R signaling in LepRb neurons primarily regulates reproductive development, skeletal physiology, and growth, whereas combined IGF1R and IR signaling is required for maintaining metabolic homeostasis. These findings identify LepRb neurons as an important neuroendocrine hub integrating IGF and insulin signaling to coordinate growth, reproduction, and metabolism in a sex-dependent manner.