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Peripheral Oxidation-Inflammation and Immunosenescence in Triple-Transgenic Mice for Alzheimer's Disease (3xTg-AD) at Early Neuropathological Stages of Disease and Decrease of Immune Impairment by Voluntary Exercise.
Biomolecules
Mónica De la Fuente, Antonio Garrido, Carmen Vida +2 more
Inflammatory-oxidative stress generated by immune cells plays an important role in aging and in age-related neurodegenerative disorders such as Alzheimer's disease (AD). Triple-transgenic mice for AD (3xTg-AD) are a suitable model for mimicking this disease in an age-dependent manner. We previously showed that peritoneal leukocyte functions and their redox-inflammatory state are altered early in female 3xTg-AD mice, which exhibit premature aging compared to non-transgenic (NTg) animals. However, their characteristics at 9 months of age, when they present an early neuropathological state, and the sex differences are not known. Here, we analyzed several spleen and thymus leukocyte functions (chemotaxis, natural killer activity, and lymphoproliferation in response to mitogens), pro-inflammatory (IL-1B, TNF-alpha) and anti-inflammatory (IL-10) released cytokine concentrations, and redox parameters (glutathione concentrations and glutathione peroxidase, glutathione reductase, and xanthine oxidase activities) in male and female 3xTg-AD mice compared to age-matched controls. We also analyzed the effects of voluntary physical exercise on immune functions. Our results show that 9-month-old male and female 3xTg-AD mice have worse immune functions, redox state, and inflammation than NTg counterparts. Physical exercise improves immune function. Thus, accelerated aging reflected by peripheral immunosenescence and oxidation-inflammation in 3xTg-AD mice precedes hallmark neuropathology, and exercise can slow down AD progression.
Real-World Weight-Loss Outcomes in Weight-Reduced Patients Treated With Tirzepatide.
Obesity (Silver Spring)
Sarah R Barenbaum, Ariel Gonzalez, Zoe Verzani +2 more
This study compared weight-loss outcomes in patients prescribed tirzepatide by weight-loss status and assessed results among patients transitioning from semaglutide.
Resistant and Refractory Obesity: The Complexity of Anti-Obesity Therapy Failure.
Int J Mol Sci
Michał Nicze, Maciej Borówka, Adrianna Dec +3 more
Pharmacotherapy is a key component of obesity management, yet treatment failure remains a prevalent challenge in clinical practice. Such failure may present as insufficient pharmacological response, early discontinuation, or post-treatment weight regain, underscoring the discrepancy between clinical trial efficacy and real-world outcomes. The effectiveness of anti-obesity medications (AOMs) is influenced by psychiatric comorbidities, including depression, anxiety, and disordered eating patterns, as well as environmental and socioeconomic factors such as limited healthcare access, weight-related stigma, and high medication costs. Individual characteristics, including physical activity, body composition, visceral adiposity, and microbiome profile, further modulate treatment outcomes. Pharmacokinetic and pharmacotherapeutic limitations such as drug-phenotype mismatch, route of administration, suboptimal formulations, and exposure to counterfeit products also compromise efficacy. No less important are genetic and immunological factors, comprising pharmacogenomic variants of both incretin and melanocortin receptors along with antidrug antibodies (ADAs), which may constitute therapy resistance. Concomitant medications and comorbid endocrine disorders can additionally attenuate weight-loss effects. The objective of this review is to characterize the multifactorial nature of resistance and refractoriness to anti-obesity therapy, and the importance of identifying pretreatment predictive factors for recognizing individuals at risk of inadequate or lack of response, thereby enabling personalized management strategies and improving long-term clinical outcomes, particularly in "difficult-to-treat" patients.
GLP-1 Receptor Agonists at the Crossroads of Circadian Biology, Sleep, and Metabolic Disease.
Int J Mol Sci
Ayush Gandhi, Ei Moe Phyu, Kwame Koom-Dadzie +2 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of type 2 diabetes and obesity, yet their actions extend beyond glycemic control and weight loss. This narrative review synthesizes current preclinical and clinical evidence examining the bidirectional relationship between glucagon-like peptide-1 (GLP-1) receptor agonists and circadian biology. A structured literature search was conducted in PubMed using combinations of the terms 'GLP-1,' 'circadian,' 'chronobiology,' 'sleep,' 'obesity,' and 'type 2 diabetes' through January 2026. Accumulating evidence indicates that GLP-1 physiology is closely coupled to circadian timing systems and sleep-wake regulation. In this narrative review, we synthesize emerging data that reframe GLP-1RAs as chronometabolic modulators, acting at the intersection of metabolism, circadian biology, and sleep. We review circadian control of GLP-1 secretion by intestinal L-cells, emphasizing the role of core clock genes and the vulnerability of incretin rhythms to circadian misalignment from shift work, nocturnal light exposure, and sleep loss. We then examine GLP-1 receptor signaling within central and peripheral clock networks, including feedback effects on hypothalamic and hepatic circadian regulation. Emerging data suggest that GLP-1 signaling is under circadian regulation and may, in turn, influence central and peripheral clock systems. Comparative discussion of semaglutide, liraglutide, and tirzepatide highlights agent-specific pharmacokinetics and emerging clinical data linking GLP-1RA therapy to sleep outcomes, particularly obstructive sleep apnea. Finally, we outline translational opportunities for chronotherapy and precision medicine, positioning GLP-1RAs as integrative tools for metabolic and sleep-related disease rather than purely weight-centric therapies. We propose that GLP-1 receptor agonists may function as chronometabolic modulators, with potential implications for personalized chronopharmacological strategies in metabolic disease.
New Drugs on the Block: Dietary Management and Nutritional Considerations During the Use of Anti-Obesity Medication.
Nutrients
Eleni C Pardali, Kalliopi K Gkouskou, Christos Cholevas +4 more
Incretin-based pharmacotherapy has rapidly transformed obesity management. However, despite its efficacy, gastrointestinal (GI) adverse events (AEs) are common and represent a major driver of treatment discontinuation. Symptoms such as nausea, vomiting, acid reflux, diarrhea, and constipation, not only impair the quality of life, but also compromise adherence, thereby limiting the real-world effectiveness of these agents. Targeted nutritional strategies may play a pivotal role in mitigating these symptoms and supporting sustained treatment. However, most clinical trials have relied on generalized lifestyle advice combined with hypocaloric dietary prescriptions, with limited integration of structured, mechanism-based nutritional counseling tailored to the physiological actions of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs. Consequently, practical guidance for clinicians and dietitians remains fragmented. The present review synthesizes the available evidence on GI AEs associated with incretin-based therapies and examines whether structured, targeted nutritional management can meaningfully reduce symptom burden. We also outline key monitoring strategies and focus on important clinical aspects for physicians and dietitians, aiming to optimize patient outcomes. In addition, we provide detailed information on the spectrum of GI AEs to guide effective management and limit intolerance. By bridging pharmacology with applied clinical nutrition, we aim to provide a pragmatic framework for improving tolerability, sustaining adherence, and translating trial efficacy into durable real-world effectiveness.
Psychiatric Adverse Events and Administration Challenges Associated with GLP-1 Receptor Agonists for Weight Loss: A Real-World Analysis.
Pharmaceuticals (Basel)
Ali Hindi, Mohamed Mekkawy, Hala Shokr
Background: Glucagon-like peptide-1 receptor agonists are increasingly prescribed for weight loss, but concerns remain regarding adverse events beyond gastrointestinal, renal, and pancreatic effects. Understanding these risks is essential to guide safe clinical application and public health policy. The study aims to characterize psychiatric risks, administration-related adverse events, and patterns of inappropriate use associated with semaglutide, liraglutide, and tirzepatide for weight management. Methods: Disproportionality analysis using proportional reporting ratios and reporting odds ratios was conducted to detect significant signals in adverse event reports within the U.S. Food and Drug Administration Adverse Event Reporting System, identifying semaglutide, liraglutide, or tirzepatide as drugs used for weight loss while excluding gastrointestinal, renal, and pancreatic adverse events. Results: Among 40,253 adverse event reports (68.6% female; median ages: semaglutide, 62 years; liraglutide, 59 years; tirzepatide, 53 years), semaglutide demonstrated the strongest disproportionality signal for psychiatric adverse events, notably anxiety (PRR 1.34, 95% CI 1.18-1.51), depression (PRR 1.83, 95% CI 1.62-2.07), and suicidal ideation (PRR 3.44, 95% CI 2.98-3.97). Tirzepatide showed markedly higher signals for injection-site reactions (PRR 7.98, 95% CI 7.8-8.18) and inappropriate use, including incorrect dosing and off-label administration (PRR 5.98, 95% CI 5.9-6.06). Conclusions: In real-world use, semaglutide is disproportionately associated with psychiatric adverse events, whereas tirzepatide demonstrates higher rates of injection-site complications and misuse. Liraglutide presents a comparatively lower risk profile. These findings underscore the need for vigilant psychiatric monitoring, patient education on injection technique and dosing, and stronger regulatory oversight to reduce misuse of GLP-1 receptor agonists for weight loss.
Exposure-adjusted safety and efficacy of GLP-I and GLP-1/GIP receptor agonists compared with non-GLP-I for weight management and type 2 diabetes: Based on FDA medical and statistical reports of 34 280 safety and 36 312 efficacy subjects.
Br J Clin Pharmacol
Aishwarya Prasad, Anshu Arora, Arun Arora +2 more
This work aimed to contextualize glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists safety and efficacy regarding weight management (WM); we analysed Food and Drug Administration (FDA) Medical Reviews to analyse 14 medications using patient-exposure year normalization and compared GLP-1 RAs with older WM medications.
A septal inhibitory circuit constrains alcohol reward and mediates liraglutide's suppressive effects on alcohol intake in mice.
Neuron
Yu Tian, Yutong Liu, Haiyang Jing +10 more
Alcohol use disorder (AUD) lacks effective brain-targeted treatments. Here, using mouse models, we show that glucagon-like peptide-1 receptor (GLP-1R) signaling in the dorsal lateral septum (dLS) regulates alcohol consumption and reward. Systemic administration of the GLP-1R agonist liraglutide decreased alcohol intake and ethanol-evoked dopamine release in the nucleus accumbens, requiring GLP-1R expression in the dLS. Alcohol consumption suppressed dLSGLP-1R neuronal activity, whereas liraglutide prevented alcohol-induced suppression of transient calcium dynamics. Inactivation of these neurons increased alcohol consumption and abolished the behavioral effects of liraglutide, whereas chemogenetic activation suppressed alcohol-directed behavior. Circuit-level analysis identified a local inhibitory projection from dLSGLP-1R neurons to estrogen receptor 1-expressing neurons in the ventral lateral septum (vLSEsr1 neurons), and targeted manipulation of this circuit confirmed its role in regulating alcohol intake. Together, these findings delineate a septal inhibitory circuit through which GLP-1R signaling modulates alcohol-related behaviors and highlight the dLS as a therapeutic target for AUD.
Circulating GDF15 and HbA1c Response to Add-On Exenatide Therapy in Type 2 Diabetes: A Post Hoc Analysis from a Multicenter Trial.
Biomedicines
Qi Wu, Kun Yang, Xinyue Liao +5 more
Objectives: To assess the influences of growth differentiation factor 15 (GDF15) on the reduction in glycated hemoglobin (ΔHbA1c) induced by exenatide in type 2 diabetes mellitus (T2DM). Methods: This analysis included 166 participants with T2DM who received exenatide as add-on therapy for 16 weeks. The effect of baseline GDF15 on ΔHbA1c was evaluated using univariate, multivariate, and bidirectional stepwise linear regression models. Baseline GDF15 was categorized into tertiles with the lowest tertile (tertile 1) serving as reference. A subgroup analysis was performed in the participants aged >35 years to investigate whether age influenced the effect of GDF15 on ΔHbA1c. Results: GDF15 levels were significantly increased from baseline following 16 weeks of exenatide treatment [721.9 (513.6, 997.8) pg/mL vs. 741.4 (510.0, 1203.4) pg/mL, p = 0.031]. Univariate linear regression analysis revealed a positive association between baseline GDF15 (tertile 3: β = 0.553, 95% CI 0.115 to 0.991, p = 0.014) and ΔHbA1c. However, no significant relationship was found between GDF15 (tertile 2: p = 0.403; tertile 3: p = 0.217) and ΔHbA1c after adjusting for age and diabetes duration. Further stepwise regression analysis indicated a non-robust association for GDF15 in the absence of age as GDF15 was excluded from the model. Among the participants >35 years old, GDF15 (tertile 3: β = 0.383, 95% CI 0.002 to 0.764, p = 0.049) remained positively associated with ΔHbA1c, even after adjusting for age. Conclusions: Elevated GDF15 might potentially diminish the reduction in HbA1c following 16-week exenatide treatment, with this effect moderated by age.
A Pharmacovigilance Analysis of Ocular Adverse Events Associated with GLP-1 Receptor Agonists.
J Clin Med
Abdullah Virk, Karen Allison
Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for type 2 diabetes in addition to other conditions such as obesity. As their use expands, understanding potential ocular safety signals is important, particularly in populations already at risk for diabetic eye disease. The aim of this study is to identify potential pharmacovigilance safety signals for ocular adverse events (AEs) related to GLP-1 RA medications to better inform future clinical practice. Methods: This study utilized the publicly available FDA Adverse Event Reporting System (FAERS) to obtain AE reports related to exenatide, tirzepatide, dulaglutide, liraglutide, and semaglutide from 2005 to 2024. Reports were categorized by demographic and geographic variables. Disproportionality analysis using reporting odds ratios (RORs) was performed to detect potential safety signals. Year-over-year trends in the proportional representation of each drug were also assessed through linear regression and time series plots. Results: Ocular AEs represented 3.61% of all GLP-1 RA related reports. Median age was 63 years, and 62.6% of reports involved female patients. Exenatide accounted for 33.61% of ocular AEs but showed a significant annual decline in reporting (-5.15% per year, p < 0.001). Semaglutide (31.37%) and tirzepatide (12.19%) demonstrated significant year-over-year increases in proportional reporting (2.23% and 0.79% per year, respectively; both p < 0.05), consistent with rapid uptake in clinical practice. Semaglutide demonstrated a modestly elevated ROR (1.46), while tirzepatide showed a low ROR (0.42), though this likely reflects shorter post-marketing exposure rather than lower clinical risk. The most frequently reported events were visual impairment, followed by vision blurred, cataract, and blindness. Conclusions: This pharmacovigilance analysis identifies potential ocular AE signals associated with GLP-1 RAs, particularly semaglutide. While semaglutide showed a statistically significant disproportional reporting signal for ocular AEs, the absence of exposure denominators, comparator groups, and the susceptibility of FAERS to reporting bias means these findings are hypothesis-generating rather than causal. Clinicians should remain vigilant and consider eye care referrals when indicated. Further research is needed to validate these associations and clarify underlying mechanisms.
An Explorative Approach to Examining the Role of Ischemia and Inflammation on the Function of Autoantibodies Against G Protein-Coupled Receptors and Their Corresponding Agonists.
Int J Mol Sci
Gerd Wallukat, Petra Lakatos, Kira Steinhorst +2 more
Autoantibodies (AAbs) play an important role in the development of autoimmune diseases. While many AAbs induce apoptosis of target cells, a distinct subgroup, termed functional autoantibodies (fAAbs) against G protein-coupled receptors (GPCRs), can modulate physiological receptor signaling without inducing cell death. The functional activity of GPCR-fAAbs may be influenced by various cofactors, including inflammation (e.g., inflammatory cytokine, ciliary neurotrophic factor (CNTF)) and ischemia. As ischemia triggers a substantial release of arachidonic acid (AA) from membrane phospholipids, the present study aimed to examine exploratively the influence of AA, eicosapentaenoic acid (EPA), and CNTF on the responses of spontaneously beating neonatal rat cardiomyocytes to GPCR agonists and GPCR-fAAbs. AA and EPA differentially influenced responses in cardiomyocytes induced by GPCR-fAAbs: AA altered the functional responses associated with adrenergic β2-fAAb, adrenergic α1-fAAb, angiotensin II (AT1)-fAAb, endothelin A (ETA)-fAAb and angiotensin 1-7 MAS-fAAbs. However, muscarinergic M2-fAAb responses remained largely unaffected. In contrast, EPA attenuated the responses to β2-fAAb, α1-fAAb, AT1-fAAb, and ETA-fAAb, while MAS-fAAb and M2-fAAb responses were not markedly altered. CNTF acted as a time-dependent modulator of cardiomyocyte chronotropic responses and influenced the magnitude of GPCR-mediated signaling on a cardiomyocyte bioassay. Together, these findings might suggest that lipid mediators such as AA and EPA or CNTF may modulate functional responses of cardiomyocytes associated with GPCR-fAAbs.
Comparative Long-Term Outcomes of Anatomical and Physiological Repair for Corrected Transposition.
Eur J Cardiothorac Surg
Yuji Tominaga, Masashi Takeshita, Takuji Watanabe +5 more
The optimal surgical strategy for congenitally corrected transposition of the great arteries (ccTGA) remains debated. This study aimed to compare the long-term outcomes of each surgical approach and to explore the optimal management strategy.
Prognostic Value of a Low-Cost LDH-Hemoglobin-Albumin Biomarker Panel in Acute Heart Failure: A Real-World Cohort from a Resource-Limited Setting.
Biomedicines
Can Baba Arin
Background: In many low- and middle-income countries, access to advanced cardiac biomarkers such as B-type natriuretic peptide (BNP) and NT-pro BNP remains limited, posing challenges for early risk stratification in patients hospitalized with acute heart failure (AHF). Identifying simple, inexpensive, and universally available laboratory markers with prognostic value is of practical clinical importance. Methods: Consecutive patients (≥18 years) hospitalized with acute heart failure (AHF) between May 2022 and November 2024 were retrospectively analyzed. After exclusion of patients with incomplete outcome data, in-hospital mortality was assessed using logistic regression analysis. Hemoglobin, serum albumin, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), and the C-reactive protein-albumin-lymphocyte (CALLY) index were evaluated as potential predictors of in-hospital mortality. Results: A total of 211 patients were included in the mortality analysis, with an in-hospital mortality rate of 10.0%. Patients were stratified by anemia and hypoalbuminemia status, revealing significant differences in unadjusted mortality rates across groups (p = 0.04). However, after adjustment for age, sex, and chronic kidney disease, the prognostic impact of anemia and hypoalbuminemia was attenuated. Elevated LDH levels remained independently associated with in-hospital mortality (adjusted odds ratio 2.84, 95% confidence interval 1.01-8.02). Higher NLR values and lower CALLY index levels showed nonsignificant trends toward adverse outcomes. Conclusions: In this real-world cohort from a resource-limited setting, LDH emerged as a practical and independent predictor of in-hospital mortality in patients with AHF. When access to natriuretic peptides is limited, LDH-supported by routinely available laboratory parameters-may assist early risk stratification and clinical decision-making.
Synergistic Therapeutic Effects of Tetrahydroberberine Combined with Protopanaxadiol on PCPA-Induced Insomnia in Rats: Involvement of the Microbiota-Gut-Brain Axis and Regulation of PI3K/AKT/AGE-RAGE Pathways.
Pharmaceuticals (Basel)
Meijia Li, Ying Wang, Zixia Liang +8 more
Aim: This study investigated the synergistic therapeutic effects and underlying mechanisms of tetrahydroberberine (THB) combined with protopanaxadiol (PPD) on p-chlorophenylalanine (PCPA)-induced insomnia in rats. Methods: Rats were randomly divided into normal, model, diazepam, THB monotherapy, PPD monotherapy, and THB + PPD combination groups. Evaluations included the pentobarbital sleep test, HE staining, ELISA, 16S rRNA sequencing, metabolomics, and Western blot. Results: Results demonstrated that the THB + PPD combination exhibited significant synergistic effects compared with monotherapies: the combination shortened sleep latency by 56.2% (vs. 44.2% for THB alone and 20.7% for PPD alone) and prolonged sleep duration by 112.8% (vs. 70.2% for THB and 59.6% for PPD) relative to the model group, while effectively restoring body weight gain. Histologically, combined treatment significantly alleviated hippocampal neuronal damage and increased the number of intact neurons in the dentate gyrus. Molecularly, it upregulated brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) levels, restored neurotransmitter balance (serotonin, dopamine, and glutamate), suppressed overactivation of the hypothalamic-pituitary-adrenal (HPA) axis (reducing corticotropin-releasing hormone and corticosterone), and decreased pro-inflammatory cytokine expression. Gut microbiota analysis revealed that the combination restored microbial homeostasis (increasing beneficial bacteria such as *Lactobacillus*) and modulated the glycine-serine-threonine metabolic pathway. Mechanistically, THB + PPD synergistically activated the PI3K/AKT neurotrophic pathway (p-PI3K and p-AKT expression increased by 1.9-fold and 2.5-fold, respectively, vs. model), inhibited the AGE/RAGE pro-inflammatory axis (RAGE expression decreased by 31.8%), and enhanced blood-brain barrier integrity by upregulating tight junction proteins (ZO-1, Occludin). Conclusions: THB combined with PPD exerts synergistic anti-insomnia effects through multi-level regulation of the microbiota-gut-brain axis, neurochemical balance, and key signaling pathways, providing a promising foundation for developing safe natural product-based combination therapies.
A KCa 2.2/2.3 Opener Reverses ET-1-Induced NLRP3 Activation in Hypertensive Mice Corpora Cavernosa.
Biomolecules
Rafael Sobrano Fais, Simon Gabriel Comerma-Steffensen, Estefano Pinilla +4 more
Hypertension-induced erectile dysfunction is associated with endothelial dysfunction in the corpus cavernosum. Membrane depolarization activates the NLRP3 inflammasome, with downregulation of endothelial Ca2+-activated K+ channels type 2.3 (KCa 2.3) and upregulation of endothelin-1 (ET-1) linked to erectile dysfunction. However, underlying mechanisms remain incompletely understood. We hypothesized that activating KCa 2.2/2.3 channels reverses erectile dysfunction and ET-1-induced NLRP3 activation in hypertensive DOCA/salt mice. Hypertension was induced in mice using a DOCA/salt model, with unilaterally nephrectomized mice as controls. We measured blood pressure, intracavernous pressure (ICP), and corpus cavernosum (CC) contractility, and performed immunoblots for KCa 2.3, caspase-1, and interleukin-1β (IL-1β). DOCA/salt mice showed impaired erectile function and increased IL-1β activity and reduced KCa 2.3 expression. Treatment with the endothelin receptor antagonist bosentan or the KCa 2.2/2.3 channel opener NS13001 reversed these dysfunctions and reduced ET-1-induced NLRP3 activation. NS13001 also restored decreased currents in endothelial cells exposed to ET-1. These findings establish that hypertension-induced erectile dysfunction involves an ET-1/membrane depolarization/NLRP3 inflammasome axis in corpus cavernosum endothelial cells, and that targeting endothelial KCa 2.2/2.3 channels represents a promising therapeutic strategy to counteract erectile dysfunction.
Mechanisms of Rat Gastrocnemius Muscular Atrophy Induced by Hindlimb Unloading.
Aerosp Med Hum Perform
Lingying Liu, Yaoyuan Cui, Ruipeng Wu +2 more
Muscle atrophy is a critical health challenge during spaceflight. This study investigated the mechanism of muscle atrophy induced by 21-d hindlimb unloading (HLU) and metabolomic changes in rat gastrocnemius muscle (GM) and plasma.
Inflammaging-induced TRAF3 degradation impairs AMP biosynthesis to drive sarcopenia.
Res Sq
Jinbo Li, Yaning Xing, Jinxiao Fan +10 more
Inflammaging is a recognized driver of age-related pathologies, yet its specific mechanistic link to sarcopenia remains poorly understood. Here, we identified a significant reduction of TNF receptor-associated factor 3 (TRAF3) in myoblasts exposed to aged serum and in skeletal muscles from both aging mice and humans. Genetic deletion of TRAF3 in myocytes or satellite cells induced early-onset sarcopenia and impaired regeneration, independent of non-canonical NF-κB signaling. Mechanistically, TRAF3 maintains energy homeostasis by stabilizing the key metabolic enzyme, adenylosuccinate lyase (ADSL), and its loss impairs AMP biosynthesis and ATP production. Muscle-specific TRAF3 restoration or AMP supplementation rescued sarcopenic phenotypes in TRAF3-deficient mice. Notably, neutrophil-derived transforming growth factor β1 (TGFβ1) caused IAP-mediated ubiquitination and degradation of TRAF3 in aged mice--a process reversible by the IAP inhibitor SM-164. Inducible neutrophil-specific TGFβ1 deletion prevented age-related sarcopenia. Our study establishes that TRAF3 is a key protective factor in muscle aging, and its loss mechanistically links inflammaging to bioenergetic deficits, suggesting new strategies to prevent age-related muscle wasting.
Transcriptome Analysis of miRNAs Involved in the Myogenic Differentiation of Goat Skeletal Muscle Satellite Cells.
Cells
Runxiao Luo, Tao Zhong, Linjie Wang +4 more
Skeletal muscle myogenesis is a crucial factor influencing meat production in livestock. MicroRNAs (miRNAs) play a significant role in skeletal muscle myogenesis. The objective of this study was to identify key miRNAs involved in the process of goat skeletal muscle satellite cell (MuSC) differentiation into myotubes. We performed miRNA expression profiling analysis during the proliferation phase (cultured in growth medium, GM) and the differentiation phase (cultured in differentiation medium for 1 day and 5 days, classified as DM1 and DM5, respectively) of goat skeletal muscle satellite cells (MuSCs). A total of 1846 miRNAs were identified in MuSC samples, of which 677 differentially expressed miRNAs (DEmiRNAs) were screened through pairwise comparisons across three groups (GM vs. DM1, GM vs. DM5, and DM1 vs. DM5), and the results were further confirmed by a quantitative real-time PCR assay. Time-series expression profiling facilitated the categorization of the DEmiRNAs into eight distinct clusters, one of which demonstrated a significantly downregulated expression pattern (p < 0.05). Functional enrichment analysis revealed that the target genes of DEmiRNAs are involved in several pathways that are critical for myogenesis, including Hippo, TGF-β, MAPK and cell adhesion molecules. Interaction network analysis identified 19 miRNAs and 56 mRNAs associated with muscle cell development. Notably, novel-m0047-5p emerged as a key regulator, exhibiting strong negative correlations (r = -0.88 to -0.89, q < 0.01) with muscle-related target genes FOSB, CPT1B, and MYOZ2. These findings elucidate miRNA-mediated regulatory networks in goat myogenesis and provide candidate molecular targets for genetic improvement of meat production traits.
Leuprolide Acetate Promotes Sensory Recovery and Modulates Dorsal Root Ganglion Responses After Sciatic Nerve Transection in Rats.
Brain Sci
Irma Hernández-Jasso, Denisse Calderón-Vallejo, José Ávila-Mendoza +5 more
Background/Objectives: Sciatic nerve injuries are among the most common classes of peripheral nerve harm and have a strong impact on quality of life, as well as a significant negative economic impact for patients, society, and governments, since they represent a frequent cause of work-related disabilities and sick leave applications. Following nerve injury, neurons, Schwann, and satellite cells undergo marked changes in phenotype, metabolic activity, neuronal survival, nervous transmission, and an exacerbated activation of the inflammatory response. Leuprolide acetate (LA), a clinically available agonist of gonadotropin-releasing hormone (GnRH), has shown clear neurotrophic properties and is considered a novel potential candidate for treating neural injuries, including sciatic nerve pathologies. This study aimed to analyze the effect of LA treatment on sensory function and dorsal root ganglia (DRG) changes in a rat sciatic nerve full-transection (SNT) model. Methods: Variations in cold and heat sensitivity were assessed using the thermal plate test, while DRG tissue sections were examined for modifications in reactive gliosis by immunofluorescence analysis, and axonal transport using a retrograde tracer. Also, changes in the expression of pro-regenerative genes Stat3, Socs3, Fos, Jun, Atf4, and Limk1 were quantified by qPCR. Results: Our results showed that LA treatment exerted a distinct neurotrophic effect, since it promoted the specific recovery of cold sensitivity, improved axonal transport, regulated the inflammatory response, and modulated the exacerbated expression of pro-regenerative genes in the SNT model. Conclusions: These findings indicate that LA therapy may have the potential to improve sensory recovery in patients with sciatic nerve injuries.
Co-cultured spheroids of piscine cells as building blocks for cultured fish meat.
Food Res Int
Yingfei Su, Shengliang Zhang, Yingqi Jiang +3 more
Cultured meat has emerged as a promising approach to enhancing global food sustainability. Current production methods, however, rely mainly on single-cell-type culture, which fails to replicate the complex composition of conventional meat. In this study, a scaffold-free co-culture system was established to generate structured microtissue comprising highly differentiated muscle and fat cells. Co-cultured spheroids with the ratios of piscine adipose-derived stem cells (PADSCs) to piscine satellite cells (PSCs) being 5:5, 7:3 and 9:1 were investigated, and the result showed that all ratios remained robust and highly viable throughout the differentiation process and successfully induced the formation of bionic tissue containing both myotubes and adipocytes. Based on transcriptome data, the cluster analysis indicated that co-cultured spheroids (the ratio of PADSCs to PSCs was 7:3) were similar to the PADSC spheroids, and the expression levels of cell cycle-related and extracellular matrix-related genes were biased towards those of PADSC spheroids. These results indicated that these co-cultured spheroids held promise as building blocks for further tissue assembly and offered a promising approach for scaling up the production of structured cultured fish meat.