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The critical role of gut-brain signalling in eating behaviour and obesity.
Nat Rev Gastroenterol Hepatol
Guillaume de Lartigue, Daniel I Brierley, Hyung Jin Choi
The process of eating can be divided into three distinct phases of behaviour: food seeking, food consumption and non-prandial activities. The durations of, and transitions between, these behavioural phases are driven by underlying interoceptive phenomena of hunger, satiation and satiety. The gut-brain axis regulates all eating phases, with the vagus nerve a primary conduit for interoceptive feedback about gut-derived mechanical and chemical cues. This Review explores the mechanisms governing each phase, focusing on how gut-derived signals are peripherally and centrally integrated to shape hunger, satiation and satiety, food preferences, and food-related learning. Chronic exposure to high-fat, high-sugar diets disrupts these mechanisms, driving a maladaptive state characterized by hyperphagia, food choice biases and habitual overeating. We examine the mechanisms underlying this maladaptive state, including vagal fibre remodelling, altered gene expression and leptin resistance, which can impair gut-brain communication, diminishing the brain's capacity to appropriately control eating behaviour and maintain energy balance. Emerging therapies, including glucagon-like peptide 1 receptor agonists, are effective in promoting weight loss but typically do not reverse the underlying causes of gut-brain axis dysfunction. By examining the mechanisms of gut-brain signalling, this Review highlights the vagus nerve as a key, yet underappreciated, target for obesity treatment.
Blood Pressure and Adrenocortical Hormone Profiles in 84 Ill Dogs with Normal Post-ACTH Cortisol Concentrations.
J Am Anim Hosp Assoc
Robert L J Runde, Sharon A Center, Ronald Lyman +1 more
Relationship between systolic blood pressure (SBP) and adrenocortical hormones in 10 normotensive (NT) control dogs and 84 ill dogs with clinical features of hypercortisolism but normal post-adrenocorticotropic hormone (ACTH) cortisol was studied. Doppler blood pressure classified dogs as NT (<140 mm Hg), prehypertensive (PHT; 140-159 mm Hg), or hypertensive (HT; ≥160 mm Hg). Serum cortisol, progesterone, 17-hydroxyprogesterone, androstenedione, and aldosterone were measured before and 1-hr after intramuscular (IM) ACTH (250 μg/dog). Ill dogs (40 NT, 29 PHT, and 15 HT) were significantly (P ≤ .04) older, smaller, and received higher ACTH dose/kg versus controls. ACTH dose/kg was not significantly associated with post-ACTH hormone concentrations. Compared to controls, baseline hormones were significantly (P ≤ .05) higher in ill dogs, except progesterone and 17-hydroxyprogesterone in HT and aldosterone in PHT dogs; significantly higher post-ACTH 17-hydroxyprogesterone and androstenedione (P ≤ .01) in NT and PHT dogs, and aldosterone (P = .03) in HT dogs occurred. No significant differences in baseline or post-ACTH hormones existed between SBP groups. Only 3/10 controls had all hormones within reference limits. Findings suggest risk for PHT and HT in ill dogs with increased noncortisol adrenocortical hormones, and show inexplicably increased adrenocortical sex hormones in NT healthy dogs.
Optimization of automated radiosynthesis method for [18F]AlF-NOTA-Octreotide and PET/CT imaging in neuroendocrine neoplasms.
EJNMMI Radiopharm Chem
Xiaoting Wan, Jiangyue Yan, Jieting Hu +11 more
Neuroendocrine neoplasms (NENs) represent heterogeneous tumors with increasing occurrence rate. Somatostatin receptor (SSTR) imaging using 68Ga-labeled analogs is crucial but limited by the relatively short half-life of this radionuclide along with its reliance on generator supply. To overcome these limitations, this study aimed to establish an automated synthesis platform compliant with Good Manufacturing Practice (GMP) standards for the preparation of a novel SSTR-targeting probe, [18F]AlF-NOTA-octreotide. Its diagnostic efficacy in neuroendocrine neoplasms was evaluated through comparison with existing 68Ga-labeled and [18F]FDG probes.
Appetite regulation following energy restriction with almond-enriched vs. nut-free diets - a randomised controlled trial.
Obes Res Clin Pract
Sharayah Carter, Alison M Hill, Jonathan D Buckley +3 more
This study assessed the impact of almonds (AL) or carbohydrate-rich snack bars (SB) on appetite and energy intake. Participants (25-65 yrs, BMI 27.5-34.9 kg/m2) were randomised to consume AL (n = 68) or SB (n = 72) during weight loss (WL) and weight maintenance (WM) diets. Fasting and postprandial appetite hormones and subjective appetite ratings (over 120 min) were measured at baseline (BL), after WL and after WM. Buffet meal energy intake was recorded at 150 min. Fasting ghrelin decreased in AL and increased in SB (group x time, p = 0.011), while leptin had a greater increase in AL versus SB post-WM (group x time, p = 0.001). Fasting glucagon and pancreatic polypeptide (PP) were consistently higher in AL compared to SB at each time point (group, p < 0.001). Fasting cholecystokinin (CCK), glucagon and leptin decreased (p < 0.001), while glucose-dependent insulinotropic polypeptide (GIP) (p = 0.004), glucagon-like peptide-1 (GLP-1), PP, peptide YY (PYY), and subjective hunger (p < 0.001) increased over time for all participants, Postprandial AUCs were consistently higher in AL than SB for glucagon and PP (p < 0.001), and GIP and GLP-1 (p < 0.05). Over time CCK and leptin AUCs decreased (WL -11% and -2%, WM -9% and -2%, p < 0.05), GIP and subjective hunger AUC increased over time (WL +17%,WM +12%, p < 0.05). Total and discretionary buffet energy intake declined over time (WL -16%, WM -25%,p < 0.05). Both groups experienced increased subjective hunger post-WL but demonstrated reduced energy intake at the buffet, suggesting effective behavioural adaptations. AL led to more favourable hormonal changes than SB, highlighting its potential appetite-regulating benefits in long-term WM strategies.
Satellite glial GLRX3 drives ageing-biased neuropathic pain via HMGB1.
Brain
Yang Yang, Bing Zhao, Xinyu Liu +6 more
Chronic neuropathic pain disproportionately affects older individuals, particularly in the context of persistent oxaliplatin-induced peripheral neuropathy (OIPN); however, the molecular mechanisms sustaining this ageing-biased chronicity remain elusive. In this study, we integrated age-stratified murine models and a multicentre longitudinal cohort of patients receiving oxaliplatin-based chemotherapy for colorectal cancer to investigate a glia-to-neuron redox circuit in the dorsal root ganglion. Using single-nucleus RNA sequencing and redox proteomics, we identified selective upregulation of the deglutathionylase glutaredoxin-3 (GLRX3) in satellite glial cells in aged mice during the chronic phase of OIPN. This upregulation leads to a pronounced loss of protein S-glutathionylation (PSSG) within the dorsal root ganglion, a pattern absent in young mice and during acute stages. Mechanistically, GLRX3, via its catalytic Cys148 residue, catalyses the deglutathionylation of high-mobility group box 1 (HMGB1) at the Cys106 site. This modification converts HMGB1 into a potent agonist for the toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex, triggering neuronal nuclear factor-κB signalling and the subsequent upregulation of transient receptor potential ankyrin 1 and vanilloid 2 channels in PACAP-positive (C1 subtype) peptidergic nociceptors, thereby sustaining long-term mechanical and cold hypersensitivity. Satellite glial cell-targeted knockdown of GLRX3 restored HMGB1 glutathionylation and reversed the pain phenotype specifically in aged mice. In the clinical cohort, advanced age was significantly associated with a higher incidence of chronic neuropathy. Longitudinal serum analysis revealed that systemic levels of PSSG and glutathionylated HMGB1 declined progressively and correlated inversely with pain duration, particularly among older individuals. Furthermore, oral γ-glutamylcysteine or pharmacologic TLR4 blockade (TAK-242) effectively alleviated refractory hypersensitivity in aged models. These findings define the satellite glial GLRX3-HMGB1-TLR4 redox axis as a critical driver of age-biased neuropathic pain. Circulating PSSG represents a novel age-stratified clinical biomarker, and targeting this redox-sensitive pathway offers a promising therapeutic strategy for geriatric and chemotherapy-related neuropathies.
Single Fiber Isolation Assay for the Assessment of Oxidative Myofiber Behavior.
J Vis Exp
Huascar Pedro Ortuste Quiroga, Yoshitaka Mita, Yasuko Manabe +2 more
Skeletal muscle is composed of multinucleated myofibers whose integrity and function are essential for movement and overall health. In neuromuscular disorders, muscle groups can be affected differentially across disease types and stages, making it important to isolate viable single fibers from representative muscles for mechanistic studies. The objective of this protocol is to provide a reliable method for isolating a high yield of intact single myofibers from the murine soleus (SOL) muscle, which is challenging to dissociate due to fiber length and fragility. By optimizing collagenase concentration and digestion time, the protocol minimizes fiber loss and preserves viability during dissociation. The optimized workflow markedly reduces residual tissue attachment to isolated fibers, thereby limiting carryover of non-fiber cells and minimizing cross-cell contamination. This technique is suitable for single-fiber analyses as well as satellite cell isolation and subsequent expansion under conditions with minimal contamination. Using this optimized workflow, we routinely obtain ~300-500 intact SOL-derived single myofibers that can be immunolabelled with high efficiency and also yield a high-quality satellite cell population with minimal fibroblasts contamination. Using comparative analyses with Extensor Digitorum Longus (EDL) muscle we underscore the value of a tailored, muscle-specific approach to evaluating therapies in neuromuscular disease research, enabling candidate pharmaceutical interventions to be tested within small, tunable experimental windows.
[Mechanisms underlying the antimicrobial and immunomodulatory activities of porcine antimicrobial peptides].
Sheng Wu Gong Cheng Xue Bao
Tingting Zhang, Yandi Pan, Rendong Fang +1 more
Porcine antimicrobial peptides (AMPs) possess excellent antimicrobial activities and multiple biological functions, playing an essential role in the host's innate immune defense against pathogen infections. With the growing limitations of antibiotics, AMPs have been extensively studied due to their mild drug resistance and potent immunomodulatory activities. Porcine AMPs as vital components in the host defense against pathogen infections have the potential to be developed as anti-infective drugs. This review focused on the research progress in porcine AMPs regarding the structure-activity relationships and the antimicrobial and immunomodulatory activities, and discussed the potential application prospects, providing a basis for the development of anti-infective drugs in veterinary medicine.
Antimicrobial Peptides and Systemic Inflammation: A Network Analysis.
Immun Inflamm Dis
Fabiano Pinheiro da Silva, Francisco Garcia Soriano, Ludhmila Abrahão Hajjar
Antimicrobial peptides (AMPs) are essential components of the innate immune system, exhibiting diverse mechanisms of action.
Cost-effectiveness of tirzepatide versus semaglutide for patients with obesity or overweight in the US: evidence from the SURMOUNT-5 head-to-head phase-3 trial.
J Med Econ
Erin Johansson, John P H Wilding, Navneet Upadhyay +6 more
This study evaluated the cost-effectiveness (from the United States [US] societal perspective) of tirzepatide at its maximum-tolerated-dose (MTD) compared to semaglutide (MTD), both administered adjunct to a reduced-calorie diet and increased physical activity. The analysis focused on individuals with obesity (body mass index [BMI] ≥ 30 kg/m2), or overweight (BMI ≥27 to <30 kg/m2 + ≥1 obesity-related complication), using data from the head-to-head Phase-3 SURMOUNT-5 trial (patients without type 2 diabetes [T2D]).
Dynamics of Body Composition and Metabolic Risk in Adolescents With Obesity Under GLP-1 Receptor Agonist Therapy.
Acta Paediatr
Adar Lopez, Liat Perl, Eyal Cohen-Sela +9 more
To explore changes in body composition in adolescents with obesity treated with glucagon-like peptide-1 receptor agonist (GLP-1 RA) and their association with metabolic syndrome (MetS) components.
Integrated Evidence from VigiBase and Clinical Trials: A Comprehensive Pharmacovigilance Analysis of Seven Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs).
Diabetes Ther
Jiaxun Li, Jizhou Liang, Wei Zhang +2 more
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are key therapies for type 2 diabetes and obesity, regulating blood glucose by mimicking endogenous GLP-1. Despite efficacy, GLP-1 RAs are associated with adverse reactions across multiple organ systems. To address the gap in class-wide comparative safety analyses beyond previous studies limited to single drugs or organ systems, this study systematically evaluated adverse events for all approved GLP-1 RAs to identify hidden risks and support clinical decision-making.
Optimal Ablation Strategies for Persistent Atrial Fibrillation With Heart Failure: Three-Year Follow-Up of a Prospective Multicenter Randomized Trial.
Circ Arrhythm Electrophysiol
Kaige Li, Xinhua Wang, Mu Qin +13 more
Catheter ablation has been shown to improve prognosis in patients with heart failure (HF) and atrial fibrillation (AF); however, the optimal ablation strategy remains undefined.
Prognostic Value of Cystatin C Across Ejection Fraction Spectrum in Heart Failure With Normal to Mild Renal Dysfunction Original Investigation.
Clin Cardiol
Lyu Lyu, Juan Xu, Qiang Yang +3 more
Cystatin C (CysC)'s predictive utility for long-term adverse outcomes in heart failure (HF) patients with normal to mild renal insufficiency remains unclear. This study investigates the relationship between CysC and adverse outcomes in HF patients across the whole ejection fraction (EF) spectrum with normal to mild renal insufficiency.
High N-Terminal Pro-B-Type Natriuretic Peptide Levels Are Associated With Lower Physical Function Independent of Sarcopenia in Community-Dwelling Older Adults: The Shizuoka Study.
Geriatr Gerontol Int
Michitaka Kato, Yoshihiro Tanaka, Takuji Adachi +10 more
Higher levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been shown to be associated with muscle deterioration and lower physical performance among patients with heart failure (HF). The aim of this study was to clarify the relationships between NT-proBNP levels, sarcopenia, and physical function among community-dwelling older adults.
Warning indicators for heart transplantation requirement at the time of hypertrophic cardiomyopathy diagnosis.
Cardiol J
Marc Ramos-Jovani, Ángela López-Sainz, Magí Brufau +12 more
Timely identification of hypertrophic cardiomyopathy (HCM) patients who may require a heart transplant (HT) in the future is crucial. Our study aimed to identify predictive factors associated with the need for HT in HCM patients.
Harnessing Herbal Power: A Systematic Review of Phytopharmaceuticals in Type 2 Diabetes Management.
J Am Nutr Assoc
Kamalika Chattopadhyay, Pankaj Kumar, Ravishankar Ram Mani +3 more
The Type 2 diabetes mellitus (T2DM) is one of the key health crises facing the world, with the prevalence expected to surpass 783 million adults by the year 2045. It causes premature disability, death and enormous social and economic costs. It is believed that the number of diabetes mellitus (DM) may increase to 592 million in 2035. Although there are conventional therapies, they are very expensive and limited. Despite the fact drugs that are produced synthetically are effective in controlling the disease, there are some side effects that are related with their long-term use. Consequently, the role of the traditional medicine such as plant extracts and pharmacological compounds derived out of plants is becoming very popular. The purpose of this review is to bring together the existing research on the effectiveness of herbal medicine in treating T2DM and especially phytochemicals based on in vitro, in vivo and clinical studies.
Efficacy and safety of co-administered cagrilintide and semaglutide versus semaglutide alone in adults with overweight or obesity with or without type 2 diabetes in Japan and Taiwan (REDEFINE 5): a multicentre, randomised, active-controlled, phase 3a trial.
Lancet Diabetes Endocrinol
Toshimasa Yamauchi, Niels-Peter Becker, Christoffer Andersen Hagemann +7 more
The combination of cagrilintide and semaglutide has been shown in global studies to induce reductions in bodyweight. We assessed the efficacy and safety of a fixed-dose combination of cagrilintide 2·4 mg and semaglutide 2·4 mg versus semaglutide 2·4 mg for weight management in an east Asian population.
Associations of Semaglutide With Skeletal Outcomes in People With Obesity, With and Without Type 2 Diabetes: A Target Trial Emulation.
Diabetes Obes Metab
Yu-Nan Huang, Min-Yu Tsou, Pin-Hung Li +6 more
To evaluate the associations between semaglutide initiation and long-term skeletal outcomes in people with obesity, stratified by type 2 diabetes (T2D) status, using target trial emulation.
Quantitative β-Cell Mass Imaging Redefines Disease Staging and Glycemic Control in Type 1 Diabetes.
Diabetes
Kentaro Sakaki, Takaaki Murakami, Hayao Yoshida +7 more
Noninvasive measurement of pancreatic β-cell mass remains an important unmet need in type 1 diabetes because conventional surrogate markers, such as C-peptide, often lack sensitivity in advanced disease. This study evaluated the glucagon-like peptide 1 receptor-targeted positron emission tomography tracer, 18F-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4), to determine its ability to visualize pancreatic β-cell mass. Positron emission tomography/computed tomography performed at 60 and 120 min after tracer injection in individuals with type 1 diabetes was compared with data from healthy control participants. No serious adverse events occurred. Pancreatic uptake was consistently lower in individuals with type 1 diabetes and showed clear separation between individuals with insulin-dependent diabetes and healthy control participants at 120 min. Pancreatic uptake at 120 min correlated with fasting C-peptide index and inversely with hemoglobin A1c and daily insulin dose per body weight. These findings support [18F]FB(ePEG12)12-exendin-4 positron emission tomography/computed tomography as a noninvasive approach for assessing β-cell mass and disease status.
Evaluating sotatercept in the treatment of pulmonary arterial hypertension.
Future Cardiol
William Salibe-Filho, Nathalia Zorze Rossetto, Luiza Sarmento Tatagiba +5 more
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling, right ventricular overload, and premature death. Despite advances achieved through endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin analogs, these agents primarily act as vasodilators and do not reverse underlying vascular pathology. Sotatercept, a first-in-class activin signaling modulator, restores the balance between pro- and antiproliferative signaling within the pulmonary vasculature via the TGF-β/activin-BMPR2 pathway, offering a novel disease-modifying mechanism. Following encouraging preclinical data, a series of clinical trials, PULSAR, SPECTRA, STELLAR, ZENITH, and HYPERION, demonstrated consistent efficacy across diverse PAH populations. Sotatercept significantly reduced pulmonary vascular resistance, improved exercise capacity, and decreased morbidity and mortality, including in patients receiving maximal background therapy. Across studies, adverse events were generally mild to moderate, with epistaxis, telangiectasia, and increased hemoglobin being the most common treatment-related events. Collectively, these findings establish sotatercept as a major advance in PAH therapy, marking a transition from purely vasodilatory approaches toward targeted modulation of vascular remodeling. By improving pulmonary hemodynamics and right ventricular function, sotatercept represents a new therapeutic option for improving clinical outcomes across different stages of PAH.