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Sex-specific metabolic responses to glucagon receptor agonism and modulation of the FGF21-glucagon axis in female mice.
J Physiol
Christoffer Merrild, Valdemar Brimnes Ingemann Johansen, Christoffer Clemmensen +1 more
Glucagon receptor agonism, particularly when combined with incretin analogues, is currently being explored as a treatment for obesity to improve cardiometabolic health, given glucagon's key role in regulating energy homoeostasis. However, male-biased preclinical studies limit our understanding of sex-specific responses to glucagon receptor activation, especially regarding fibroblast growth factor 21 (FGF21), a major downstream effector of glucagon signalling. To test whether responses to glucagon receptor agonism are sex dependent and modulated by FGF21, we compared a long-acting glucagon analogue (LA-Gcg) with the GLP-1 analogue semaglutide in diet-induced obese male and female mice. We then used female Fgf21 knockout (KO) mice to probe the role of the FGF21-glucagon axis in the response to glucagon receptor agonism. LA-Gcg induced greater weight loss, reduced food intake and more strongly altered hepatic gene expression in males, whereas semaglutide effects were comparable between sexes. LA-Gcg impaired glucose tolerance more severely in females than in males. This impairment was exacerbated in female Fgf21 KO mice, despite similar reductions in body weight between genotypes. Notably, FGF21 deficiency potentiated diet-induced obesity in females but had minimal impact under chow diet, fasting or voluntary exercise. Collectively, these findings reveal that both sex and FGF21 modulate metabolic responses to glucagon-based therapies, emphasizing the importance of including female models in preclinical metabolic research to better predict therapeutic efficacy. KEY POINTS: Biological sex is known to affect metabolism, yet this variable remains largely underexplored in metabolic research. In males, glucagon's metabolic benefits often involve another hormone, FGF21 (fibroblast growth factor 21), but this relationship is largely unstudied in females. A long-acting glucagon (LA-Gcg) treatment caused less weight loss in obese female mice, failing to reduce their food intake, unlike in males. LA-Gcg also worsened glucose tolerance in females. Female mice lacking the Fgf21 gene were more susceptible to diet-induced obesity; although LA-Gcg treatment still reduced their weight and cleared liver fat, the absence of FGF21 worsened the drug-induced glucose intolerance. Our findings highlight sex-specific differences in metabolic responses to glucagon, emphasizing the need to consider sex as a key variable in the development of glucagon-based therapies.
Vitreous hemorrhage in a patient on tirzepatide: Coincidence or drug induced?
Oman J Ophthalmol
Sitara Azeem, Lujain Al Bulushi, Buthaina Isa Sabt
Tirzepatide is a synthetic polypeptide classified as glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist. It stimulates insulin secretion from the pancreas and helps lower blood sugar levels in patients with type 2 diabetes mellitus. It also reduces appetite and helps in weight reduction management. We report a case of unilateral vitreous hemorrhage in a middle-aged woman on tirzepatide for weight loss. A 55-year-old female, nondiabetic, on tirzepatide for weight loss presented with sudden visual loss in the right eye while being on tirzepatide. Her ocular history is known for angle-closure glaucoma status postsurgical peripheral iridectomy in both eyes many years back. Her medical history is notable for palpitations and is currently managed with beta blockers. At presentation, the best-corrected visual acuity in the right eye was 0.16 and 1.0 in the left eye. Fundus examination revealed vitreous hemorrhage in the right eye. Vitreous hemorrhage spontaneously resolved and uncorrected visual acuity improved to 1.0 over a period of four months. The key point to be conveyed from this case is the need for more studies into whether there is a causal relationship between tirzepatide and vitreous hemorrhage in nondiabetic patients and to promote caution when administering tirzepatide.
Benchmarking size-exclusion chromatography columns for the analysis of therapeutic peptides and model oligonucleotides.
J Chromatogr A
Mathias Buff, Alexandre Goyon, Kelly Zhang +1 more
Eleven modern size-exclusion chromatography (SEC) columns, including prototype columns designed to minimize non-specific interactions, were systematically evaluated for the analysis of peptides and oligonucleotides. Column physical properties and chromatographic performance were assessed under various mobile phase conditions. Notably, a reduced plate height close to 1 was achieved for one prototype column, representing a marked improvement over typical SEC performance (2 < hmin < 3). Mobile phase composition was optimized to balance chromatographic efficiency and analyte denaturation. The most denaturing conditions (30 % acetonitrile, 0.1 % trifluoroacetic acid) provided the best performance for linear, macrocyclic, disulfide-constrained, and lipid-conjugated peptides by effectively suppressing hydrophobic and ionic interactions. Columns with pore sizes ≥ 100 Å showed optimal performance, with UP-SW2000, Biozen dSEC-1, and BioCore SEC-120 columns (100-125 Å) yielding the best results. Column and mobile phase selection were particularly critical for hydrophobic peptides such as liraglutide and semaglutide; for these analytes, a phosphate-based mobile phase containing 20 % isopropanol was proposed to limit denaturation and potentially enable the characterization of non-covalent aggregates. For oligonucleotides, mobile phase composition had a limited impact, whereas stationary phase chemistry was decisive. Only two columns (UP-SW2000 and ACQUITY Premier SEC 125 Å) provided acceptable separations, enabling resolution of n-2 and n-3 shortmer impurities of 20-mer linear and structured oligonucleotides with resolutions close to 1. Coupling two 150-mm SEC columns in series further enhanced shortmer separation within 30 min.
GLP-1 receptor agonists and immune checkpoint inhibitor therapy: a narrative review on mechanistic and clinical evidence.
Future Oncol
Connor Frey
Obesity paradoxically increases sensitivity to immune checkpoint inhibitors (ICIs) despite elevating cancer risk, creating a clinical opportunity where metabolic dysfunction may generate a target-rich immune microenvironment. However, immunosuppressive mechanisms, including regulatory T-cells, myeloid-derived suppressor cells, and pro-inflammatory macrophages, can limit durable anti-tumor responses. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) extend beyond metabolic comorbidity management, functioning as metabolic-immunologic adjuvants capable of reprogramming the tumor microenvironment in obese patients receiving ICIs. A literature search was conducted in PubMed/MEDLINE through December 2025 using MeSH headings related to glucagon-like peptide-1 receptor agonists and immune checkpoint inhibitors. Mechanistically, GLP-1R signaling activates cAMP-PKA-AMPK pathways that suppress NF-κB-driven inflammation and promote macrophage repolarization, improving CD8 T-cell metabolic fitness, enhancing central memory formation, and reducing lipid-induced T-cell exhaustion. Real-world observational data across renal cell carcinoma, non-small cell lung cancer, colorectal cancer, and neuroendocrine neoplasms suggest improved overall survival, fewer immune-related adverse events, and lower cardiometabolic complications with concurrent GLP-1RA and ICI therapy. Pharmacovigilance concerns regarding pancreatitis, ICI-induced diabetes, and immune-related toxicities remain incompletely characterized. This review critically appraises mechanistic insights, real-world evidence, and safety considerations, proposing a translational-clinical research agenda to prospectively validate GLP-1RAs as rational adjuncts to checkpoint blockade.
Sensing performance of ScTiO3 film-based EIS arrays through co-sputtering for pH sensing and heart failure biomarker monitoring.
Talanta
Tung-Ming Pan, Chia-Yu Kuo, Jim-Long Her +1 more
In this work, a ScTiO3 sensing film array was fabricated on a p-type Si substrate using a co-sputtering technique and subsequently integrated into electrolyte-insulator-semiconductor (EIS) platforms for both pH sensing and N-terminal pro-B-type natriuretic peptide (NT-proBNP) detection, a clinically important biomarker for heart failure (HF) diagnosis. To evaluate the structural, interfacial, and sensing characteristics, the films underwent RTA at temperatures between 600 and 800 °C. Extensive material characterization, including X-ray diffraction, X-ray photoelectron spectroscopy, Auger electron spectroscopy, transmission electron microscopy, and atomic force microscopy, revealed a strong correlation between the microstructural evolution of the ScTiO3 films and their sensing performance. Superior sensing characteristics were observed in the film annealed at 700 °C, which recorded the highest sensitivity (65.07 mV/pH) alongside impressive stability metrics, including a 0.26 mV/h drift rate and 1.2 mV hysteresis. Furthermore, to enable specific NT-proBNP detection, the ScTiO3 surface was first functionalized with APTES and then conjugated with EDC/NHS-activated antibodies, facilitating precise antigen-antibody interactions. The resulting ScTiO3-based array EIS biosensor demonstrated excellent analytical performance, delivering a high sensitivity of 10.84 mV/pCNT-proBNP over a wide dynamic detection range from 10-4 to 106 pg/mL. Collectively, these results highlight the strong potential of a ScTiO3 sensing film array as high-performance platforms for reliable pH monitoring and advanced biomedical diagnostics, particularly for sensitive and accurate NT-proBNP detection in HF applications.
Efficacy and safety of sacubitril/valsartan in patients on peritoneal dialysis: a systematic review and meta-analysis.
J Bras Nefrol
Caio Lima da Silva, Pandora Eloa Oliveira Fonseca, Viviane Calice-Silva +3 more
Sacubitril/valsartan is a recommended medication for managing heart failure (HF). However, its role in peritoneal dialysis (PD) patients remains uncertain. We conducted this systematic review and singlearm meta-analysis to assess the efficacy and safety of sacubitril/valsartan in this population.
GLP-1 Receptor Agonists.
N Engl J Med
Clifford J Rosen, Julie R Ingelfinger
Glucagon-like peptide-1 (GLP-1) receptor agonists are incretin analogues that promote glucose-mediated insulin release and are used to treat type 2 diabetes mellitus and obesity. GLP-1 receptor agonists and GLP-1 and glucose-dependent insulinotropic peptide agonists have several mechanisms of action, including reduction of gastric emptying, inhibition of glucagon secretion, beneficial changes in the intestinal microbiome, and direct effects on hypothalamic nuclei to enhance satiety (which promotes weight loss). Beyond the impressive effects of GLP-1 receptor agonists on blood glucose levels and body weight, large-scale randomized, controlled trials have shown that GLP-1 receptor agonists reduce cardiovascular risk and slow progression to renal failure in persons at high risk and those with type 2 diabetes. Adverse side effects from GLP-1 receptor agonists are mostly gastrointestinal but may also include loss of muscle and bone mass. Questions remain about long-term adherence, weight regain after discontinuation of treatment, and the functional implications of the loss of muscle and bone mass. Recent and ongoing targeted studies suggest the possibility of additional uses for GLP-1 receptor agonists.
Emerging Role of Dual Glucagon-Like Peptide-1 (GLP-1)/Glucose-Dependent Insulinotropic Polypeptide (GIP) Receptor Agonists in Cardiovascular Prevention.
Cureus
Nicolle Contreras Figueroa, Maynor Jose Lopez Mendoza, Asdrubal Ulloa +3 more
Dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have emerged as a novel therapeutic class with potential relevance for cardiovascular prevention, particularly in the context of obesity and type 2 diabetes mellitus. Incretin physiology provides the biological foundation for this approach, as GLP-1 and GIP exert complementary metabolic and vascular effects. While GLP-1 receptor agonists have demonstrated well-established reductions in major adverse cardiovascular events, GIP has regained interest due to evidence suggesting preserved vascular and anti-atherosclerotic actions despite reduced insulinotropic efficacy in diabetes.  Dual receptor agonism integrates these pathways, leading to substantial improvements in cardiometabolic risk factors. Agents such as tirzepatide induce marked and sustained weight loss, with significant reductions in visceral adiposity, a key driver of cardiovascular disease. These effects are accompanied by robust improvements in glycemic control and insulin sensitivity, resulting in attenuation of glucotoxicity and lipotoxicity, both of which contribute to endothelial dysfunction and myocardial injury. Additional benefits include reductions in blood pressure, favorable modulation of lipid profiles, and suppression of systemic inflammatory markers, alongside improvements in endothelial function and vascular stiffness. Pharmacologically, dual GLP-1/GIP receptor agonists are engineered to provide balanced receptor activation, allowing superior metabolic efficacy compared with single GLP-1 receptor agonists. Clinical trial data indicate cardiovascular safety and improvements in surrogate cardiovascular endpoints, with reductions in major cardiometabolic risk factors comparable to those achieved with established incretin therapies. However, definitive evidence of incremental cardiovascular outcome benefits remains limited.
Surgical resection of an adrenocorticotropic hormone-producing pulmonary typical carcinoid with mediastinal lymph node metastasis and high programmed death-ligand 1 expression.
Int Cancer Conf J
Masakazu Matsuda, Fumihiko Kinoshita, Yukina Takeichi +9 more
The programmed death-ligand 1 positivity rate in typical carcinoid is generally low; however, cases with programmed death-ligand 1 expression are more frequently associated with lymph node metastasis and have a poorer prognosis. While immune checkpoint inhibitors were incorporated into adjuvant chemotherapy regimens for programmed death-ligand 1-positive non-small cell lung cancer, their efficacy in pulmonary carcinoids remains unclear. A 47-year-old woman presented to a local clinic with moon face. Laboratory testing revealed elevated levels of adrenocorticotropic hormone and cortisol and adrenocorticotropic hormone-dependent Cushing's syndrome was suspected. For further evaluation, the patient was referred to our hospital. Computed tomography revealed a nodule in the left lower lobe of the lung and enlargement of the left hilar lymph node, suggesting ectopic Cushing's syndrome. Left lung cancer (cT1bN1M0, cStage IIB) was suspected, and the patient underwent robot-assisted thoracoscopic left lower lobectomy with ND2a-2 lymph node dissection for diagnostic and therapeutic purposes. Pathological examination confirmed a diagnosis of typical carcinoid (pT1bN2M0, pStage IIIA) with high programmed death-ligand 1 expression. Considering the presence of mediastinal lymph node involvement and programmed death-ligand 1 expression, the patient received four courses of cisplatin and vinorelbine, followed by treatment with atezolizumab. Postoperatively, her adrenocorticotropic hormone levels normalized, and the patient has been alive 18 months postoperatively without recurrence. Programmed death-ligand 1-positive typical carcinoids are associated with a higher frequency of lymph node metastasis and poorer prognosis. Additional case investigations are required to assess the efficacy of immune checkpoint inhibitors in typical carcinoid.
Small-cell carcinoma of the cervix with acute-onset psychotic symptoms associated with clinically diagnosed ectopic ACTH production: a case report.
Front Oncol
Kanako Ozaki, Junya Fujino, Kaoru Niimi +11 more
Small-cell carcinoma of the cervix (SCCC) is a rare and highly aggressive histological subtype of cervical cancer, associated with poor prognosis. SCCC is histologically classified as a neuroendocrine tumor and has the potential to produce ectopic hormones, leading to various paraneoplastic syndromes. This report is a rare case of recurrent SCCC presenting with psychiatric symptoms due to endogenous Cushing's syndrome caused by ectopic adrenocorticotropic hormone (ACTH) production. The patient initially developed mood and behavioral disturbances as the disease progressed, leading to hospitalization under the suspicion of a primary psychiatric disorder. However, further evaluation, prompted by the discovery of severe hypokalemia, revealed Cushing's syndrome associated with clinically diagnosed ectopic ACTH production in the setting of recurrent disease. Her psychiatric symptoms rapidly remitted following the administration of a cortisol synthesis inhibitor. This case highlights the importance of considering endocrine disorders as potential causes of psychiatric manifestations in patients with cancer, particularly those with neuroendocrine tumors such as SCCC. Acute and marked elevation of endogenous cortisol can induce distinct psychiatric symptoms, such as manic features and grandiose delusions, that often respond better to endocrine treatment aimed at normalizing cortisol levels rather than to antipsychotic therapy alone. Clinicians should be aware of this rare but important clinical presentation as timely diagnosis and management can improve patient outcomes.
Central amygdala neuropeptide Y neurons drive hedonic ingestive behaviour independent of energy homeostasis.
Int J Obes (Lond)
Neda Rafiei, Caitlin S Mitchell, Philip Jean-Richard-Dit-Bressel +5 more
Neuropeptide Y (NPY), a key orexigenic neurotransmitter, is widely expressed in the central nervous system, including in a distinct subpopulation of neurons within the central nucleus of the amygdala (CeA). While CeA NPY neurons contribute to energy regulation during chronic stress or high-fat diet exposure, the role of these neurons in modulating ingestive behaviour under standard conditions, particularly in response to caloric and non-caloric cues remains poorly understood.
A chimeric natriuretic peptide (Ev-NP) inhibits isoproterenol (ISO)-induced hypertrophic growth in in vivo and in vitro models by enhancing cGMP and its downstream signaling targets: In silico docking and binding efficacy analysis with NPR-A and NPR-B receptors.
Peptides
Jayashree Bheeman, Ananthan Krishnan Dhanabalan, Gopinath Nagaraj +4 more
A chimeric natriuretic peptide (Ev-NP) was engineered and created with an intention of having a dual NPR-A/NPR-B activation, resistance to degradation, and with a strong renal, and anti-hypertrophic actions in the heart. In the present study, we aim to investigate the anti-hypertrophic properties of a novel chimeric natriuretic peptide, Ev-NP (37 amino acids), against isoproterenol (ISO)-induced hypertrophy in H9c2 cells in vitro and in a rat model in vivo. The effects on anti-hypertrophy and cGMP stimulation were evaluated in H9c2 cells exposed to ISO, both with and without Ev-NP, at concentrations ranging from 10 to 50 nM over 24 h. A significant dose-dependent increase in cGMP was observed in Ev-NP-treated H9c2 cells compared to controls. Furthermore, Ev-NP treatment significantly (P < 0.001) decreased ISO-induced hypertrophic growth in H9c2 cells by elevating cGMP levels. In H9c2 cells overexpressing Npr1 and co-treated with Ev-NP, a stronger anti-hypertrophic effect was observed, as demonstrated by a significant reduction (P < 0.001) in hypertrophic marker gene expression (α-sk, BNP, and β-MHC) compared to cells treated only with ISO. Furthermore, cytokine array analysis showed that Ev-NP treatment normalized ISO-induced up-regulation of pro-inflammatory and growth factor proteins in H9C2 cells. The in vivo anti-hypertrophic study also showed that Ev-NP significantly reduced (90%) the hypertrophic growth caused by ISO in Wistar rats. Importantly, treatment with Ev-NP restored the ISO-induced reductions in cGMP and NPR-A levels in the rat hearts. In silico analysis revealed that Ev-NP exhibited a stronger affinity for the NPR-A receptor, with a binding energy of -490.17 kcal/mol, compared to NPR-B binding energy of -390.77 kcal/mol. The native ANP exhibited a binding energy of -314.68 kcal/mol with NPR-A. These findings suggest that Ev-NP has promising anti-hypertrophic properties, and its therapeutic potential can be harnessed to treat and manage cardiac hypertrophy and heart failure in humans.
Impairment of Macrophage Functions by the Senescence-Associated Secretory Phenotype of Vascular Smooth Muscle Cells-Brief Report.
Arterioscler Thromb Vasc Biol
Dimitrios Tsitsipatis, Tatiana Rodriguez Rivera, Mary Kaileh +6 more
This study aimed to determine the effect of senescent vascular smooth muscle cells (VSMCs) on foam cell formation and macrophage phagocytic activity in atherosclerotic conditions.
Reprogramming aging astrocytes in Alzheimer's disease.
Trends Neurosci
Maria Alfonso-Triguero, Amaia M Arranz
Alzheimer's disease typically unfolds within an aging brain, where astrocytic transcriptional programs are extensively remodeled. A recent study by Choi and colleagues shows that reinstating an aging-dependent Sox9 (SRY-box transcription factor 9)-MEGF10 (multiple EGF-like domains 10) axis restores amyloid clearance and preserves cognition in mouse models. These findings suggest that astrocyte dysfunction reflects destabilized, yet recoverable, homeostatic programs rather than irreversible degeneration.
Acyl-CoA-binding protein (ACBP): a poor-prognosis biomarker in sepsis and a target for disease mitigation.
Signal Transduct Target Ther
Flavia Lambertucci, Omar Motiño, Uxía Nogueira-Recalde +25 more
Sepsis remains a major clinical challenge, with high mortality and long-term disability despite current interventions. Here, we identify the tissue hormone acyl-CoA-binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), as a biomarker and driver of poor outcome in sepsis. ACBP/DBI was elevated in the plasma of septic patients and associated with organ dysfunction and increased mortality. In murine models of endotoxemia, Escherichia coli infection, and polymicrobial sepsis, genetic deletion or antibody-mediated neutralization of ACBP/DBI conferred robust protection by dampening cytokine storm and preserving organ function. Across these three models, neutralization of ACBP/DBI with monoclonal antibodies restored thermoregulation and reduced mortality. Mechanistically, ACBP/DBI inhibition enhanced resilience to lipopolysaccharide-induced sterile inflammation and improved bacterial clearance by macrophages and granulocytes in vivo and in vitro. These effects were observed in monomicrobial infection models and confirmed by high-dimensional immunophenotyping in a polymicrobial sepsis model. Notably, ACBP/DBI inhibition could be favorably combined with glucocorticoids, enhancing survival and reversing histopathological, transcriptional or metabolic signatures of septic shock across heart, kidney, liver, lung, spleen and plasma. These findings position ACBP/DBI as a mechanistic amplifier of sepsis pathophysiology and propose its neutralization, alone or in combination with corticosteroids, as a promising therapeutic strategy to interrupt the fatal trajectory of septic shock.
Mitochondrial Calcium Dysregulation and Targeted Therapies in Heart Failure.
Rev Cardiovasc Med
Mengting Liu, Yunpeng Jin
Heart failure (HF) is steadily increasing in prevalence and poses a major global health challenge, with substantial medical and economic burdens. HF represents the terminal stage of diverse cardiac disorders and is characterized by poor prognosis despite the availability of conventional pharmacological treatments, underscoring the urgent need for novel therapeutic approaches. Accumulating evidence highlights a strong association between HF and mitochondrial dysfunction, of which dysregulated mitochondrial calcium (mCa2+) homeostasis plays a pivotal role in disease pathogenesis. Ca2+ serves as an essential signaling messenger that regulates energy metabolism and also governs cell survival and myocardial contractility. Thus, this review introduces the mechanisms of mCa2+ uptake and efflux and the association of these processes with HF and emerging therapeutic strategies. We also discuss mCa2+ uniporter (MCU) inhibitors and Elamipretide, a mitochondria-targeted peptide. Collectively, this work provides novel insights and preclinical evidence supporting mitochondria-based interventions for HF.
SELFormer-guided discovery of xanthohumol and cirsilineol as multi-target natural therapeutics for type 2 diabetes: computational prediction and experimental validation.
Food Funct
Junyu Zhou, Chen Li, Meiling Liu +1 more
Type 2 diabetes mellitus (T2DM) requires multi-target therapeutic approaches addressing both insulin resistance and insulin secretion deficits. Although natural compounds are promising multi-target candidates, systematic identification of their polypharmacological profiles remains challenging. The objective of this study was to establish a computational framework for identifying natural compounds with multi-target therapeutic potential against T2DM through integrated structure-activity analysis and experimental validation. We developed an SELFormer deep learning model to predict natural compound activities against six T2DM-related proteins including glucagon-like peptide-1 receptor (GLP1R), kinesin family member-11 (KIF11) for insulin secretion and insulin receptor (INSR), peroxisome proliferator-activated receptor-gamma (PPARG), fibroblast growth factor receptor-1 (FGFR1) and insulin-like growth factor-1 receptor (IGF1R) for insulin resistance. Uniform Manifold Approximation and Projection (UMAP) for dimension reduction clustering characterized chemical space distributions and molecular docking validated multi-target binding. Selected compounds were experimentally validated using 3T3-L1 adipocytes and mouse insulinoma (MIN6) pancreatic β-cells. The SELFormer model achieved R2 = 0.937 and RMSE = 0.331 on the training dataset and R2 = 0.918 and RMSE = 0.353 on the testing dataset, with minimal overfitting (ΔR2 = 0.019). Among approximately two million screened compounds, 35 natural compounds demonstrated high predicted activity (pIC50 > 7), clustering into eight distinct chemical families. Multi-target network analysis and molecular docking identified curcumin, xanthohumol, hesperetin, (-)-epicatechin, and cirsilineol as lead candidates with favorable binding energies ranging from -7 to -10 kcal mol-1 across the six targets. Food source analysis identified strawberries, grapes, and tea as rich dietary sources of these bioactive compounds. In 3T3-L1 adipocytes, all five compounds significantly enhanced insulin-stimulated glucose uptake at 10 μM, achieving efficacy comparable to that of metformin. In MIN6 cells, xanthohumol and cirsilineol increased glucose-stimulated insulin secretion to levels comparable to exendin-4, while curcumin, hesperetin, and (-)-epicatechin produced modest but significant increases. In conclusion, this integrated computational and experimental framework identified food-derived natural compounds with validated dual-pathway therapeutic activity against T2DM, providing a systematic and reproducible methodology for multi-target drug discovery in complex metabolic disorders.
Self-assembled mesoporous bioglass polyphenol nanozymes for repairing musculoskeletal trauma.
Biomaterials
Shuao Zhao, Yesheng Jin, Zhihao Jia +7 more
Volumetric Musculoskeletal Trauma (VMST), which is characterized by volumetric muscle loss accompanied by bone injury, poses a significant challenge to regenerative medicine. While current therapies primarily focus on the individual regeneration of muscle or bone, there is no systematic and integrated treatment strategy. In this study, we developed a CuMBG-PA, a copper-doped nanozyme based on mesoporous bioactive glass (MBG) and procyanidin (PA), for integrated muscle and bone repair of VMST. CuMBG-PA self-assembles into a stable polyphenol network via Cu-PA coordination bonds, enhancing PA stability and reactive oxygen species-scavenging capacity. In vitro and in vivo experiments demonstrated that CuMBG-PA promoted osteogenesis and myogenesis while exhibiting high biocompatibility and antibacterial activity. Single-cell RNA-sequencing results revealed that CuMBG-PA synergistically induces stem cell differentiation and promotes tissue repair through multiple myoskeletal shared metabolic pathways. Mechanistically, CuMBG-PA exerts its beneficial effects by increasing the number of Proteoglycan 4 (Prg4) + fibro/adipogenic progenitor cells (FAPs), which highly express fibronectin and insulin-like growth factor. In addition, PRG4 regulates immune cells, removes overactivated muscle satellite cells, reduces muscle fibrosis, and promotes functional recovery during regeneration. In summary, this work demonstrates that the novel self-assembled CuMBG-PA nanozyme represents a potential biomaterial-based strategy for integrated muscle and bone repair in VMST.
TRPV2 is essential for calcium signalling in the early stages of myogenesis.
Biochem Biophys Res Commun
Yanzhu Chen, Kimiaki Katanosaka, Yuki Katanosaka
Skeletal muscle responds to stressors such as exercise and muscle injury by adaptive remodelling. The resilience of skeletal muscle involves not only mature muscle fibres but also the adjacent muscle satellite cells (MuSCs). We previously found that transient receptor potential vanilloid type 2 (TRPV2) is expressed in MuSCs and is essential for MuSC proliferation and activation in MuSC-specific conditional knockout mice. These mice show no mechanical-load-induced muscle hypertrophy and delayed injury-induced muscle regeneration. The effect of TRPV2 on Ca2+ signalling during early myogenesis is unknown; however, here, we demonstrate that tranilast, an inhibitor of TRPV2, suppressed IP3R-derived Ca2+ oscillations in early myogenesis. The addition of adenovirus (Ad)-TRPV2 or Ad-Cre recombinase to floxed-TRPV2 cells modulated TRPV2 expression, and demonstrated the TRPV2 dependence of IP3R and MEF2c expression, nuclear translocation of MEF2c, and Ca2+ oscillations. These findings indicate that TRPV2 regulates intracellular Ca2+ signalling during early myogenesis and highlight its potential as a target for the prevention and treatment of muscle disorders.
Effect of Semaglutide on Body Weight, Blood Lipid Profile, and Adipokine Status in Obese Patients.
Kardiologiia
A V Tyurina, N S Kurochkina, M V Yezhov
Aim        To evaluate the dynamic impact of an 8-month glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy with semaglutide on anthropometric metrics, blood lipid profiles, and adipokine status in obese patients, with and without type 2 diabetes mellitus (T2DM).Material and methods    The study included 65 patients with obesity, 26 of whom had T2DM. All participants were prescribed semaglutide, with dose titration up to 1 mg once weekly over 8 months. Before and after the treatment period, the following variables were assessed: anthropometric data (body weight, body weight index, waist circumference), biochemical parameters (lipid profile, glucose, aspartate aminotransferase, alanine aminotransferase, creatinine), and adipokine concentrations (leptin, adiponectin, resistin) via immunofluorescence assay.Results  Semaglutide therapy was associated with a statistically significant reduction in body weight (p&lt;0.001), body mass index (p&lt;0.001), and waist circumference (p&lt;0.001). Improvements in the lipid profile were observed over time, including decreased concentrations of low-density lipoprotein cholesterol (p=0.001), triglycerides (p&lt;0.001), and total cholesterol (p=0.001), alongside an increase in high-density lipoprotein cholesterol (p&lt;0.01). Therapy significantly impacted adipokine status: a statistically significant increase in anti-atherogenic adiponectin (p&lt;0.001) and a decrease in leptin levels (p&lt;0.001) were recorded, indicating improved adipose tissue metabolic function. However, no significant changes in resistin concentrations were found. Additionally, positive effects on liver and kidney function markers were noted, manifested by reductions in aspartate aminotransferase and alanine aminotransferase activity, as well as creatinine levels. In the subgroup of patients with T2DM, a statistically significant improvement in glycemic control was observed.Conclusion         Semaglutide therapy for 8 months in obese patients yielded a robust cardiometabolic impact, characterized by significant weight reduction, optimized lipid profiles, and improved liver and kidney function markers, alongside a favorable restructuring of adipokine status. These results support the use of GLP-1 RAs not only for glycemic and weight control but also as a multifaceted cardioprotective therapy for obese patients.