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Cost-effectiveness of semaglutide versus dulaglutide for Type 2 Diabetes in China: A Markov Model analysis.

PLoS One

Qiying Chen, Tianyu Chen, Weicheng Lin +1 more

From the perspective of China's basic medical insurance, to evaluate the cost-effectiveness of semaglutide versus dulaglutide for type 2 diabetes mellitus (T2DM) in China, informing clinical and health policy decisions.

GLP-1 receptor agonist adjunct therapy stabilises Ramadan dysglycaemia in insulin-treated diabetes: a CGM-based study.

Diabetes Res Clin Pract

Tanveer Ashraf, Nader Lessan

Patients with type 1 and insulin-treated type 2 diabetes are at higher risk of hypo- and hyperglycaemia during Ramadan fasting. The role of incretin-based add-on therapy (GLP-1 receptor agonist semaglutide and the GLP-1/GIP dual agonist tirzepatide) in attenuating Ramadan dysglycaemia in insulin-treated type 2 diabetes has not been characterised using continuous glucose monitoring. Emerging evidence indicates that exaggerated post-iftar hyperglycaemia, drives Ramadan dysglycaemia in insulin-treated individuals.

Microbiota-driven gut-brain signaling underlies antidepressant effects of a GLP-1 analog.

Cell Host Microbe

Liang Bian, Yang Cai, Yuan Zhang +11 more

Despite widespread clinical use of glucagon-like peptide-1 receptor (GLP-1R) agonists for metabolic disease, their neuropsychiatric effects remain poorly understood and controversial. Here, we demonstrate that liraglutide alleviates depression through a gut-brain pathway that operates independently of GLP-1R. Using both pharmacological and genetic approaches, we demonstrated that liraglutide retained antidepressant efficacy in GLP-1R antagonist-Exn9-treated mice or in Glp1r-/- mice, whereas gut microbiota depletion abolished its effects. Multi-omics analyses revealed that liraglutide increased the abundance of Lactobacillus delbrueckii, which in turn restored the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG). The elevation of 2-AG mediated the antidepressant effects by normalizing excessive neuronal activity in emotional processing brain regions. Importantly, fecal microbiota transplantation from liraglutide-treated mice or Lactobacillus delbrueckii colonization replicated the antidepressant effects. These findings uncover a non-canonical mechanism of action for GLP-1 analogs, highlighting a specific microbiota-endocannabinoid metabolic pathway as a potential therapeutic target for depression.

Cerebral hypoperfusion and the vascular-metabolic-immune-glymphatic network in Alzheimer's disease: mechanisms, diagnosis, and therapy.

Neuroscience

Mingyuan Yao, Annan Liu, Jing Song +3 more

Alzheimer's disease (AD), characterized by progressive cognitive decline, represents a major public health challenge in aging societies. Since the proposal of the amyloid cascade hypothesis, Aβ-targeted therapeutic strategies have dominated this field for over three decades. Although recent anti-Aβ antibodies have shown modest promise, their limited clinical benefits coupled with safety concerns underscore the necessity of re-evaluating the pathological mechanisms underlying AD. Cerebral hypoperfusion (CH), a detectable alteration emerging in the preclinical stage of AD, has garnered increasing attention for its potential driving role in disease pathogenesis. This review proposes a "vascular-metabolic-immune-glymphatic" (VMIG) pathological network model originating from CH: CH induces pericyte damage, astrocyte end-feet impairment, and extracellular matrix degradation, thereby resulting in neurovascular unit dysfunction; reduces oxygen and glucose delivery, precipitating mitochondrial energy failure and reactive oxygen species overproduction, which in turn initiates neuroinflammatory cascades; and attenuates arterial pulsation-driven flow while disrupting perivascular space architecture, culminating in glymphatic system clearance dysfunction. These mechanisms are intricately interconnected, establishing a self-perpetuating pathological loop. Building upon the VMIG framework, this review integrates multimodal neuroimaging techniques (ASL-MRI, Aβ/tau-PET, DTI-ALPS) with peripheral biomarkers (VEGF/Ang-2, sTREM2/GFAP, sPDGFRβ/Aβ42 ratio) to establish a comprehensive system for early diagnosis and stratified assessment of AD. Furthermore, we advocate for temporally sequenced combinatorial therapeutic strategies targeting the pathological network and discuss the translational potential of nanoparticle-based co-delivery systems. The VMIG model offers an integrative framework for understanding the multi-system dysregulation inherent to AD, facilitating a paradigm shift from single-target intervention toward network-based restoration.

Apelin-13 activates the BMP4/SMAD pathway through APJ to enhance osteoblastic differentiation and mineralization.

Tissue Cell

Chunyan Wang, Zhanyu Li, Hongmei Yang +3 more

Osteoblastic differentiation and mineralization are essential processes for bone formation and remodeling. Apelin, an endogenous ligand for the Apelin receptor (APJ), has been involved in various physiological functions, however, its function in osteogenesis remains unclear. The present research was dedicated to exploring the impacts of Apelin-13 on the osteoblastic differentiation process within MC3T3-E1 cells. The results showed that APJ expression was upregulated during osteogenic induction. Apelin-13 greatly increased the expression of osteogenic markers ALP, OCN, OPN, and Col1A1, promoted ALP activity and mineralization, and raised RUNX-2 expression at both mRNA and protein levels. Furthermore, Apelin-13 activated the BMP4/SMAD1/5/8 signaling pathway. These effects were abolished by LDN193189, a specific inhibitor of BMP signaling, and by APJ knockdown, indicating that Apelin-13 exerts its pro-osteogenic effects through APJ via the BMP4/SMAD pathway.

Efficacy of Sacubitril/Valsartan in Treating Hemodialysis Patients with Reduced Ejection Fraction Heart Failure: A Retrospective Study.

Iran J Kidney Dis

Yan Guo, Weihua Li, Zongli Diao

Heart failure with reduced ejection fraction (HFrEF) is a prevalent and challenging complication among patients undergoing hemodialysis. Sacubitril/Valsartan (Sac-Val), an angiotensin receptor-neprilysin inhibitor, has shown promise in improving cardiac outcomes in HFrEF patients. This study aims to evaluate the efficacy and safety of Sac-Val in treating HFrEF in patients undergoing hemodialysis.

Neutrophil Percentage-to-Albumin Ratio as a Novel Biomarker in Patients with Group 1 Pulmonary Arterial Hypertension.

Niger J Clin Pract

I Aktaş, E Yaşar

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease characterized by increased pulmonary vascular resistance, right ventricular failure, and systemic inflammation. Novel biomarkers reflecting disease severity and prognosis are needed for improved risk stratification in PAH.

Atrazine alters kisspeptin signaling and downstream neuroendocrine regulation following embryonic exposure in zebrafish.

Toxicology

Sydney C Stradtman, Umamaheswari Sathisaran, Benjamin K Dierolf +3 more

Atrazine is an herbicide used to control broadleaf and grassy weeds but is also a known endocrine disrupting chemical classified by the US EPA for its effect on the luteinizing hormone (LH) surge. The US EPA's maximum contaminant level (MCL) for atrazine in drinking water is 3 parts per billion (ppb; µg/L), though concentrations may exceed this during peak crop seasons. Because drinking water is the primary exposure route, studying environmentally relevant concentrations near the MCL is critical for understanding public health impacts. Atrazine has been shown in epidemiological and toxicological studies to disrupt neuroendocrine and reproductive functions, including suppression of gonadotropin-releasing hormone (GnRH) neuron activity, leading to decreased LH and follicle-stimulating hormone (FSH) surges. Given the breadth of observed effects, this study hypothesized that atrazine targets an upstream neuroendocrine regulator-the kisspeptin signaling pathway-due to its dual role in reproductive and dopaminergic regulation. Kisspeptin expression was characterized in developing zebrafish, showing increases every 24 h from 1 to 120 h post fertilization (hpf). Zebrafish were exposed during embryogenesis (1-72 hpf) to atrazine at 0, 0.3, 3, or 30 ppb. Immunofluorescence at 120 hpf showed reduced kisspeptin expression in the habenula at 3 ppb and near-complete loss of kiss1/kiss2 expression with brain disorganization at 30 ppb. Kisspeptin, LH, and FSH levels were measured at 168 hpf and 6 months post fertilization (mpf). Age- and sex-dependent alterations were observed. Behavioral tests revealed anxiety-like phenotypes in larvae and adults. These findings indicate atrazine disrupts neuroendocrine and behavioral function through kisspeptin pathway dysfunction.

IL-6 Activity is Required for Maximal Catecholamine Release During High-Intensity Exercise in Men.

Mol Metab

Andreas K Ziegler, Tim Schauer, Sara F Myrup +4 more

High-intensity exercise triggers a coordinated activation of metabolic, endocrine, and immune pathways, yet the mechanisms integrating these responses remain incompletely understood. Interleukin-6 (IL-6), released during exercise, has been proposed as a systemic signal linking skeletal muscle activity to whole-body stress responses. We tested whether exercise-induced IL-6 is required for full sympathoadrenal activation and immune cell mobilization during intense exercise in humans. Healthy young men received the IL-6 receptor (IL-6R) antibody tocilizumab prior to high-intensity interval exercise. IL-6R blockade reduced circulating epinephrine by ∼50%, lowered plasma glucose levels, and attenuated lactate accumulation, resulting in a smaller decline in blood pH. Immune cell mobilization was selectively impaired, with reduced recruitment of lymphocytes, CD8+ T cells, CD56ˆbright natural killer (NK) cells, monocytes, neutrophils, and dendritic cells, while CD4+ T cells, CD56ˆdim NK cells, and B cells were unaffected. Although upstream hypothalamic-pituitary-adrenal (HPA)-axis hormones corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) were unchanged, adrenocorticotropic hormone (ACTH) was significantly reduced and associated with pH and catecholamine responses in the control condition. A lower lactate-to-pyruvate ratio during IL-6R blockade suggests enhanced pyruvate oxidation as a potential upstream mechanism. These findings position IL-6 as an integrative metabolic signal that mediates organ crosstalk and amplifies the HPA and sympathoadrenal response during high-intensity exercise. By linking skeletal muscle metabolic stress to endocrine activation, glucose regulation, and immune cell mobilization, IL-6 appears to coordinate the complex systemic fight-or-flight response to intense physical exertion.

Adenoma receptors and histologic characteristics determining management outcomes.

J Clin Endocrinol Metab

Luiz Eduardo Wildemberg, Mônica R Gadelha

Patient responses to medical therapy for acromegaly are variable. Adenoma features, including histologic characteristics and receptor density, are closely associated with distinct clinical behavior and therapeutic outcomes. Densely granulated pure somatotropinomas respond more favorably to somatostatin receptor subtype 2 (SST2)-selective ligands (octreotide and lanreotide) compared with sparsely granulated adenomas. In contrast, sparsely granulated adenomas may respond more favorably to pasireotide, which has a higher affinity for somatostatin receptor subtype 5 (SST5). Expression levels of SST2 receptors are also associated with responsiveness to octreotide and lanreotide, whereas response to pasireotide is linked to higher SST5 expression. Recent prospective studies have highlighted that treatment strategies guided by biomarkers determining therapeutic response are more effective than standard, non-biomarker-based approaches. Current evidence supports the incorporation of biomarkers into decision-making for medical management of acromegaly, while these approaches are being further validated.

Left atrial stiffness, exercise intolerance and injury biomarkers predict adverse outcomes in patients with heart failure with preserved ejection fraction.

NPJ Cardiovasc Health

Navazh Jalaludeen, Faye Forsyth, Jamie O'Driscoll +9 more

Heart failure with preserved ejection fraction (HFpEF) is a complex condition associated with high morbidity and mortality. This exploratory study aimed to assess the prognostic value of left atrial (LA) stiffness, exercise tolerance, and selected biomarkers in patients with HFpEF. We evaluated LA mechanics using 2D speckle tracking in 43 patients (mean age: 77.2 years) from the OPTIMISE HFpEF study (NCT03617848). Biomarkers such as N-terminal pro-brain-type natriuretic peptide, growth differentiation factor 15, and galectin-3 were measured. Patients also completed a six-minute walk test. Over a mean follow-up of 24.5 months, there were five deaths (11.4%) and 21 all-cause hospitalisations (48.8%). LA stiffness (HR: 1.81; p = 0.028) and N-terminal pro-brain-type natriuretic peptide (HR: 1.01; p = 0.013) were independent mortality predictors. For hospitalisations, six-minute walk distance (HR: 0.99; p = 0.011) and growth differentiation factor 15 (HR: 1.01; p = 0.007) were significant independent predictors. This exploratory analysis indicates that LA stiffness, N-terminal pro-brain-type natriuretic peptide, exercise intolerance, and growth differentiation factor 15 independently predict adverse events in HFpEF. Implementing a comprehensive therapeutic approach, including lifestyle modifications, medical therapy, and, if necessary, more advanced interventions to improve LA mechanics, functional capacity, and clinical biomarkers, may improve outcomes for HFpEF patients.

Serum withdrawal establishes a stress-dominant entry state during myogenic differentiation.

Front Cell Dev Biol

Zongnan Lyu, Chunxue Shao, Renyu Yang +4 more

Skeletal myogenesis in C2C12 cultures is typically induced by switching confluent cells from high-serum growth medium to low-serum differentiation medium. Because serum withdrawal is itself an acute physiological perturbation, early post-switch transcriptional changes may reflect varying mixtures of lineage progression and stress adaptation.

Correction: Renalase knockdown inhibits proliferation of mouse satellite cells.

Mol Biol Rep

Yuri Kato, Katsuyuki Tokinoya, Kai Aoki +1 more

Functional characterization of HR-CATH2, a novel cathelicidin from Hoplobatrachus rugulosus with anti-sepsis activity.

Zool Res

Hang Liao, Shian Lai, Kai Wang +9 more

Cathelicidins are central effectors of innate host immunity against invading microorganisms and represent a promising source of next-generation anti-infective agents. However, current understanding of both antimicrobial activity and immunomodulatory function within this peptide family remains incomplete. In the present study, a novel cathelicidin peptide, designated HR-CATH2, was identified from the skin of the Chinese tiger frog ( Hoplobatrachus rugulosus). The peptide consisted of 30 amino acid residues (GRCNLLCKAKKKLRAVGNKIKEIKNVVFNR) and adopted a highly amphipathic α-helical structure. Functional analyses indicated that HR-CATH2 exerted potent antimicrobial activity through induction of intracellular reactive oxygen species (ROS) accumulation and direct disruption of bacterial membrane integrity. Moreover, HR-CATH2 inhibited overproduction of proinflammatory cytokines (interleukin-6, interleukin-1β, and tumor necrosis factor-α) and nitric oxide (NO) in RAW264.7 cells through lipopolysaccharide (LPS) binding and consequent inactivation of MAPK signaling. In vivo, HR-CATH2 markedly attenuated the acute inflammatory response and reduced mortality in mice subjected to cecal ligation and puncture (CLP)-induced sepsis. Together, these findings identify HR-CATH2 as a multifunctional cathelicidin with antibacterial, LPS-neutralizing, and anti-inflammatory activities, and support its potential as a therapeutic candidate for bacterial infectious diseases, including sepsis.

Patient Experiences With GLP-1 Receptor Agonists.

JAMA Netw Open

Isabella de Vere Hunt, Mariana Ramirez-Posada, Christopher Sam Babu +3 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are transformational therapies in the treatment of obesity; yet discontinuation rates are high, and patients experience rapid weight regain after stopping treatment. Few scientific publications have reported patients' experiences of taking GLP-1 RAs in a variety of health contexts outside its use as treatment for type 2 diabetes.

Risk Factors for Hypoglycemia in Type 2 Diabetes Mellitus Patients Using Once-Weekly Semaglutide: A Matched Case-Control Study.

Ther Clin Risk Manag

Palanisamy Amirthalingam, Fawaz Ahmed Alarawi, Loay Mohammed Jassas Alagwar +11 more

The semaglutide once-weekly injection (Sema-OWI) is widely accepted for managing type-2 diabetes mellitus (T2DM) patients, particularly those seeking weight loss. However, hypoglycemia is continually challenging healthcare practitioners, and the underlying factors have yet to be conclusively reported. The study aimed to investigate the underlying characteristics of T2DM patients undergoing sema-OWI treatment.

MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia.

Front Med (Lausanne)

Nicholas A Jamnick, Patrick D Livingston, Caleb J Gammon +3 more

Cancer cachexia is a multifactorial metabolic syndrome marked by progressive skeletal muscle loss, reduced function, and increased mortality. Mitochondrial dysfunction is a key driver of this phenotype. MOTS-c, a mitochondrial-derived peptide that regulates metabolic homeostasis and mimics exercise signaling, may counteract cachexia, but its role remains largely unexplored, and human studies using MOTS-c in subjects with cancer cachexia are needed.

Genotype Predicts Heart Failure Independent of LVEF, Peak VO2, and NT-proBNP Levels in Hypertrophic Cardiomyopathy.

JACC Heart Fail

Athanasios Bakalakos, Alexandros Protonotarios, Menelaos Pavlou +11 more

Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by left ventricular hypertrophy and progression to heart failure (HF). Approximately 40% of cases are caused by variants in genes encoding sarcomere proteins.

Effects of Total Flavonoids From Rubus chingii Hu on the Hypothalamic-Pituitary-Ovarian Axis and Inflammatory Response in Polycystic Ovary Syndrome Rats.

Food Sci Nutr

Mengfan Peng, Baosong Liu, Lanyue Cao +5 more

Polycystic ovary syndrome (PCOS) is a common reproductive disorder in women of childbearing age, posing serious risks to both physical and mental health. Dysregulation of the hypothalamic-pituitary-ovarian (HPO) axis and inflammatory responses are key pathological mechanisms, yet there are currently no specific therapeutic drugs available. Therefore, this study investigates the ameliorative effects of total flavonoids from Rubus chingii Hu (RHF) on HPO axis function and inflammatory response in a rat model of PCOS induced by letrozole. The results demonstrated that RHF restored the disrupted estrous cycle in PCOS rats. It significantly reduced ovarian weight, index, length, width, area, and volume. Moreover, RHF treatment decreased the ovarian mRNA levels of BCL-2-associated X protein (Bax) and aspartate specific cysteine protease (Caspase)-3 while increasing that of B-cell lymphoma-2 (Bcl-2), collectively ameliorating ovarian pathological changes. Concurrently, RHF significantly lowered serum levels of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and testosterone (T), while elevating follicle-stimulating hormone (FSH), estradiol (E2), and sex hormone-binding globulin (SHBG), indicating its potential to mitigate hypothalamic-pituitary-ovarian (HPO) axis dysfunction. Furthermore, RHF reduced peripheral blood counts of white blood cells (WBC), platelets (PLT), red blood cell distribution width (RDW), the neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), and platelet-to-lymphocyte (PLR) ratios, as well as serum interleukin-18 (IL-18), IL-1β, tumor necrosis factor-α (TNF-α), and IL-6. In ovarian tissue, RHF downregulated the protein and mRNA expression of NLRP3, caspase-1, the N-terminal fragment of gasdermin D (GSDMD-NT), IL-18, and IL-1β, and lowered the mRNA levels of IL-6 and TNF-α, thereby attenuating both systemic and local ovarian inflammatory responses. Taken together, these findings demonstrate that RHF confers protective effects in PCOS rats, which are associated with the amelioration of HPO axis function and suppression of inflammatory responses.

LncRNA IRAIN inhibits mantle cell lymphoma progression by inducing cell cycle arrest and apoptosis: an in vitro study.

Sci Rep

Ping Lin, Yiping Zhang, Liling Lu +2 more

Long non-coding RNA (lncRNA) insulin-like growth factor 1 receptor antisense imprinted non-protein coding RNA (IRAIN) and lysine-specific demethylase 1 (LSD1) are aberrantly expressed in various malignancies. However, their roles in the progression of mantle cell lymphoma (MCL) remain unclear. This study aimed to investigate the expression pattern and biological role of IRAIN in MCL progression and to further explore the relationship between IRAIN and LSD1. In this study, the expression levels of IRAIN and LSD1 in MCL cells were detected by RT-qPCR. An IRAIN-overexpressing lentiviral vector (LV-IRAIN-up) was constructed and transduced into MCL cells, and the transduction efficiency was verified by flow cytometry (FACS) and RT-qPCR. The effects of IRAIN overexpression on cell viability, apoptosis, and cell cycle progression were evaluated using CCK-8 assays and FACS analysis. In addition, RT-qPCR and Western blot analyses were performed to determine the regulatory effects of IRAIN overexpression on LSD1 expression, apoptosis-related proteins (including Bax, Bcl-2, pro-caspase-3, and cleaved-caspase-3), and cell cycle-related proteins (Cyclin D1, CDK2, and p21). Furthermore, LSD1 was overexpressed in IRAIN-overexpressing MCL cells to investigate its effects on cell proliferation, apoptosis, and cell cycle progression. The results demonstrated that IRAIN expression was significantly downregulated, whereas LSD1 expression was markedly upregulated in MCL cells. IRAIN overexpression significantly inhibited cell viability, promoted apoptosis, and induced G1-phase cell cycle arrest. Meanwhile, IRAIN overexpression markedly downregulated the expression of LSD1, Bcl-2, pro-caspase-3/cleaved-caspase-3, Cyclin D1, and CDK2, while upregulating the expression of Bax and p21. Further experiments showed that LSD1 overexpression partially reversed the inhibitory effects of IRAIN overexpression on MCL cell proliferation, apoptosis induction, and G1-phase arrest. Collectively, these findings suggest that IRAIN may participate in the regulation of proliferation, apoptosis, and cell cycle progression in MCL cells, potentially through modulation of LSD1. These results provide preliminary experimental evidence for further understanding the potential biological function of IRAIN in MCL.