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Comparative network pharmacology analysis of ketamine and xanomeline in major depressive disorder: Shared and distinct molecular mechanisms.
Prog Neuropsychopharmacol Biol Psychiatry
Xin Ding, Kenji Hashimoto, Jian-Jun Yang
Major depressive disorder (MDD) is a leading cause of disability worldwide, and currently available antidepressants remain limited by delayed onset of action, incomplete response, and adverse effects. Ketamine is a rapid-acting antidepressant, whereas xanomeline, an M1/M4 muscarinic receptor agonist, may represent a mechanistically distinct non-monoaminergic strategy. However, the molecular basis by which xanomeline may influence depression-related pathways, and its relationship to ketamine, remain unclear. We used network pharmacology and molecular docking to compare the shared and distinct molecular mechanisms of xanomeline and ketamine in MDD. Potential drug targets were collected from public databases and intersected with MDD-related targets. Protein-protein interaction analysis was performed to identify hub genes, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Drug-pathway-target-disease networks were constructed, and shared core targets were further evaluated by molecular docking. We identified 368 overlapping targets for xanomeline-MDD and 714 for ketamine-MDD. Three KEGG pathways were shared between the two networks: EGFR tyrosine kinase inhibitor resistance, Ras signaling, and Rap1 signaling. EGFR, insulin-like growth factor 1 receptor (IGF1R), and SRC proto-oncogene, non-receptor tyrosine kinase, emerged as common core targets. Xanomeline was more strongly associated with receptor tyrosine kinase and PI3K/AKT-related signaling, whereas ketamine was more strongly linked to synaptic transmission, NMDA receptor-related functions, and glutamatergic signaling. Molecular docking supported structurally plausible binding of both drugs to EGFR, IGF1R, and SRC. These findings suggest partial convergence on downstream plasticity-related signaling nodes despite distinct upstream mechanisms and warrant further experimental investigation. However, the results should be interpreted as hypothesis-generating rather than as evidence of shared functional target engagement.
Host antimicrobial peptide LL-37 inhibits CovS kinase activity and antagonizes CovR-Mediated activation in group A Streptococcus.
Biochem Biophys Res Commun
Lian Wu, Lina Wang, Shurong Chen +5 more
The pathogenicity of Group A Streptococcus (GAS) is tightly regulated by the CovRS two-component system; however, the nature of the direct interaction between CovR and CovS, and how host signals modulate this system, remain poorly understood. Using surface plasmon resonance (SPR), we confirmed that CovR binds CovS with high affinity. Functional assays further demonstrated that CovR enhances the activation of CovS. The host-derived antimicrobial peptide LL-37 directly interacts with CovS and inhibits its kinase activity. Moreover, LL-37 antagonizes CovR-mediated activation of CovS in a dose-dependent manner. Together, these in vitro findings elucidate a molecular mechanism by which a host antimicrobial peptide modulates a key bacterial virulence regulator. They provide a mechanistic framework for understanding host-pathogen signaling interplay and highlight the CovR-CovS interface as a potential target for future anti-virulence strategies against GAS.
Semaglutide and Cardiovascular Outcomes in People with Type 2 Diabetes: A SUSTAIN-6 Post Hoc Analysis by Weight Loss Category.
Diabetes Ther
Angelo Navas, Joshua Noone, Nathan Laney +5 more
Type 2 diabetes (T2D) is a known risk factor for cardiovascular (CV) disease. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, improve glycemic control and are associated with weight loss, but the impact of weight loss on major adverse cardiovascular events (MACE) when taking semaglutide is not fully understood. This post hoc analysis of the SUSTAIN-6 trial aimed to examine the correlation between weight loss with semaglutide and the occurrence of MACE (nonfatal myocardial infarction, nonfatal ischemic stroke, and CV death).
Dual-system engineered bacteria and dendritic cells enable precise intratumoral IL-12 delivery and potent antitumor immunity.
Cell Rep Med
Yuan Deng, Heng Liang, Arabella H Wan +17 more
Interleukin-12 (IL-12) potently stimulates antitumor immunity, but its clinical use is limited by systemic toxicity and poor spatial control. Here, we develop a dual-engineered delivery system that combines Escherichia coli Nissle 1917 (EcN) programmed for hypoxia- and quorum-sensing-regulated IL-12 expression with engineered dendritic cells (eDCs) that facilitate bacterial delivery and immune support. In murine colorectal cancer and liver metastasis models, eDC-EcN-IL12-QS preferentially localizes to tumors, increases intratumoral IL-12 and IFN- γ levels, enhances dendritic cell activation and CD8+ T cell infiltration, and suppresses tumor growth and metastatic burden. The system also prolongs survival and remains controllable by antibiotic-mediated clearance. These findings support a programmable microbial-cellular strategy for localized cytokine delivery and immune activation in immunologically cold tumors.
FMO1 disrupts mitochondrial functional homeostasis through ROS-mediated mechanisms to drive chondrocyte senescence and hypertrophy.
Free Radic Biol Med
Ruohui Tang, Debin Guo, Shidan Li +6 more
The induced membrane technique is a clinical strategy for managing large bone defects, which relies on endochondral ossification. However, the metabolic mechanisms regulating this process remain largely uncharacterized. We utilized scRNA-seq to analyze chondro-osseous dynamics during membrane-induced osteogenesis, with a specific focus on the role of FMO1.
Cryo-EM structure of the human Mas receptor reveals N-terminal occlusion of the orthosteric ligand binding pocket.
J Mol Biol
Shota Suzuki, Kotaro Tanaka, Kouki Nishikawa +1 more
The Mas receptor (MasR) is a class A G protein-coupled receptor (GPCR) that mediates the counter-regulatory arm of the renin-angiotensin system through the ACE2-angiotensin-(1-7)-MasR axis and represents a promising therapeutic target for cardiovascular and metabolic disease. Despite its physiological importance, the structural basis of MasR has remained unknown. Here we report cryo-EM structures of human MasR in complex with heterotrimeric Gq at resolutions of 2.9 Å and 3.1 Å, determined for the full-length receptor and an N-terminally truncated variant (del2-25), respectively. These structures reveal that the receptor's own N-terminal peptide (residues 2-11) threads into and occludes the orthosteric binding pocket, functioning as an endogenous pseudo ligand. Functional mutagenesis and molecular dynamics simulations demonstrate that this N-terminal cap stably occupies the pocket but is dispensable for constitutive Gq coupling, distinguishing MasR from other N-terminal cap-forming GPCRs. Structural comparison with Mrgpr family members reveals a conserved Gq-coupling interface at the cytoplasmic face alongside divergent extracellular pocket architectures and identifies Y2526.59 as a structural element that occludes a conserved sub-pocket present in Mrgpr paralogs. Molecular docking simulation of the MasR agonist AR234960 provides a structural template for orthosteric ligand design. Together, these findings establish the structural framework for MasR.
Incretin-Based Anti-obesity Medications in Polycystic Ovary Syndrome: The Evidence Map.
Drugs
Mojca Jensterle, Andrej Janez
Polycystic ovary syndrome (PCOS) is a common, heterogeneous condition that is tightly linked to obesity, visceral adiposity and insulin resistance. Lifestyle intervention and off-label use of metformin provide only modest and unsustained weight loss, insufficient to reverse obesity-driven pathophysiology in most women with PCOS and obesity. Incretin-based anti-obesity medications, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists (dual GIP/GLP-1RAs), offer a biologically plausible way to target adipose dysfunction, hyperinsulinemia and chronic inflammation that drive PCOS in a large subset of patients. In this narrative, product-segmented review, we map the evidence for liraglutide, semaglutide and tirzepatide in PCOS across mechanistic, clinical, and safety domains, and highlight key evidence gaps that limit current practice. Liraglutide has the densest PCOS-specific evidence, demonstrating reproducible weight loss across small and heterogeneous cohorts, reductions in visceral adiposity and hepatic fat, improved glycemia and inflammatory markers, and early signals for androgen and fertility benefits in selected phenotypes. Semaglutide data remain sparse but conceptually rich, demonstrating weight-loss efficacy and mechanistic insights, alongside preliminary signals of increased likelihood of natural conception. Tirzepatide currently has no PCOS-specific evidence and cannot be recommended beyond extrapolation from obesity and diabetes trials. Across all agents, reproductive outcomes, periconceptional and pregnancy safety, adolescent use, long-term cardiovascular-kidney-metabolic trajectories, obstructive sleep apnea, musculoskeletal health and phenotype-stratified response remain major evidence gaps. We propose a multidimensional, metabolic high-risk PCOS phenotype as the most rational current target for incretin therapy, while emphasizing that well-designed, PCOS-specific trials are essential before these drugs can be viewed as PCOS-modifying therapies rather than powerful, but still adjunctive, weight-loss agents.
Pharmacological blockade of CRHR1 prevents early-onset puberty and enhanced anxiety-like behavior induced by early-life adversity in female Sprague Dawley rats.
Horm Behav
Angarika Balakrishnan, Sheta Roy, Vivian Lin +2 more
Pubertal development is regulated by hypothalamic neuroendocrine signaling and is sensitive to interactions between stress- and reproductive-related pathways. In particular, corticotropin-releasing hormone (CRH) signaling via corticotropin-releasing hormone receptor 1 (CRHR1) represents a key point of crosstalk between stress and pubertal maturation. Early-life adversity, such as the maternal separation (MS) model in rodents, has been shown to increase CRH expression and therefore has the potential to dysregulate CRHR1 signaling. We previously reported that MS-exposed female rats display early pubertal onset, with heightened anxiety-like behavior that was correlated with pubertal timing. The current study examined whether CRHR1 dysregulation mediates the effects of MS on both pubertal timing and anxiety-like behavior, as assessed by the acoustic startle response (ASR), in female rats. CRHR1 signaling was pharmacologically manipulated using the CRHR1 antagonist antalarmin during MS exposure. Pubertal development and ASR were assessed, as well as pre-pubertal hypothalamic CRHR1 expression. Protein quantification of pre-pubertal hypothalamic cell membrane and cytoplasmic fractions revealed that MS increases CRHR1 internalization in the arcuate nucleus and in the anterior hypothalamus following MS. As expected, MS significantly advanced pubertal timing; however, accelerated puberty was normalized by treatment with antalarmin during MS. Treatment with a high dose of antalarmin, however, delayed puberty in both MS and control animals. MS also increased ASR in adolescent females, which was prevented by antalarmin treatment during MS. Additionally, antalarmin decreased cFos activity in the basolateral amygdala (BLA) and bed nucleus of stria terminalis (BNST). Together, these findings support a potential model in which altered CRHR1 signaling during negative early environments disrupts HPA-HPG axis crosstalk, triggering early onset of puberty and increased anxiety-like behavior in female rats. Targeting CRHR1 signaling during sensitive developmental windows may provide a therapeutic avenue for mitigating these long-term impacts of early life stress.
Comparative efficacy of phase 2-3 therapies for non-cirrhotic metabolic dysfunction-associated steatohepatitis: An updated network meta-analysis.
Med
Tsubasa Tsutsumi, Nicole Shu Ying Tang, Cheng Han Ng +26 more
Metabolic-dysfunction-associated steatohepatitis has a rapidly expanding phase 2-3 drug pipeline, yet comparative evidence across mechanisms remains limited, and most trials are placebo controlled.
Real-world Impact of GLP-1 Receptor Agonists on Health-related Quality of Life in Type 2 Diabetes and Obesity (SEVERAL Study).
Clin Ther
José Seijas-Amigo, Ángel Salgado-Barreira, Carlota Roca-Martinez +20 more
To evaluate the real-world impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on health-related quality of life (HRQoL) and metabolic outcomes in adults with type 2 diabetes and obesity.
Serial Assessment of NT-proBNP and High-Sensitivity Cardiac Troponin with Glucagon-Like Peptide-1 Receptor Agonist Therapy in Type 2 Diabetes: Insights from EXSCEL.
Am Heart J
Veraprapas Kittipibul, Maggie Nguyen, Paul Welsh +6 more
In the EXSCEL trial, exenatide did not reduce major adverse cardiovascular events (MACE), but heterogeneity of benefit and the role of cardiac biomarkers remain uncertain. We evaluated the prognostic value of baseline and 1-year changes in N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (cTnI), and whether baseline biomarker concentrations modified exenatide effects.
Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Outcomes in Patients With Atherosclerotic Cardiovascular Disease and Obesity Without Diabetes.
Am J Cardiol
Usman Ali Akbar, Avilash Mondal, Mounica Vorla +7 more
The Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) trial demonstrated cardiovascular benefits of semaglutide in patients with obesity without diabetes; however, the real-world effect across multiple GLP-1 receptor agonist (GLP-1 RA) agents in patients with established atherosclerotic cardiovascular disease (ASCVD) and overweight or obesity without diabetes mellitus remains unknown. We conducted a target trial emulation using data from the TriNetX US Collaborative Network (January 1, 2010-December 1, 2025) in adults aged ≥45 years with established ASCVD (history of myocardial infarction, stroke, or coronary or peripheral revascularization), BMI ≥27 kg/m², and without type 2 diabetes. New initiation of any GLP-1 RA (liraglutide, semaglutide, dulaglutide, or exenatide) was compared with no GLP-1 RA use. The primary outcome was all-cause mortality; secondary outcomes were acute myocardial infarction, stroke, and heart failure hospitalization over 5 years, analyzed using Cox proportional hazards and Fine-Gray subdistribution hazard models to account for the competing risk of death. Among 14,844 propensity-matched patients without diabetes (7,422 per group; median age 63 [IQR 55-71] years; 64% women), GLP-1 RA use was associated with lower all-cause mortality (HR 0.68; 95% CI 0.53-0.88; P=.003), acute myocardial infarction (sHR 0.63; 95% CI 0.41-0.98; P=.040), and heart failure hospitalization (sHR 0.61; 95% CI 0.39-0.95; P=.028); no significant association was observed for stroke (sHR 0.76; 95% CI 0.52-1.10; P=.146). Findings were consistent in landmark and age subgroup analyses; a sensitivity analysis including patients with diabetes (N=31,910 matched pairs) showed similar associations. In conclusion, these real-world findings are broadly directionally consistent with the SELECT trial and provide complementary observational evidence across multiple GLP-1 RA agents in patients with established ASCVD and overweight or obesity without diabetes mellitus, though causal inference cannot be established from observational data alone.
Trehalase-trehalose axis in the human brain: A potential modulator of neuroprotection and neurodegeneration.
Neurobiol Aging
Kalle Keisu, Arttu Autio-Kimura, Johanna Mappes +1 more
Trehalase, the primary enzyme responsible for the degradation of gastrointestinal trehalose ("mushroom sugar"), is well-characterised in the human gut, but has not been conclusively identified in the human brain. Trehalose itself has shown promise in neuroprotection through diverse molecular mechanisms, including the autophagy-driven clearance of cellular debris and neurotoxic aggregates. However, the mechanisms activating trehalose and its integration into human central nervous system processes remain elusive. To investigate the modulatory role of trehalase in the trehalose-mediated neuroprotection, we analysed two independent RNA-seq datasets derived from post-mortem human brain tissue. Hypothesis testing of age- and multiple sclerosis-associated changes in trehalase gene expression revealed significant decrease in both aged donors and patients with multiple sclerosis compared to controls. Differential gene correlation analysis combined with pathway enrichment showed that trehalase-associated gene networks shift according to bimodal age segmentation, implicating pathways related to autophagy, mitophagy, oxidative phosphorylation, and neurodegeneration. Moreover, trehalase expression correlated positively with oligodendrocyte proportions in many brain regions and negatively with neuronal proportions in the hippocampus, suggesting cell-type-specificity. A robust positive association with sirtuin 1 expression further links trehalase to established neuroprotection. These results provide the first direct evidence of trehalase expression in the human brain and suggest that the trehalase-trehalose axis may function as a mediator of cellular homeostasis and neuroprotection in neurons and glia. Our results position trehalase as a candidate biomarker and modulator of trehalose-linked pathways in ageing and neurodegeneration, warranting future studies integrating both trehalase and trehalose profiling in paired samples.
Mortality and clinical outcomes in patients with mild autonomous cortisol secretion: Adrenalectomy versus nonoperative management.
Surgery
Niranjna Swaminathan, Zhixing Song, Peter Abraham +4 more
Mild autonomous cortisol secretion (MACS) is the most common hormonal abnormality in adrenal incidentalomas, but the benefits of adrenalectomy remain unclear.
Endogenous TRPV1 agonist OLDA prevents mu-opioid receptor desensitization and preserves analgesia in sensitized nociceptive circuits.
Neuropharmacology
Mario Heles, Daniel Vasconcelos, Jiri Palecek
Opioid analgesics acting primarily through the μ-opioid receptor (MOR) are profoundly limited by receptor desensitization, tolerance and opioid-induced hyperalgesia. Recent work has identified functional crosstalk between MOR and the transient receptor potential vanilloid 1 (TRPV1) channel, whereby TRPV1 activation can suppress β-arrestin-dependent MOR desensitization. Whether endogenous TRPV1 ligands contribute to this regulation in intact nociceptive circuits has remained unknown. Here we show that N-oleoyldopamine (OLDA), an endogenous vanilloid, preserves MOR signaling and opioid analgesia by preventing MOR desensitization in the spinal cord. Using electrophysiological recordings from rat spinal cord dorsal horn neurons, we demonstrate that prolonged exposure to the MOR agonist DAMGO induces robust functional desensitization, abolishing opioid-mediated inhibition of synaptic transmission. Co-incubation with OLDA prevents this desensitization in a concentration-dependent manner, maintaining DAMGO efficacy without altering basal synaptic activity. Under neuropathic conditions induced by chronic constriction injury, low concentrations of OLDA that are ineffective in naïve tissue become sufficient to preserve MOR responsiveness, consistent with enhanced TRPV1 sensitization after nerve injury. In vivo, intrathecal OLDA restores opioid-evoked thermal and mechanical hypoalgesia in a chemokine-induced MOR desensitization model. Together, these findings identify OLDA as an endogenous regulator of TRPV1-MOR crosstalk that selectively preserves opioid signaling in sensitized nociceptive circuits. Our results extend recent mechanistic insights into TRPV1-dependent control of β-arrestin pathways and reveal an intrinsic modulatory system that may be harnessed to improve the durability and safety of opioid analgesia in chronic pain.
Impacts of genetic selection on satellite cell function in poultry.
Front Physiol
Joseph Yimiletey, Sandra G Velleman, Hui Yu
Over the past several decades, intensive genetic selection has markedly increased growth rate, breast muscle yield, and production efficiency in commercial broilers. These gains have been accompanied by substantial changes in muscle organization, physiology, metabolism, and cellular regulation. Satellite cells, the resident muscle stem cells, play a key role in posthatch muscle growth by supplying nuclei to adjacent growing myofibers, thereby supporting the muscle hypertrophy process. This review summarizes the role of satellite cells in poultry muscle development and discusses how genetic selection for rapid muscle growth has reshaped satellite cell proliferation, differentiation, molecular profiles, and functional heterogeneity, with important consequences for muscle growth and quality. Moreover, increasing evidence suggests that changes in satellite cell function associated with genetic selection may contribute to the development of breast muscle myopathies, particularly wooden breast in broiler chickens. Moving forward, continued refinement of poultry production systems will benefit from deeper insights into satellite cell biology to support efficient muscle growth while reducing the occurrence of muscle myopathies.
Exploring Weight Loss Medication Discourse: Mixed Methods Analysis of US-Based Facebook Posts.
JMIR Infodemiology
Elizabeth Dennard, Katrina Makres, Amrutha Alibilli +9 more
Despite the documented clinical efficacy of weight loss medications, few large-scale mixed methods studies have captured the experiences of individuals taking these medications.
Semaglutide 2.4 mg for Obese Patients with MASH: A Cost-Effectiveness Analysis from the Italian NHS Perspective.
Clinicoecon Outcomes Res
Enrico Torre, Sergio Di Matteo, Chiara Martinotti +7 more
Metabolic dysfunction-associated liver disease (MASLD) and its progression to steatohepatitis (MASH) are highly prevalent among obese patients, contributing substantially to healthcare costs. Semaglutide, a GLP-1 receptor agonist, has shown metabolic and hepatic benefits in this population. This study assessed the cost-effectiveness of Wegovy® (semaglutide 2.4 mg) versus no pharmacological treatment in obese patients with MASH ≤F3 without diabetes, from the perspective of the Italian National Health Service (NHS).
Semaglutide-associated Twiddler syndrome.
JCEM Case Rep
Thomas Seiler, Fabian Noti, Markus Laimer +2 more
52-year-old woman with cardiac sarcoidosis and a dual-chamber implantable cardioverter defibrillator (ICD) was treated with semaglutide for refractory obesity (body mass index (BMI) of 40.1 (kg/m2)). After rapid weight loss of 25 kg, she developed painful device mobility and right ventricular lead dysfunction. Chest x-ray revealed lead entanglement consistent with Twiddler syndrome, which is a mechanical complication in which a pacemaker or ICD rotates within its pocket, causing the leads to twist or dislodge and resulting in device malfunction. Lead extraction was complicated by cardiac tamponade. After recovery, she underwent successful reimplantation of a single-chamber ICD. Patients with cardiac implantable electronic devices who are treated with glucacon-like-peptide-1 receptor agonists may have an increased risk of Twiddler syndrome, as substantial weight loss can increase generator mobility in the subcutaneous pocket. Clinicians should recognize this rare but potentially life-threatening complication.
Pharmacological therapy in the obese patient: is it only a matter of fat loss?
Eur Heart J Suppl
Claudio Borghi, Alessio Bragagni
Obesity is a chronic, multifactorial condition strongly associated with increased cardiovascular and metabolic risk, as well as the development of systemic complications. Recent evidence from randomized controlled trials-including SELECT, STEP-HFpEF, STEP-HFpEF DM, SUMMIT, and SURMOUNT-5-has demonstrated the effectiveness of glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonists in the treatment of obesity, with clinical benefits that appear to extend beyond weight reduction alone. In addition to substantial reductions in fat mass, these agents improve cardiovascular parameters (including reductions in major adverse cardiovascular events), functional capacity, and quality of life. Additional benefits have been observed at the metabolic level, with reductions in glycated haemoglobin, blood pressure, triglycerides, and systemic inflammatory markers such as high-sensitivity C-reactive protein. These results confirm that pharmacological modulation of the incretin axis should not be viewed merely as an adjunctive strategy for weight loss, but rather as an integrated therapeutic intervention capable of modifying overall cardiovascular risk and improving the inflammatory and metabolic profile of the obese patient. In light of these findings, a re-evaluation of the role of pharmacological therapy in the clinical management paradigm of obesity is warranted.