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Endothelial insulin-like growth factor 1 receptor-targeted vessel normalization potentiates neuroendocrine cancer immunotherapy.

Trends Pharmacol Sci

Weici Laurence Liu, Wenjun Mao

Angiogenesis fuels cancer progression, yet its immunomodulatory role in neuroendocrine malignancies remains poorly understood. Recently, Wang et al. identified a blood-brain barrier-like vascular gate that mediates immune exclusion and immunotherapy resistance in small-cell lung cancer. Targeting this barrier with OSI-906 enhances CD8+ T-cell infiltration and immunotherapy efficacy.

Therapeutic Potential of Incretin-Based Therapies for Alcohol Use Disorder - A narrative review of available clinical evidence.

Biol Psychiatry

Mette Kruse Klausen, Anders Fink-Jensen

Alcohol use disorder (AUD) remains a major global health burden, yet pharmacological treatment options are limited, and an urgent need for novel molecular targets for the treatment of AUD exists. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been used for more than two decades to treat type 2 diabetes and, subsequently, overweight and obesity. Unexpected effects, including reduced alcohol intake, have been reported by patients as well as by clinicians and these - often anecdotal - reports have been supported by a growing body of data from large registry studies, target trial emulation analyses, preclinical experiments in mice, rats, and non-human primates, and randomized clinical trials, associating the use of GLP-1RAs with reduced alcohol consumption. This convergence has sparked growing interest in GLP-1RAs as a novel therapeutic strategy for AUD. In this narrative review, we synthesize current evidence on the effects of GLP-1RAs in individuals with AUD. To date, only three randomized controlled trials have examined GLP-1RAs in AUD, showing reductions in alcohol cue brain reactivity and alcohol consumption, particularly among individuals with overweight or obesity. We will also report on observational data, including large registry studies, target trial emulation analyses, and real-world data, which consistently associate GLP-1RA use with reduced alcohol consumption. Case reports and social media analyses further corroborate reductions in alcohol craving and consumption. Mechanistically, emerging evidence points to modulation of reward circuitry, incentive salience, gastric emptying, and metabolic signaling. Overall, GLP-1RAs represent a promising and mechanistically novel approach to AUD treatment, warranting confirmation in larger, long-term randomized trials.

A comparative evaluation of multiple enlarged perivascular space segmentation tools.

Magn Reson Imaging

James D LeFevre, W Hudson Robb, Dandan Liu +8 more

Enlarged perivascular spaces (ePVS) are a marker of cerebral small vessel disease, potentially reflecting reduced waste clearance. Because manual quantification is unfeasible in large datasets, we developed and evaluated an automated tool.

Implications of Generic Semaglutide Availability on the Cost-Effectiveness of GLP-1RA for Guideline-Indicated Patients With Type 2 Diabetes.

Can J Cardiol

Ethan McNally, Abhinav Sharma, Pedro Marques +3 more

Glucagon-Like Peptide-1 Receptor Agonists in Orthopedics: A Scoping Review of Emerging Applications.

Indian J Orthop

Anil Regmi, Bishwa Bandhu Niraula, Abdus Sami +3 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are currently being utilized extensively to treat obesity and type 2 diabetes. Recent data suggest their broad applications in the field of orthopedics, due to their beneficial effects on bone metabolism, cartilage preservation, and surgical outcomes. The current scoping review attempts to thoroughly assess the role of GLP-1 RAs in orthopedic care by synthesizing the most recent data on their effects on bone health, cartilage preservation, arthroplasty outcomes, and spine surgery.

ACE2/Angiotensin 1-7/Mas Receptor Axis in Thermogenic Adipose Tissue: Age-Related Implications for Pediatric Obesity.

Pediatr Int

Jun Mori

Pediatric obesity is a growing global health challenge, and effective and sustainable therapeutic options remain limited. Although lifestyle modifications remain the cornerstone of treatment, pharmacological and surgical interventions are restricted among pediatric populations, highlighting the need for novel pathophysiology-based strategies. Increasing evidence indicates that the renin-angiotensin system, particularly the nonclassical angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7 (Ang1-7)/Mas receptor (MasR) axis, plays an important role in metabolic regulation beyond classical cardiovascular functions. The ACE2/Ang1-7/MasR axis exerts pleiotropic metabolic effects, including anti-inflammatory and insulin-sensitizing actions, and has emerged as a key regulator of adipose tissue biology. Experimental studies have demonstrated that activation of this pathway stimulates brown adipose tissue (BAT), induces browning of white adipose tissue (WAT), and increases energy expenditure, thereby attenuating diet-induced obesity and attracting considerable attention as potential therapeutic targets. However, accumulating evidence from human imaging studies and experimental models suggests that BAT activity and thermogenic plasticity decline with age, which may affect the metabolic efficacy of interventions targeting thermogenic adipose tissue. Age-related differences in adipose tissue responsiveness may therefore contribute to discrepancies among previous studies examining Ang1-7-mediated thermogenic effects. This review summarized the current evidence regarding the role of the ACE2/Ang1-7/MasR axis in regulating thermogenic adipose tissue, with a focus on BAT activation and WAT browning in obesity. We further discuss age-related considerations that may modulate responsiveness to this pathway. Given that BAT activity is intrinsically high during childhood and adolescence, ACE2/Ang1-7 axis modulation may represent a promising therapeutic strategy for pediatric obesity.

[Effects of electroacupuncture guided by the vessel-collateral theory on short-term ventricular remodeling following STEMI-PCI surgery: a randomized controlled clinical study].

Zhen Ci Yan Jiu

Shuang Wu, Ming-Hui Xia, Hong-Ru Zhang +1 more

Based on the vessel-collateral theory, "qi deficiency and blood stasis leading to collateral obstruction and accumulation", electroacupuncture was delivered in patients with ventricular remodeling after percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI), and the clinical efficacy was evaluated.

Pulmonary congestion assessed by lung ultrasound in stable ambulatory patients with heart failure and preserved ejection fraction in primary care.

Fam Pract

Eva Leceaga-Gaztambide, Mar Domingo, Josep M Manresa +11 more

Heart failure with preserved ejection fraction (HFpEF) accounts for a growing proportion of heart failure cases. Pulmonary congestion, particularly subclinical congestion, is often underestimated by symptoms and physical examination. Lung ultrasound enables detection of extravascular lung water through B-lines, even in early stages, but its role in HFpEF patients managed in primary care remains poorly defined.

Investigation into the efficacy and safety profile of oral small-molecule GLP-1 receptor agonists in type 2 diabetes and obesity: a systematic review and meta-analysis.

Front Endocrinol (Lausanne)

Li Li, Dianpeng Shui, Xiong Zhang +2 more

This meta-analysis aimed to evaluate the efficacy and safety of oral small-molecule glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 2 diabetes (T2D) and obesity.

Systemic and cardiac pathology induced by a clinically relevant USP8 activating mutation.

Dis Model Mech

Tamara González-Costa, Abel Galicia-Martín, Daniel Calle +6 more

Cushing's disease (CD), the most common endogenous Cushing's syndrome, is caused by activating mutations in the ubiquitin-specific protease 8 (USP8) gene. These mutations drive adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas and hypercortisolism. Clinical manifestations include muscle weakness, osteopenia, cataracts and cardiovascular dysfunction. To investigate the pathogenic mechanisms of USP8 gain of function, we generated a conditional transgenic mouse model expressing human USP8 (referred to as hUSP8) carrying the most prevalent activating mutation in CD adenomas (p.S718del). Systemic expression of hUSP8S718del in mice induced diffuse corticotroph hyperplasia of ACTH+ cells, rather than pituitary microadenomas, and did not lead to hypercortisolemia. Despite preservation of the hypothalamic-pituitary-adrenal axis, transgenic mice developed skeletal muscle atrophy, bone abnormalities, corneal keratitis with cataracts and cardiac dysfunction. Notably, myocardial-specific expression of hUSP8S718del recapitulated cardiac defects seen in mice with ubiquitous expression, demonstrating the direct role of USP8 activation in the heart. These findings show that expression of a clinically relevant USP8 gain-of-function mutation in mice recapitulates key features of a USP8-associated syndrome. Our results reveal tissue-specific effects of USP8 beyond pituitary tumorigenesis and identify a direct contribution of USP8 activation to cardiac pathology.

Towards an integrated and proactive management of pulmonary hypertension in systemic sclerosis: a practical approach for early diagnosis and optimal patient management.

Rheumatol Adv Pract

Dilia Giuggioli, Francesco Del Galdo, Michele D'Alto +1 more

Pulmonary arterial hypertension (PAH) is a severe vascular complication of SSc and a leading cause of disease-related mortality. Despite the availability of validated screening tools and treatment recommendations, diagnosis delay and suboptimal therapeutic implementation remain frequent in real-world practice. The 2022 European Society of Cardiology/European Respiratory Society guidelines and 2025 EULAR recommendations advocate systematic annual screening and initial combination therapy with an endothelin receptor antagonist and a phosphodiesterase type 5 inhibitor at PAH diagnosis. In SSc patients already receiving a dual combination, escalation to triple therapy including selexipag, or in selected cases switching to riociguat, should be promptly considered. Given the rapid progression and poorer prognosis of SSc-PAH, follow-up within 3 months of diagnosis is critical. Structured referral networks, implementation of the DETECT algorithm and involvement of a dedicated case manager and/or nurse can further improve timely diagnosis and continuity of care. Optimizing SSc-PAH management requires a proactive, integrated approach that bridges rheumatology and cardiology expertise.

From FLOW to translational positioning in chronic kidney disease: mechanistic complementarity of SGLT2 inhibitors and GLP-1 receptor agonists.

Transl Res

Xue Tian, Xiaoying Ma, Enxue Song +5 more

Chronic kidney disease is a central node of the cardio-kidney-metabolic continuum and carries substantial residual cardiovascular and kidney risk. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have reproducibly reduced kidney disease progression and heart failure risk in CKD outcomes trials, whereas GLP-1RAs have established cardiovascular benefit across cardiometabolic populations. The FLOW trial (Evaluate Renal Function With Semaglutide Once Weekly) established hard kidney-outcome evidence for semaglutide in type 2 diabetes with CKD, although whether this renal benefit represents a broader GLP-1RA class effect remains unresolved. This review synthesizes current evidence through a translational framework centered on mechanistic complementarity rather than simple add-on therapy. SGLT2 inhibitors predominantly provide proximal tubular and hemodynamic offloading, coupled with fasting-mimetic metabolic reprogramming that may improve oxygen-stress balance and cellular housekeeping. GLP-1RAs predominantly support an immune-vascular repair program by dampening sterile inflammation, preserving endothelial integrity, and limiting fibrotic amplification. These pathways appear to converge at mitochondrial homeostasis, autophagy, and barrier stability. We argue that the most useful clinical implication at present is not a fixed prescribing algorithm, but a phenotype-aware way to frame residual risk, sequence future studies, and define mechanistic endpoints for combination strategies across chronic kidney disease phenotypes.

Association between GLP-1 receptor agonists and alcohol-related hospitalisations among adults with alcohol use disorder: multi-target trial emulation study.

BMJ Open

Patricia J Rodriguez, Jay B Lusk, Hemalkumar B Mehta +8 more

To evaluate the association between use of newer glucagon-like peptide-1 receptor agonists (GLP-1 RAs; semaglutide, tirzepatide) and alcohol-related hospitalisations among adults with alcohol use disorder (AUD) and type 2 diabetes (T2D) or obesity.Retrospective cohort study using target trial emulation.

Safety Signals of GLP-1 Receptor Agonists: A Multi-Method Pharmacovigilance Analysis of FAERS (2018-2025) With Sensitivity-Stratified Prioritisation, Notoriety-Bias Assessment, and Cross-Database Validation.

Diabetes Obes Metab

Shiyi Xu

GLP-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes and obesity, but their post-marketing safety profile-particularly psychiatric, vascular, neoplastic and rare ophthalmic events-remains incompletely characterised and is vulnerable to confounding by indication, secondary-suspect attribution and notoriety bias.

The central amygdala gates exogenous glucagon-like peptide 1 signals.

Mol Metab

Miguel Duran, Ningxiang Zeng, Elam J Cutts +4 more

Nuclei within the limbic system like the central amygdala (CeA) play a critical role in mediating fear, motivation, reward, and appetitive behavior. Although previous reports demonstrate the presence of the glucagon-like peptide-1 receptor (GLP-1R) in limbic nuclei, how limbic neurons mediate the actions of systemically administrated GLP-1R agonists is unclear. In this study, we investigated the CeA's response to peripherally administered GLP-1R agonist Exendin-4 (Ex-4) in vivo, and determined the functional requirement of select CeA neuron populations in acute Ex-4 induced hypophagia. Using fiber photometry, we observed that Ex-4 promoted a rapid and lasting activation of CeA neurons that was blocked by pretreatment with the GLP-1R antagonist Exendin-9. We then tested the functional requirement of CeA neuron activation in mediating Ex-4 induced hypophagia of standard grain chow using inhibitory chemogenetics. Chemogenetic inhibition of all CeA neurons significantly suppressed the hypophagic actions of Ex-4. Then using selective mouse Cre-drivers, we found that chemogenetic inhibition of protein kinase c delta (PrkcdCeA) and GLP-1R (Glp1rCeA), but not somatostatin (SstCeA), neurons also attenuates the full hypophagic effect of Ex-4. Having observed that inhibition of Glp1rCeA modestly attenuated Ex-4 induced hypophagia of standard chow, we then tested whether these neurons might mediate Ex-4 suppression of energy-dense, palatable diet. We used intermittent high-fat diet (HFD) access and found that inhibition of Glp1rCeA neurons significantly rescued the reduction of HFD consumption by Ex-4. Collectively, these data demonstrate that the CeA responds to peripherally administered GLP-1R agonists and that multiple CeA neuron populations are required for the complete effect of GLP-1R agonist mediated hypophagia.

Humanin peptide ameliorates reproductive dysfunction and restores neuroendocrine mechanisms in SSRI-treated male rats.

Reprod Biol

Rümeysa Esra Köm Akipek, Eda Çoban Ercan, Mehmet Emre Akipek +6 more

Selective serotonin reuptake inhibitors (SSRIs) such as paroxetine frequently induce male sexual dysfunction by disrupting neuroendocrine balance and central dopaminergic pathways. This study investigated whether humanin, a mitochondria-derived peptide, could mitigate paroxetine-induced reproductive and behavioral impairments in male Sprague-Dawley rats. In Phase 1, fifty rats were randomized into control, sham, paroxetine (20 mg/kg/day via oral gavage), humanin (1 mg/kg/day via subcutaneous infusion), and paroxetine + humanin groups (n = 10/group) to evaluate sexual behavior, sperm quality, serum hormones, and dopaminergic activity within the nucleus accumbens (NAc) and medial preoptic area (MPOA). In Phase 2, central neurochemical dynamics in a separate cohort of healthy rats (n = 8) were assessed using in vivo microdialysis coupled with HPLC-ECD to measure extracellular dopamine and its metabolites in the NAc. Paroxetine significantly impaired sexual motivation and performance, reduced sperm motility, concentration, and mitochondrial membrane potential, elevated prolactin, and suppressed testosterone, luteinizing hormone, and dopamine levels in both the NAc and MPOA (p < 0.05). Humanin co-administration significantly reversed these adverse effects, restoring ejaculatory frequency, copulatory efficiency, sperm parameters, and hormonal balance. Furthermore, humanin counteracted the paroxetine-induced dopaminergic suppression in the MPOA and NAc, while acute microdialysis revealed a supportive upward trend in dopamine turnover under basal conditions. These findings demonstrate that humanin exerts potent pro-fertility and neuroprotective effects against antidepressant-induced sexual dysfunction. By preserving mitochondrial integrity and modulating central dopaminergic and neuroendocrine circuits, humanin emerges as a promising therapeutic agent for preserving male reproductive health during SSRI treatment.

Effects of vertical edge presence on foot trajectory during obstacle crossing in younger and older adults.

Hum Mov Sci

Ryota Sakurai, Yuki Suda, Yuka Miura +1 more

Adjusting limb movements when stepping over obstacles is essential to avoid tripping, especially in older adults among whom age-related physical decline increases the risk of falls. This study aimed to determine whether older adults modify their foot movements according to obstacle shape, particularly the presence of a vertical edge, and whether their responses differ from those of younger adults. Data from 12 younger and 13 older adults were analyzed. Participants stepped over obstacles placed 5 m away under four conditions that varied in shape and dimensions. Raised rectangular obstacles with clearly defined vertical edges and raised arch-shaped obstacles without vertical edges were presented in small (2.5 cm high × 8 cm deep) and large (5 cm high × 16 cm deep) sizes. Foot trajectories during the swing phase from toe-off to heel contact were compared using Statistical Parametric Mapping (SPM). Compared with raised arch-shaped obstacles, younger adults raised their leading foot higher when crossing both small and large raised rectangular obstacles, beginning at approximately 30% of the swing phase and continuing until immediately before the obstacle was crossed. By contrast, SPM did not reveal significant differences in foot trajectory patterns between raised rectangular and arch-shaped obstacles in older adults. However, discrete foot-clearance measures at obstacle crossing showed significant shape-related differences in both groups. These findings suggest that trajectory-level adaptation to obstacle shape was less clearly expressed in older adults than in younger adults under the examined conditions and that obstacle-shape effects may be detected differently by full-trajectory and discrete analyses.

CSF clearance through arachnoid fenestrations to olfactory meningeal lymphatics.

Cell

Seon Pyo Hong, Cheolhwa Jin, Myung Jin Yang +14 more

Meningeal (dural) lymphatics are essential for cerebrospinal fluid (CSF) clearance to cervical lymph nodes, yet the precise pathway is incompletely understood. Using a multifaceted approach in mice, we examined tracer dynamics and the CSF outflow pathway from the subarachnoid space (SAS) to the nasal mucosa and identified a discrete arachnoid region surrounding the olfactory bulbs with abundant fenestrations. Similar arachnoid fenestrations were found in cynomolgus monkeys. Fluorescent tracers in the SAS passed through arachnoid fenestrations into dural lymphatics, which traversed the cribriform plate foramina, joined the nasal lymphatics, and drained to the cervical lymph nodes. In aged mice, the known reduction in CSF outflow was accompanied by lymphatic atrophy in the olfactory dura and nasal mucosa and by fewer arachnoid fenestrations and smaller cribriform plate foramina. Importantly, the lymphatics and CSF clearance were restored to normal by intranasal delivery of vascular endothelial growth factor-C (VEGF-C), thereby documenting the reversibility of the aging-related impairment in CSF clearance.

Development and validation of novel prognostic hepatic-cardiac index and hemodynamic prediction models in pre-capillary pulmonary hypertension patients.

Sci Rep

Jun Tong, An Wang, Chuanxue Wan +6 more

Pulmonary arterial hypertension (PAH) is a life-threatening disorder marked by progressive elevation of pulmonary vascular resistance and ultimate right heart failure. Its diagnosis and risk stratification largely depend on invasive right heart catheterization (RHC). This study aimed to integrate routine laboratory and echocardiographic data to develop a novel multi-organ prognostic indicator and construct non-invasive hemodynamic estimation prediction models. This was a multi-center retrospective study enrolling a total of 44 routine laboratory and echocardiographic indices of pre-capillary pulmonary hypertension. Key prognostic variables were screened using Least absolute shrinkage and selection operator-Cox (LASSO-Cox) regression and random survival forest (RSF) analysis. The novel composite index was constructed based on correlation analysis with hemodynamic parameters. Prognostic performance was evaluated using Cox regression, Time-Dependent Receiver Operating Characteristic (time-dependent ROC) curve analysis, stratified analysis, and decision curve analysis (DCA). Linear prediction models for invasive hemodynamic parameters were established using variable selection and internal validation. A total of 179 patients with pre-capillary pulmonary hypertension were included. Using LASSO-Cox and random survival forest, 13 core prognostic variables were identified, including total bilirubin (TB) and B-type natriuretic peptide (BNP). The novel hepatic-cardiac index--TBI (log [total bilirubin × BNP]) was constructed and validated as an independent prognostic factor (HR=1.64, 95%CI: 1.287-2.09, P=0.0001). Predictive efficacy at 36 months was significantly higher for TBI (area under the curve, AUC = 0.777) than for BNP (AUC = 0.723, P = 0.021 with false discovery rate [FDR] adjustment). Stratified analysis confirmed that TBI remained prognostic in patients with BNP levels between 200 and 800 pg/mL (χ2=7.075, P = 0.008). Additionally, non-invasive linear prediction models for mean pulmonary arterial pressure(mPAP), pulmonary vascular resistance (PVR), and PVR×CO (cardiac output) were established with moderate accuracy (R2=0.575, 0.507, 0.523, respectively) Integration of laboratory and echocardiographic parameters enables improved non-invasive evaluation in pulmonary hypertension. The novel hepatic-cardiac index (TBI, log[TB×BNP]) serves as a robust and independent prognostic biomarker. Routine non-invasive indices can reliably estimate key hemodynamic parameters in clinical practice.

Preventative semaglutide and tirzepatide treatment does not alter disease progression in the 5xFAD mouse model of Alzheimer's disease.

Cell Rep Med

Anika Vear, Sofie Amalie Olsen, Emilie Cathrine Holst Lange +3 more

There is growing evidence that long-acting mimetics of the gut-derived incretin hormones GLP-1 and GIP act as disease-modifying therapies for Alzheimer's disease (AD). Here, we temporally characterize the efficacy of the approved incretin receptor agonists semaglutide, a GLP-1R agonist, and tirzepatide, a GLP-1R/GIPR co-agonist, in preventing AD progression. In 5xFAD mice treated for 2 or 4 months, both incretin therapies lower body weight and improve glucose tolerance, yet neither compound produces measurable effects on memory or learning tasks, amyloid-β plaque deposition, or glial cell activation. In a non-amyloidogenic model, 3 days of incretin pre-treatment does not alter microglial activation or the expression of inflammatory markers following lipopolysaccharide (LPS) administration in mice. Our findings indicate that chronic semaglutide or tirzepatide treatment, even when initiated before overt pathology and delivered for a prolonged period, does not slow neuropathological progression in 5xFAD or LPS-treated mice.