Research Hub
The living record of
peptide science.
PubMed studies synced daily. Active clinical trials. Evidence updates when the science materially changes. Monthly synthesis for practitioners.
Layer 1
Study feed
Event rates in major Phase 3 heart failure trials over the last 20 years.
ESC Heart Fail
Alberto Aimo, Giorgia Panichella, Andrea Ripoli +3 more
To determine whether control-arm event rates in heart failure (HF) randomized clinical trials (RCTs) published in New England Journal of Medicine from 2004 to 2024 declined over time, despite intensification of background therapy.
The effects of chronic administration of Cannabidiol and Cannabidiol-Selexipag combination on haematological parameters, oxidative stress, BNP, and TNF-α in a rat model of Pulmonary Arterial Hypertension.
Cardiovasc J Afr
Chayil Gunpath, Anand Nadar
Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by pulmonary vasoconstriction and inflammation, leading to increased pulmonary pressure, right heart failure, and high mortality. Cannabidiol (CBD), a non-psychoactive cannabinoid, exhibits anti-inflammatory and antioxidant properties. This study investigates the therapeutic potential of CBD, alone and in combination with Selexipag, in a rat model of monocrotaline (MCT) -induced PAH.
Evaluation of the systemic right ventricle in transposition of the great arteries using fast strain encoded cardiovascular magnetic resonance.
J Cardiovasc Magn Reson
Ailís Ceara Haney, Andreas Ochs, Jeanna Darino +8 more
Patients with a systemic right ventricle (SRV) experience increased morbidity and mortality, highlighting the need for precise assessment of systolic function. Fast Strain-ENCoded imaging (fSENC) is a novel strain measurement method that allows early detection of cardiac impairment and has demonstrated significant diagnostic and prognostic value. This study aimed to evaluate global and regional cardiac function using fSENC in patients with SRV due to transposition of the great arteries following Senning/Mustard repair (TGA) or congenitally corrected TGA (ccTGA).
From Satiety to Substance Use: Neural Mechanisms of GLP-1 Signaling in Appetite and Reward.
Biol Psychiatry
Caitlin Baumer-Harrison, Morgan Graham, Bart C De Jonghe +1 more
The central glucagon-like peptide-1 (GLP-1) system encompasses homeostatic and hedonic neural circuits. GLP-1-producing neurons within the brainstem project broadly to GLP-1 receptor (GLP-1R)-containing brainstem, hypothalamic, limbic, and mesolimbic nuclei. The diverse expression of the GLP-1R throughout metabolic and reward nuclei positions this system to integrate motivated behavior with physiological state. GLP-1 acts as a state-dependent "behavior-ending" signal that suppresses appetite, promotes satiety, and dampens hedonic and motivational reward value-effects that extends beyond palatable foods. GLP-1R agonists, which can partially cross the blood-brain-barrier, engage central GLP-1Rs via circumventricular organs and adjacent nuclei leading to polysynaptic relays that suppress feeding and drug-seeking behaviors. An abundance of preclinical and clinical evidence highlights the efficacy of GLP-1R agonists for the treatment of obesity and other metabolic disorders. Emerging evidence also indicates the therapeutic application may extend to other disorders characterized by reward-related maladaptive behaviors, including substance use disorders.
Probable tirzepatide-associated limbic encephalitis with status epilepticus in a patient with extreme obesity: a case report.
Neurol Sci
Andrea Mazzeo, Valerio Alaimo, Luigi M Grimaldi
A 59-year-old man (240 kg, BMI ≈ 100 kg/m2) with type 2 diabetes developed progressive drowsiness, confusion, behavioral changes (irritability and aggressive behavior), coma and status epilepticus 72 h after the third weekly dose of tirzepatide 2.5 mg subcutaneously. Brain MRI showed left mesial temporal (hippocampal–amygdalar) swelling and restricted diffusion without contrast enhancement; cerebrospinal fluid was acellular with normal biochemistry and negative multiplex PCR and antibody panel. Seizures were partially controlled with benzodiazepines, levetiracetam and lacosamide. High-dose intravenous methylprednisolone (2 g/day × 3 days, then tapered) granted complete control of seizures within 24 h. Tirzepatide was permanently discontinued. Naranjo score was 8 (probable adverse drug reaction). Follow-up MRI at 16 days revealed persistent mesial temporal signal abnormality. Emerging reports describe tirzepatide-associated autoimmune encephalitis with seizures and psychiatric/behavioral symptoms, as well as seizures secondary to metabolic complications such as SIADH-related hyponatremia; to our knowledge this is among the first reports of probable tirzepatide-associated steroid-responsive limbic encephalitis with status epilepticus in a patient with extreme obesity, highlighting that serious neurological adverse events, although rare, warrant neurological vigilance when using dual GLP-1/GIP receptor agonists.
Teneurin C-terminal associated peptide-1 attenuates chronic stress in male rats.
Behav Pharmacol
Lauren E Mueller, Justin N Siemian, David A Lovejoy +2 more
Hyperactivity of the hypothalamic-pituitary-adrenal axis core stress response system can lead to anxiety, chronic stress, and other neuropsychiatric disorders, such as major depressive disorder and posttraumatic stress disorder. Mitigating this response requires novel interventions to overcome the delayed efficacy and nonspecificity that characterize the currently available, suboptimal chronic stress treatments. Teneurin C-terminal Associated Peptide (TCAP)-1, a naturally occurring neuropeptide, is an established regulator of corticotropin-releasing factor (CRF) mediated stress responses. Although prior work has characterized the ability of TCAP-1 to attenuate the physiological and behavioral expression of stress in acute stress models, the effect of TCAP-1 on chronic stress remains unexplored. Using a chronic unpredictable stress model, the impact of TCAP-1 on the expression of chronic stress in male rats was investigated. Administration of TCAP-1 attenuated plasma corticosterone levels by 56.4% and increased open field center time by 282.04%, reflecting improvements in the physiological and behavioral manifestations of chronic stress, respectively. In contrast, a nonpeptide CRF1 receptor antagonist, CP-154,526, demonstrated no effect on the chronic stress-induced physiological and behavioral profile. These results provide evidence for the neuromodulatory role of TCAP-1 in the chronic stress response, supporting its potential as a clinically relevant anxiolytic. The divergence between TCAP-1 and CP-154,526 in this chronic model is consistent with the broader clinical failure of CRF1 receptor antagonists in phase 2 human trials and highlights the potential translational advantage of TCAP-1's distinct, upstream mechanism of action.
Postmortem Evidence of CRH Neuron Reduction in Narcolepsy Without Cataplexy With Borderline Hypocretin-1 Levels.
J Sleep Res
Ling Shan, Suzan Linssen, Rolf Fronczek +3 more
Narcolepsy is classified as type 1 (NT1) or type 2 (NT2) mainly according to hypocretin deficiency rather than cataplexy. While CRH neuron loss in the PVN has been described in NT1, it remains unclear whether similar changes occur in narcolepsy without cataplexy. We report a 42-year-old woman with excessive daytime sleepiness since age 15, without cataplexy. Two multiple sleep latency tests and lumbar punctures performed 8 years apart showed mean latencies of 8.3 min with three SOREMPs and 10.8 min with two SOREMPs, along with borderline low-intermediate hypocretin-1 levels of 100 pg/mL initially and 122 pg/mL at follow-up. HLA DQB1*06:02 was positive, and brain magnetic resonance imaging was normal. The patient later developed severe depression and committed suicide. CRH neuron counts were compared with a control and a NT1 hypothalamus. All hypothalami were formalin-fixed, paraffin-embedded and processed for thionin staining and immunohistochemistry for hypocretin and CRH, with neurons manually counted. Only the anterior hypothalamus was available from this case, precluding the assessment of hypocretin neurons, although CSF levels indicated a borderline low-intermediate reduction. Thionin staining confirmed that the PVN was fully included in our case and revealed an almost complete loss of CRH-positive neurons in the PVN compared with controls, consistent with findings in NT1. This report indicates that narcolepsy without cataplexy, accompanied by borderline low CSF hypocretin-1 levels, is associated with a marked reduction in CRH neurons in the PVN, which may contribute to excessive daytime sleepiness and impaired wakefulness regulation, without triggering cataplexy.
Sleep matters: rethinking its role in growth hormone deficiency treatment.
Endocrine
Isabela Antunes Ishikura, Sergio Tufik, Monica L Andersen
PURPOSE: This letter has the purpose of alerting the medical community to the impact of sleep debt on growth hormone (GH) therapy, mostly applied to pediatric and puberty ages. METHODS: We discussed the role of sleep in GH release, especially N3 sleep. RESULTS: During sleep, hypothalamus is stimulated to secrete growth hormone–releasing hormone (GHRH) which activates synthesis and secretion of GH by anterior pituitary gland. Studies focusing on the interaction of sleep and GH release are scarce and have controversial results. Some studies have found a direct effect of N3 sleep in GH pulse, indicating the importance of adequate sleep during treatment in patients with GH deficiency. Modern lifestyles often lead to inadequate sleep, which can severely disrupt bodily functions, particularly in people with endocrine conditions, since sleep is essential for proper hormonal balance. CONCLUSION: For individuals demonstrating regression in GH therapy and reporting sleep-related concerns, the use of sleep hygiene practices or the exploration of possible sleep disorders can help advance therapeutic efficacy and overall patient well-being.
Audiologic Assessment and Management of Teprotumumab-Associated Ototoxicity: An Updated Narrative Review.
Audiol Res
John Williams, Alex Elkins, Alp Sarigul +2 more
Introduction: Teprotumumab (Tepezza®), an insulin-like growth factor-1 receptor (IGF-1R) antagonist, is the first FDA-approved targeted therapy for thyroid eye disease (TED). While effective for reducing proptosis and inflammation, increasing post-marketing evidence has linked teprotumumab to auditory adverse events. IGF-1 signaling is essential for cochlear maintenance and neuroprotection; therefore, systemic IGF-1R inhibition presents a biologically plausible mechanism for ototoxicity. Despite growing recognition of these effects, no standardized approach exists for audiologic assessment or monitoring of patients receiving teprotumumab. This review aimed to (1) summarize proposed mechanisms and the reported spectrum of teprotumumab-related auditory effects, (2) evaluate current methods used to assess and monitor these patients, and (3) identify areas of consensus and ongoing uncertainty. Methods: An updated narrative review of the literature was conducting using PubMed, CINAHL, and Google Scholar using Boolean strings targeting teprotumumab exposure and hearing-related outcomes. Studies from 2022 onward were identified using Boolean search strings targeting teprotumumab exposure and hearing-related outcomes. Peer-reviewed English language studies reporting audiometric findings were eligible for inclusion. Results: Ten studies met inclusion criteria. Reported effects most commonly included bilateral high-frequency SNHL, tinnitus, and aural fullness, typically emerging after three to six infusions. Many cases demonstrated persistent deficits despite drug discontinuation. Baseline audiometric assessment was not uniformly reported across studies, and monitoring protocols varied considerably, with inconsistent incorporation of speech testing and immittance measures. Conclusions: Teprotumumab-associated ototoxicity is increasingly recognized and potentially irreversible. Current evidence is insufficient to guide standardized monitoring. Prospective studies are urgently needed to establish evidence-based audiologic surveillance protocols.
Food-grade utilization of bovine slaughterhouse by-products for developing cost-effective media supplements in cultivated meat applications.
Food Sci Anim Resour
Ji Won Park, Da-Young Lee, Ermie Jr Mariano +6 more
Bovine slaughterhouse by-products are nutrient-dense materials with significant potential as food-grade supplements for serum-reduced media in cultivated meat production. This study reviews key biological processes underlying skeletal muscle development and regeneration, focusing on satellite cell activation and the myogenic regulatory factors essential for in vitro muscle culture. The current limitations of fetal bovine serum, including ethical concerns, high cost, and batch-to-batch variability, are reviewed alongside emerging serum-free strategies based on recombinant proteins, food-derived ingredients, and adult livestock serum. A compositional evaluation of bovine blood and organ by-products indicated high levels of bioactive proteins, essential amino acids, fatty acids, and minerals relevant to muscle cell proliferation and differentiation. Plasma and serum were showed to differ in albumin- and globulin-associated functions, antioxidant activity, and cytokine-related profiles. Organs such as liver, heart, spleen, and tongue exhibited high levels of essential amino acids and functional lipids, while specific tissues contained elevated concentrations of zinc, magnesium, iron, and calcium. Overall, bovine slaughterhouse by-products represent promising food-compatible ingredients for the development of serum-free or serum-reduced culture media. Their valorization may reduce culture costs, support sustainable resource use, and facilitate scalable cultivated meat production.
Thymosin α1 Augments CD8⁺ T-Cell Activation and Reverses Exhaustion In Vitro.
Asian Pac J Cancer Prev
Smriti Mishra, Gaurang Telang, Anurag Sureshbabu +4 more
Thymosin alpha 1 (Tα1) is a thymic peptide hormone secreted by the thymus gland with known immunomodulatory properties, yet its specific effects on human CD8⁺ T-cell function remain incompletely understood. This study investigates the influence of Tα1 on CD8⁺ T-cell proliferation, activation, cytokine secretion, and exhaustion status in vitro.
Lean Mass and Musculoskeletal Preservation in GLP-1-Based Obesity Treatment: Nutrition, Exercise, Supplementation, and Monitoring Strategies.
Metabolites
Roko Šantić, Lovre Martinović, Nikola Pavlović +5 more
Background/Objectives: GLP-1-based obesity pharmacotherapy has shifted clinical attention from the magnitude of weight loss to the quality of weight loss. This review evaluates whether body composition changes during treatment with GLP-1-based agents represent clinically meaningful muscle loss and identifies nutrition, supplementation, exercise, and monitoring strategies that may help preserve lean mass, function, bone health, and nutritional adequacy. Methods: A comprehensive narrative review was performed using focused searches of PubMed, publisher-hosted journal platforms, and reference lists of key primary studies and recent evidence syntheses through March and May 2026. Evidence was organized around body composition, muscle quality and function, dietary protein and micronutrient adequacy, exercise, supplementation, bioelectrical impedance analysis, imaging, and emerging biomarkers. Results: Semaglutide and tirzepatide preferentially reduce fat mass, including visceral and ectopic adiposity, while producing smaller but consistent reductions in lean mass or lean soft tissue. However, DXA-derived lean mass and BIA-derived fat-free mass are not equivalent to skeletal muscle, and lean tissue loss does not necessarily indicate impaired strength or physical performance. The most defensible supportive care model combines food-first nutritional counseling, adequate protein intake, structured resistance exercise, management of gastrointestinal adverse effects, and risk-based monitoring of micronutrient inadequacy. Protein supplementation and nutritionally complete meal replacements may be useful when intake is insufficient, whereas creatine, essential amino acids or leucine, beta-hydroxy-beta-methylbutyrate, fiber, probiotics, omega-3 fatty acids, and multi-ingredient products remain adjunctive options supported mainly by indirect or phenotype-specific evidence. Conclusions: Future GLP-1 trials and clinical care should move beyond body weight and total lean mass toward integrated assessment of muscle quantity, muscle quality, function, bone, and nutritional adequacy, and standardized BIA-based clinical monitoring where advanced imaging is not feasible.
Personalized Combination of a Ketogenic Diet and Low-Dose Semaglutide for Cardiometabolic Health: A Retrospective Case Series.
J Pers Med
Genevieve Parker, Madeline D Morris, Jeter R Heggie +9 more
Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have demonstrated efficacy for weight loss in obesity; however, up to 40% of weight lost may derive from lean body mass. The ketogenic diet independently improves insulin sensitivity and promotes fat oxidation while preserving lean tissue. This study aimed to describe changes in body composition, insulin sensitivity, and cardiometabolic markers in patients who followed a personalized ketogenic dietary protocol while receiving low-dose semaglutide over a 6-month insulin resistance reversal program. Methods: Seven analyzed adults (six female, one male) with overweight or obesity (baseline BMI 25.6-47.2 kg/m2) participated in a clinician-supervised 6-month program combining a whole-food ketogenic diet with semaglutide (≤1.0 mg/week). Body composition and fasting metabolic markers were assessed at 1, 3, and 6 months. Results: Mean total weight loss was 21.9 kg, of which a mean of 92% was attributable to BIA-estimated fat mass. Skeletal muscle mass was largely preserved as measured by BIA (mean loss 1.2 kg), and one patient gained lean tissue. Fasting insulin declined by a mean of 15.6 µIU/mL. Visceral fat decreased by a mean of 37.0%. Six of seven patients showed reductions in high-sensitivity C-reactive protein. Triglycerides decreased in six of seven patients, and HDL cholesterol increased in all seven. LDL cholesterol responses were heterogeneous. Conclusions: In this small, uncontrolled case series, combining a ketogenic diet with low-dose semaglutide was associated with substantial fat loss, apparent preservation of lean mass as measured by BIA, and improvements in insulin sensitivity and cardiometabolic markers. Because the semaglutide dose and dietary protocol were individualized to each patient's response, the program illustrates a personalized approach to insulin resistance. These preliminary findings are hypothesis-generating and warrant confirmation in controlled prospective studies.
Advances in skin aging: integrating epigenetic, cellular, and immune mechanisms for targeted therapy.
Immun Ageing
Jinxuan Su, Hongzhong Jin
As the largest and most externally exposed organ, the skin is particularly vulnerable to aging, rendering skin aging a widespread clinical and aesthetic concern. Driven by both intrinsic and extrinsic factors, skin aging is characterized by progressive functional decline and structural remodeling that compromise barrier integrity, disrupt dermal homeostasis, and ultimately diminish quality of life. At the upstream regulatory level, skin aging-associated epigenetic modifications drive epigenetic drift that compromises transcriptional fidelity and primes cells toward senescence. At the cellular level, regulatory mechanisms converge on cellular senescence and profound mitochondrial remodeling. At the microenvironmental level, the failure of senescent cell clearance (immunosenescence) and the emergence of a chronic pro-inflammatory milieu (inflammaging) create a self-reinforcing immune-inflammatory axis. This axis exacerbates cytokine production, extracellular matrix remodeling, and progressive tissue degeneration. We further highlight emerging mechanism-targeted interventions, including epigenetic and mitochondrial modulators, senotherapeutics, biologics, immunotherapies, regenerative and device-based therapies. A deeper understanding of these interconnected molecular mechanisms and targeted therapies may offer a roadmap for future therapeutic innovation and translational research in skin aging.
Alzheimer's disease in the Plasticene era: a clinicopathological update on the dual sequestration of amyloid and tau as hijacked innate immune responses.
Free Neuropathol
Michael A S Guth
Background: The defining neuropathological hallmarks of Alzheimer's disease (AD)-amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFTs)-are now understood to exist along a continuum with brain aging, yet their fundamental trigger in sporadic disease remains enigmatic. The clinical failure of therapies targeting these proteins, despite their successful removal, underscores a critical dissociation between hallmark pathology and core pathogenesis. Objective: This clinicopathological update synthesizes emerging evidence on pervasive environmental nanoplastics (NPs) with the persistent paradoxes of AD to propose the dual sequestration hypothesis (DSH). Methods and Results: We suggest that Aβ plaques and tau NFTs could be reinterpreted as evolutionarily conserved, compartment-specific innate immune sequestration mechanisms-an extracellular "sarcophagus" and an intracellular "lockbox"-based on their roles in microbial defense and stress response. We posit that in the modern "Plasticene" era, indestructible NPs detected in human cerebrospinal fluid (CSF) and brain tissue act as permanent, inorganic nucleation seeds that hijack these responses, forming indigestible synthetic protein complexes. NPs directly nucleate Aβ fibrillation and tau hyperphosphorylation, initiating the sequestration response. Chronic microglial engagement with these complexes triggers a state of "immune frustration," leading to a maladaptive phase transition. This pivot could be explained by glutamate excitotoxicity, which drives microglial NLRP3 inflammasome activation and pyroptotic cell death. Lytic pyroptosis liberates intact synthetic seeds into the paravascular space, where they are distributed via glymphatic flow, physically obstructing clearance and providing a mechanistic model for the stereotypical progression of Braak stages. Conclusion: The DSH offers a unified explanation for the therapeutic failure of anti-Aβ/anti-tau antibodies (which remove the biological response but not the synthetic trigger) and amyloid-related imaging abnormalities (ARIA) as an inflammatory rebound. It necessitates a paradigm shift in neuropathological practice, calling for novel detection techniques to visualize the synthetic core within classical lesions, thereby unifying environmental etiology with canonical pathology. The presence of synthetic NPs at the physical center of Aβ plaques and tau tangles in human AD brain tissue is currently a prediction of the DSH awaiting empirical validation, not an established finding.
Hematopoietic Rejuvenation via Natural Senolytic NSPCC1 Delays Inflammatory Aging.
Biology (Basel)
Wei Wang, Shenglong Yang, Rongjinlei Zhang +7 more
Chronic inflammation accelerates the aging process, and targeted clearance of senescent cells shows potential in alleviating age-related decline. PCC1, a potent senescent cell clearance agent in grape seed extract (GSE), has limited applications due to its low oral bioavailability. This study introduced a novel GSE formulation, Natural Senolytics PCC1 (NSPCC1), which significantly enhanced PCC1 absorption and metabolic characteristics. Validation in two mouse aging models demonstrated that oral administration of NSPCC1 markedly extended lifespan and promoted healthy aging. The formulation improved the capacity for hematopoietic stem/progenitor cell differentiation and reduced age-related myeloid cell bias. Comprehensive histological analysis revealed attenuated aging phenotypes in bone marrow and skin, improved peripheral blood erythroid parameters, and a partial increase in blood antioxidant capacity, alongside reduced M1 macrophage infiltration and fibrosis in liver, kidney, and lung tissues. These effects were validated through histological assessments, including H&E, Masson, F4/80, and iNOS staining. This study highlighted the pivotal role of hematopoietic stem cells in aging and established NSPCC1 as a promising natural intervention for age-related pathologies. Its enhanced efficacy lays the groundwork for deeper exploration of natural products in aging biology and provides crucial support for the development of safe and effective anti-aging therapies.
Angiotensin II and angiotensin-(1-7) neurotransmissions in the medial amygdala differently control cardiovascular and anxiogenic-like responses to stress in rats.
J Psychopharmacol
Willian Costa-Ferreira, Lucas Gomes-de-Souza, Paula C Bianchi +4 more
BackgroundThe medial amygdala nucleus (MeA) has been implicated in stress responses. However, the local neurochemical mechanisms involved are not completely understood.AimsThis study examined how angiotensin II and angiotensin-(1-7) neurotransmissions within the MeA contribute to cardiovascular, autonomic, and anxiogenic-like responses to acute restraint stress (ARS) and repeated restraint stress (RRS) in rats.MethodsSelective angiotensinergic receptor antagonists and agonists were microinjected into the MeA, and physiological and behavioral responses were evaluated during ARS and the 10th restraint session (i.e., RRS).ResultsDuring ARS, tachycardia was potentiated by angiotensin II, the AT1 receptor antagonist losartan, and angiotensin-(1-7), whereas antagonism of AT2 receptors with PD123319 or Mas receptors with A-779 attenuated this effect. AT2 receptor antagonism also reduced the pressor response and sympathetically mediated cutaneous vasoconstriction. In addition, angiotensin II, losartan, and angiotensin-(1-7) reduced the anxiogenic-like behavior in the elevated plus maze following ARS. RRS did not affect gene expression of angiotensinergic receptors in the MeA. Consistently, angiotensin-(1-7) produced similar effects during ARS and the 10th restraint session. However, contrary to findings obtained in acutely stressed animals, angiotensin II and losartan failed to influence responses during the 10th restraint session. Interestingly, AT2 receptor antagonism, which reduced tachycardia in ARS, enhanced it under chronic stress.ConclusionsThese findings indicate that angiotensin II/AT1-AT2 receptors and angiotensin-(1-7)/Mas receptor axes within the MeA regulate cardiovascular and anxiety-related responses to acute stress, and their roles are influenced by repeated stress exposure.
Elabela in Lipid-Related Cardiometabolic Dysfunction: A Critical Narrative Review.
Metabolites
Zuzanna Chęcińska-Maciejewska, Ewa Pruszyńska-Oszmałek, Paweł Kołodziejski +2 more
Elabela (ELA/APELA/Toddler) is an endogenous peptide ligand of the apelin receptor APLNR (also known as APJ) and, together with apelin, forms the apelinergic signalling system. Its role in embryonic development, the cardiovascular system, the kidneys and the endothelium is becoming increasingly well characterised, whilst its function in metabolic regulation remains unresolved. Elabela activates pathways essential for metabolic homeostasis-PI3K/Akt, AMPK-related pathways, redox regulation, inflammatory control and pro-survival cascades-but no study has shown that it directly regulates adipocyte lipid metabolism. This narrative review categorises the evidence at the receptor, organ, immunometabolic and intra-adipocyte levels, and also considers the adipose tissue microenvironment as a distinct level of potential relevance. The available data support a role for Elabela as a candidate mediator of lipid-related metabolic dysfunction-via anti-inflammatory, antioxidant and tissue-protective mechanisms-with macrophage lipid metabolism representing the most informative immunometabolic interface. Human studies remain scarce, heterogeneous and limited by a lack of standardisation in assay methods and the unresolved specificity of isoforms. Elabela should therefore be regarded as a candidate indirect modulator of metabolic homeostasis and a candidate biomarker of cardiometabolic stress or adaptation-not as a confirmed direct regulator of adipocyte lipid metabolism.
Risk of Long-Term Clozapine Medication over Decades for Cardiac Adverse Events Including Heart Failure and Its Pathophysiology: A Japan and China Retrospective Cohort Analysis.
Med Sci (Basel)
Ruri Okubo, Nobutomo Yamamoto, Xiaojun Shao +13 more
Background/Objectives: Clozapine is the sole antipsychotic approved for treatment-resistant schizophrenia, but it is a double-edged therapeutic option due to various lethal adverse reactions. This study aimed to assess the risk of long-term clozapine medication-induced cardiotoxicity, which has not yet been fully elucidated. Methods: This study is a multicenter retrospective cohort study of patients with schizophrenia in Japan and China who received clozapine monotherapy. Cases for which serum NT-proBNP concentration and LVEF derived from echocardiography were available in 2025 were included. In addition, blood examinations, including those administered by the Japanese Clozaril Patient Monitoring Service, were statistically analyzed as independent variables. Results: Among a total of 315 cases, including 99 Japanese (clozapine exposure duration: 57.5 ± 4.0 months) and 216 Chinese (208.1 ± 11.0 months) cases, were enrolled. In both Japan and China, age-standardized prevalence of heart failure among patients with prescribed clozapine were higher compared to general population, with odds ratios of 3.2 (95%CI: 1.4-6.4) and 6.9 (95%CI: 3.6-12.0), respectively. The risk factors for stage-B heart failure associated with clozapine were prolonged exposure duration, higher plasma levels of clozapine, and increasing monocytes. Unexpectedly, over 70% of cases with stage-B heart failure associated with clozapine identified in this study did not have metabolic complications. Other than those with cardiomyopathy, myocardial infarction, ileus, or chronic renal failure, no cases with ejection fraction < 50% were observed, suggesting that stage-B heart failure associated with clozapine is speculated to be likely suggestive of HFpEF. Conclusions: Traditionally, psychiatry has focused on myocarditis and cardiomyopathy developing several weeks and months after initiation of clozapine medication; however, this study revealed asymptomatic heart failure as a third cardiac adverse reaction of clozapine that develops years later. Therefore, regular monitoring of NT-proBNP contributes to improving long-term prognosis of treatment-resistant schizophrenia with prescribed clozapine.
PROTAC-Mediated DPP-4 Degradation: A New Solution for Type 2 Diabetes.
J Med Chem
Wei Zeng, Liangzhu Feng
Dipeptidyl peptidase-4 (DPP-4) is an important aggravating factor in the progression and exacerbation of type 2 diabetes mellitus (T2DM), a condition characterized by diminished insulin responsiveness because it rapidly degrades glucagon-like peptide-1 (GLP-1) and other peptide with similar physiological function. Although several small-molecule DPP-4 inhibitors have been developed for the clinical management of T2DM, their therapeutic benefits are only moderate, as the fail to achieve for sustained inhibition of DPP-4. Hence, targeted degradation of DPP-4 using proteolysis-targeting chimera (PROTAC) technology offers an alternative strategy for sustained glycemic control in T2DM.