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Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.
Sci Adv
Rendan Yang, Yu Sun, Wenzheng Wang +9 more
Mild mitochondrial stress could extend lifespan across species, yet the underlying mechanism remains unclear. Here, we show that inhibition of mitochondrial respiration induces a sustained transcriptional program that enhances lysosomal proteolysis during aging in Caenorhabditis elegans. Mechanistically, this response is primarily regulated by the intestinal GATA transcription factor ELT-2, which retains high expression and directly binds to GATA motifs in the promoters of lysosomal protease genes to promote their transcriptional activation. Moreover, we identified R249 within the conserved zinc-finger DNA binding domain of ELT-2 as a key residue required for its transcriptional activity. Notably, this mitochondrion-ELT-2-lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPRmt) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, is essential for mitochondrial stress-induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2-dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.
Fetal ultrasound parameters associated with N-terminal pro-B-type natriuretic peptide levels in umbilical cord blood: a cross-sectional study.
Matern Health Neonatol Perinatol
Shoko Saito, Mari Tadakawa, Hirotaka Hamada +2 more
Current Doppler and functional ultrasound parameters, such as the cardiovascular profile score, umbilical artery pulsatility index, and ductus venosus pulsatility index, are valuable for detecting advanced fetal cardiac decompensation; however, they have limited ability in identifying subtle hemodynamic changes. This critical gap in current fetal assessment highlights the need for reliable markers that can identify subtle cardiac stress before overt failure. In this study, we aimed to identify fetal ultrasound parameters associated with umbilical venous N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, a biomarker associated with fetal cardiac load.
Calycosin protects against post-myocardial infarction heart failure by activating the NRF2/HO-1 signaling pathway.
J Thorac Dis
Juan Zhang, Yilin Zhang, Zibo Xie +6 more
Myocardial infarction (MI) is the most common cause of heart failure (HF). Calycosin (CAL), an active component of Radix astragali, has been reported to improve HF. However, the functional effect of CAL on the progression of post-MI HF has not been extensively clarified. This study aimed to investigate whether the cardioprotective effects of CAL are related to ferroptosis.
Association between brain natriuretic peptide and invasive hemodynamics in left ventricular assist device HeartMate3-supported patients.
Int J Artif Organs
Elie Kozaily, Azalfa Lateef, Vishal N Rao +9 more
We report a serum BNP cut-off of 800 pg/mL above which all patients with LVAD HeartMate-3 had elevated biventricular filling pressures, suggesting it may be used to prompt invasive ramp study during routine post-LVAD clinic visit. We found stepwise increase in BNP levels across hemodynamic groups, with the lowest levels in patients with normal filling pressures, intermediate in those with elevated right or left-sided filling pressure and highest in those with elevated biventricular filling pressures. Furthermore, most patients with BNP above median value (335 pg/mL) required speed changes for either elevated right sided or left sided filling pressures. Conversely, patients with BNP below 335 pg/mL rarely required speed change. In conclusion, elevated serum BNP in patients with durable LVAD HeartMate-3 may have clinical value in prompting invasive hemodynamic assessment.
Pain Expectation in Individuals With High Autistic Traits: Decision-Evaluation Processes and Oxytocin Modulation.
Ann N Y Acad Sci
Jiafeng Zhu, Shihao Chen, Wenting Zhang +4 more
Pain reflects both sensory input and predictive processes shaped by expectations. Individuals with high autistic traits (HATs) often exhibit atypical pain responses, potentially due to alterations in anticipatory processing. This study investigated pain anticipation in HAT individuals and examined the modulatory effects of oxytocin using behavioral, computational, and pharmacological approaches. In experiment 1, HAT and low autistic trait (LAT) individuals completed a cue-based pain anticipation task. Anticipatory processing was characterized through two components: decision-related processes and evaluative responses. HAT individuals showed altered decision-making, characterized by greater caution under uncertainty and reduced processing efficiency under certain high-pain conditions. They also exhibited more negative evaluative responses, which were associated with poorer psychological health. In experiment 2, HAT participants received intranasal oxytocin or placebo. Oxytocin selectively influenced decision-related processes under uncertainty, increasing evidence accumulation and reducing nondecision time while also increasing the tendency to choose high-pain outcomes under ambiguous conditions. In contrast, oxytocin showed limited effects on evaluative measures. These findings suggest that pain anticipation in HAT individuals involves partially distinct decision-related and evaluative components and that oxytocin exerts process-specific effects on anticipatory processing.
Digestive Hormones and Their Impact on Bariatric and Pharmacologic Weight-Loss Therapies.
Endocr Rev
Maxime Amoyel, Claire Carette, Tigran Poghosyan +2 more
Obesity is a growing global health challenge associated with major cardiometabolic complications. While bariatric surgery remains the most effective treatment for severe obesity, recent advances in incretin-based pharmacotherapy, multi-receptor agonists, and endoscopic bariatric procedures have substantially expanded therapeutic options. Beyond mechanical restriction, these interventions exert their effects through complex hormonal and neurophysiological mechanisms involving gut-brain signaling, gastric motility, and enteroendocrine adaptations. Gut-derived hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), amylin, and leptin, play a central role in the regulation of hunger, satiation, and satiety by integrating nutrient sensing, vagal afferent signaling, and central hypothalamic pathways. Surgical procedures such as laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass induce profound and durable hormonal remodeling, whereas endoscopic sleeve gastroplasty primarily modulates gastric physiology with more modest and heterogeneous endocrine effects. Intragastric balloons induce a transient delay in gastric emptying and achieve moderate short-term weight loss, although their metabolic and weight-loss effects appear limited in durability. In parallel, GLP-1 receptor agonists and emerging multi-agonist therapies reproduce several post-bariatric hormonal adaptations and achieve clinically meaningful weight loss. In this review, we summarize current knowledge on digestive hormone physiology and provide an updated overview of the hormonal mechanisms underlying pharmacologic, endoscopic, and surgical bariatric interventions, highlighting their respective roles within a continuum of obesity treatment strategies.
TMEM216 inhibits breast cancer lung metastasis by modulating IGF1R-IRS4 signaling pathway.
Nat Commun
Yingying Wang, Xinyang Bai, Zhiyuan Du +12 more
Breast cancer (BC) metastasis remains a major cause of mortality, yet the molecular mechanisms driving this process are incompletely understood. This study identifies TMEM216, a transmembrane protein implicated in ciliary homeostasis, as a suppressor of lung metastasis in BC. Using mammary-specific Tmem216 knockout mice, we demonstrate that Tmem216 deficiency promotes lung metastasis without affecting primary tumor proliferation. Clinical analyses reveal reduced TMEM216 expression in metastatic lesions and aggressive cell lines, correlating with poor patient distant metastasis-free survival. Mechanistically, TMEM216 interacts with IGF1R and binds to IRS4 via the conserved K79-D1049 interaction, disrupting the IGF1R-IRS4 complex formation and suppressing IGF pathway activation. Rescue experiments in vitro and in vivo confirm that TMEM216-mediated metastasis inhibition depends on IGF signaling modulation. Tissue microarray analyses further establish an inverse correlation between TMEM216 levels and IGF1R phosphorylation in BC patients, with low TMEM216 expression associated with advanced metastasis. These findings delineate TMEM216 as a critical regulator of the IGF1R-IRS4 axis, offering therapeutic opportunities for targeting metastatic BC.
The potential role of H2S in the anti-infective function of antimicrobial peptides.
Nat Commun
Xu Wang, Shuangyu Li, Wenzhuang Shi +10 more
Antimicrobial peptides (AMPs) are essential components of the innate immune system in animals, playing crucial roles in defending against microbial infections. Hydrogen sulfide (H2S), a vital gasotransmitter, is involved in regulating a wide array of physiological functions. However, the role of H₂S in the anti-infective actions of AMPs remains poorly understood. Here, we demonstrate the crucial role of H2S in mediating the anti-infective functions of AMPs across diverse animal species. LL-37/CRAMP, the human cathelicidin family AMP and its mouse homolog, induce H2S production predominantly through 3-mercaptopyruvate sulfurtransferase (3MST) in Escherichia coli and Clostridium perfringens. The generated H₂S further participates in reactive oxygen species (ROS) accumulation, leading to bacterial death by oxidative damage. Additionally, LL-37 activates the Akt signaling pathway, upregulating cystathionine γ-lyase (CSE) expression to generate H2S in macrophages. This process plays a potential role in facilitating the immunomodulatory activity of LL-37/CRAMP and we confirmed that H2S is involved in their in vivo anti-infective activity of LL-37. Moreover, besides LL-37/CRAMP, we reveal that AMPs from various animal species also induce H2S production in bacteria and macrophages. Overall, our findings highlight a previously unrecognized role of H2S in AMP anti-infective function, which is ubiquitous across AMPs from different animals.
EQ-5D Health Utility Gains with Once-Weekly Semaglutide 2.4 mg in People with MASH and F2/F3 Fibrosis: An Analysis of ESSENCE.
JHEP Rep
Margarida Augusto, Robert Bauer, Simon Clancy +3 more
Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of metabolic dysfunction-associated steatotic liver. It is highly prevalent, particularly among individuals with overweight or obesity, and substantially impairs health-related quality of life. Semaglutide 2.4 mg received accelerated approval from the US Food and Drug Administration in August 2025 for adults with noncirrhotic MASH and fibrosis stages F2-F3 based on results from the ESSENCE trial. This study aimed to estimate the impact of semaglutide on health utility in this population.
Semaglutide vs Metabolic and Bariatric Surgery and Cardiovascular Outcomes in Obesity.
Endocr Pract
Ting-Chun Tseng, Sunny Ssu-Yu Chen, Hui-Yuan Chen +1 more
To compare cardiovascular outcomes associated with metabolic and bariatric surgery (MBS) versus semaglutide therapy among adults with obesity, stratified by type 2 diabetes mellitus (T2DM) status.
GLP-1 receptor agonists, metabolic syndrome, and Alzheimer's disease: Lessons and opportunities from the EVOKE trials.
J Neuroendocrinol
Pragati Gupta, Valeria Pozzilli, Anastasia De Giovanni +4 more
Metabolic syndrome and Alzheimer's disease (AD) are increasingly recognised as interconnected, sharing vascular, metabolic and inflammatory pathways that accelerate brain ageing and cognitive decline. This review critically examines the evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for diabetes and obesity, may influence AD related pathways or reduce AD risk in metabolically vulnerable populations. Metabolic syndrome and AD related cognitive impairment share biological mechanisms including vascular damage, insulin resistance and chronic inflammation, suggesting that therapies targeting metabolic dysfunction could influence neurological outcomes. GLP-1RAs are notable for combining systemic benefits, like weight loss, improved glycaemic control, and reduced cardiovascular risk, with possible but incompletely established central nervous system effects. Experimental studies suggest that some GLP-1RAs may reduce amyloid and tau pathology, support mitochondrial function, and limit neuroinflammation, although recent preclinical studies and limited brain penetrance argue against a direct neuroprotective effect. Observational data suggest lower dementia rates among users compared with other antidiabetic treatments. However, the recent EVOKE and EVOKE + trials showed that oral semaglutide did not slow clinical progression in early symptomatic AD, despite positive biomarker effects. This highlights the challenge of translating biological plausibility into meaningful clinical benefit and refocuses attention on disease stage, target population, and mechanism. Beyond summarising evidence, this review advocates a more cautious and mechanism specific framework: preserving cognitive health may require addressing systemic metabolic dysfunction rather than targeting the brain alone. GLP-1 RAs have failed to show an effect in symptomatic AD, but their effects on metabolism might still be beneficial at earlier stages, such as the preclinical phase of AD. Future studies should determine whether earlier intervention in metabolically enriched groups can alter AD related cognitive, vascular, and biomarker trajectories.
Obesity management for kidney TRANSPLANTation: protocol for the vanguard phase of an innovative randomised controlled trial, embedded in routine care (OK-TRANSPLANT 2).
BMJ Open
Kristin K Clemens, Jennifer Irwin, Michael Chiu +14 more
Large randomised controlled trials (RCTs) of obesity interventions have excluded those with advanced chronic kidney disease (CKD) including recipients of dialysis. Obesity management is critically important to their health and healthcare, including their ability to access kidney transplant.
Advances in Cardiovascular Pharmacotherapy. X. Glucagon-Like Peptide-1 Receptor Agonists in Heart Failure and Mechanisms of Protection.
J Cardiothorac Vasc Anesth
Paul S Pagel, Dustin Hang, Julie K Freed +1 more
The first part of this two-part article discussed the physiology of glucagon-like peptide-1 (GLP-1), described the discovery and development of GLP-1 receptor agonists (RAs), examined the findings of major clinical trials and their substudies showing that GLP-1 RAs reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes and atherosclerotic cardiovascular disease, and finally, reviewed the evidence indicating that semaglutide protects against MACE in patients with obesity and established cardiovascular disease but not type 2 diabetes. This second part reviews recent clinical trials indicating that these drugs reduce symptom burden, increase exercise tolerance, and improve quality of life in patients with heart failure with preserved but not reduced ejection fraction. The article also discusses mechanisms by which GLP-1 RAs produce cardiovascular protection in patients with atherosclerotic cardiovascular disease or heart failure.
Advances in Cardiovascular Pharmacotherapy. IX. Protection Against Major Adverse Cardiovascular Events by Glucagon-like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus and Obesity.
J Cardiothorac Vasc Anesth
Paul S Pagel, Dustin Hang, Julie K Freed +1 more
The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of insulinotropic peptides that replicate the effects of endogenous GLP-1 but have a prolonged duration of action. GLP-1 RAs have had a remarkably profound impact on the treatment of type 2 diabetes and obesity because they substantially improve glycemic control and produce considerable weight loss. The U.S. FDA's requirement that pharmaceutical companies establish the cardiovascular safety of new type 2 diabetes medications coincided with the development of GLP-1 RAs and mandated that trials be conducted to assure that their adverse cardiovascular effect profiles were noninferior to placebo. This FDA requirement proved to be fortuitous because many of the newly developed GLP-1 RAs were shown to cause unanticipated cardiovascular and renal protective effects, which led to their expanded use beyond patients with type 2 diabetes or obesity to those with atherosclerotic cardiovascular disease, chronic kidney disease, and heart failure with preserved ejection fraction. This first of two articles on the cardiovascular pharmacology of GLP-1 RAs briefly discusses the physiology of GLP-1, describes the discovery and development of GLP-1 RAs, examines the findings of major clinical trials and their substudies showing that GLP-1 RAs reduce major adverse cardiovascular events in patients with or at high risk for atherosclerotic cardiovascular disease and type 2 diabetes, and finally, reviews the evidence indicating that the GLP-1 RA semaglutide protects against major adverse cardiovascular events in patients with obesity and established cardiovascular disease but not type 2 diabetes.
Immune surveillance and immune evasion of senescent cells.
Nat Rev Immunol
Pau Garcia-Baucells, Manuel Serrano, Corina Amor
Senescence, which is defined as a state of stable cell cycle arrest, can occur in all tissues of the body. The surveillance and clearance of senescent cells by the immune system is necessary for tissue homeostasis; when this immune surveillance does not occur efficiently, for example, during tumorigenesis and ageing, it has pathological consequences. For example, if the immune clearance of senescent cells is evaded, such as through recruitment of immunosuppressive cells, expression of immune checkpoint molecules by senescent cells or suppression of antigen presentation, senescent cells accumulate and lead to tissue dysfunction. Therefore, therapeutic modulation of the immune surveillance of senescent cells could be effective for the prevention and treatment of age-associated diseases including cancer. In this Review, we discuss our current understanding of the tissue-specific and context-specific processes that influence immune surveillance of senescent cells. We highlight the need for further research examining senescence across additional settings as well as the role of unexplored immune cell populations.
Impact of a durable left ventricular assist device on inflammation and cardiac remodelling in subjects with advanced heart failure.
Open Heart
Daniel Hlavacek, Anna Cinkajzlova, Marek Kollar +6 more
This study aimed to explore the association of long-term left ventricular assist device (LVAD) support with changes in inflammation and cardiac remodelling in subjects with advanced heart failure (HF).
Peptide Supplements and Their Therapeutic Applications in Sports Medicine.
Am J Sports Med
Kushagra Tewari, Timothy P Liu, Christina Im +4 more
The peptide supplement market has experienced rapid growth due to marketing claims of enhanced performance and accelerated recovery from musculoskeletal injury. These peptides are increasingly popular with patients and athletes and are often perceived as low risk, despite the absence of efficacy or safety data for many emerging peptides.
Antimicrobial Peptides of the Skin: Roles in Skin Cancer and Clinical Applications.
Exp Dermatol
Elizabeth Botto, Zoe M Lipman, Laurie A Temiz +2 more
Cutaneous antimicrobial peptides (AMPs) are increasingly recognized for their multifaceted roles in skin disease and cancer, and thus application for therapeutic potential. Beyond their contributions to innate defence and the skin's microbiome, AMPs have been implicated in inflammatory skin conditions and cutaneous malignancies. Comprehensive summaries of AMPs' roles in skin cancer and related current clinical developments remain scarce, despite abundant emerging evidence of pro- and anti-tumour properties in other fields. This review provides a comprehensive discussion of AMPs, including dermcidin, psoriasin (S100A7), human cathelicidin (LL-37), RNase-7 and the human β-defensins, in the context of skin cancer research and clinical developments. These AMPs influence skin tumorigenesis through microbiome regulation, innate immune pathways and chronic inflammation, and although the mechanistic details are subject to scrutiny, several AMP-derived therapies, including LL-37 and LTX-315, have been developed for their potential in cutaneous oncology.
Real-world effectiveness of tirzepatide among youth with type 2 diabetes and/or obesity: a multicenter analysis.
J Pediatr Endocrinol Metab
Yllka Valdez, Natalie Segev, Neha Parimi +6 more
Tirzepatide has demonstrated efficacy for adults and youth with type 2 diabetes (T2D) and adults with obesity, but real-world pediatric data remain limited. We evaluated clinical outcomes among youth prescribed tirzepatide across three academic centers.
Liver Fat Changes in Patients With Type 2 Diabetes by Presence of Genetic Hepatic Steatosis: A Post Hoc Analysis of SURPASS-3 MRI.
Liver Int
Kenneth Cusi, Amalia Gastaldelli, Laura Fernández Landó +3 more
The patatin-like phospholipase 3 (PNPLA3) I148M genetic variant is highly associated with steatotic liver disease. In the SURPASS-3 MRI substudy, tirzepatide significantly reduced liver fat content (LFC) versus insulin degludec in insulin-naïve patients with type 2 diabetes with metabolic dysfunction-associated steatotic liver disease. The influence of PNPLA3 I148M allele on changes in LFC in response to tirzepatide is unknown. This post hoc analysis evaluated changes in MRI-assessed LFC and cardiometabolic parameters by presence (genotypes GG and CG) or absence (genotype CC) of the PNPLA3 I148M allele after 52-week treatment. Tirzepatide-treated participants experienced significant reductions in LFC, weight, HbA1c, and overall greater improvement in lipids and liver enzymes regardless of the presence of PNPLA3 I148M allele. Findings were consistent across genotype subgroups. In this exploratory analysis, the presence of PNPLA3 I148M allele did not seem to affect tirzepatide-induced improvement in LFC and several cardiometabolic parameters in patients with type 2 diabetes. Trial Registration: ClinicalTrials.gov identifier: NCT03882970.