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peptide science.

Mechanobiological landscape of muscle stem cells.

Skelet Muscle

Kotaro Hirano, Yuji Hara

γ-Aminobutyric acid enhances myogenesis and heat/cold stress resistance in bovine muscle satellite cells.

Front Vet Sci

Abid Manzoor, Sajida Naseem, Zhiqi Fu +5 more

γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the central nervous system and is involved in the development of neural tissue as well as the regulation of its functions. Meanwhile, GABA has also been demonstrated to confer multiple physiological benefits, including alleviating stress and improving metabolic homeostasis. This study investigated GABA effects on proliferation, differentiation, and temperature stress protection of bovine skeletal muscle satellite cells (BSCs).

Cardiometabolic and Renal Outcomes in Semaglutide Users with Type 2 Diabetes Achieving Glycemic and Weight Goals: An Observational Cohort Study.

Adv Ther

Xi Tan, Wan-Lun Tsai, Yuanjie Liang +4 more

Within the cardiovascular-kidney-metabolic syndrome (CKM) framework, semaglutide has demonstrated benefits beyond glycemic control and weight loss in clinical trials. However, most real-world studies in type 2 diabetes (T2D) have limited assessment of broader cardiometabolic and renal outcomes. We evaluated CKM-relevant outcomes among individuals with T2D who achieved substantial hemoglobin A1c (HbA1c) and weight improvements after initiating semaglutide in real-world settings.

Semaglutide in obesity and type 2 diabetes: A review of clinical trial evidence from 1 to 5 semaglutide treatment effect in people with obesity program.

Indian J Pharmacol

Aastha Khanna, Vipin Kumar, Sahil Gola

Obesity and type 2 diabetes mellitus (T2DM) are widespread health concerns that often coexist, contributing to increased cardiometabolic risks and premature death. Despite advancements in both lifestyle interventions and medical treatments, achieving lasting weight reduction and stable glycemic control remains a major clinical challenge. This review examines findings from the semaglutide treatment effect in people with obesity 1 (STEP) 1-5 trials, which assessed the effectiveness, safety, and long-term outcomes of once-weekly semaglutide 2.4 mg for weight management in adults. These trials included individuals with and without T2DM, enabling comparison across different populations and interventions. In nondiabetic participants (STEP 1, 3, and 4), semaglutide led to average weight reductions between 10% and 17%, while in patients with T2DM (STEP 2), the reduction was around 10%. The inclusion of intensive behavioral therapy in STEP 3 further enhanced weight loss outcomes. Results from STEP 4 highlighted notable weight regain following treatment withdrawal, reflecting the relapsing nature of obesity. STEP 5 confirmed semaglutide's ability to maintain significant weight loss (~15%) and improve metabolic health over a 2-year period. The most common side effects were gastrointestinal in nature but were generally manageable and nonsevere. Collectively, these trials support semaglutide 2.4 mg as an effective and sustainable option for managing obesity and overweight, including in people with T2DM. The data also emphasize the importance of combining pharmacological therapy with lifestyle modifications and recognize obesity as a long-term condition that necessitates continuous treatment.

Weight loss maintenance after tirzepatide cessation in people with overweight/obesity: a real-world follow-up of the phase 3 SURMOUNT-CN trial.

Life Metab

Congling Chen, Zhen Ying, Qi Tang +11 more

Tirzepatide, a dual GIP/GLP-1 receptor agonist, has shown unprecedented efficacy in weight loss and improving metabolic parameters in clinical trials. However, the durability of these benefits after treatment cessation remains poorly understood. This study aimed to investigate the effect of tirzepatide cessation on body weight change in people with obesity or overweight. This real-world, observational 26-week follow-up study included participants who completed 52 weeks' study treatment during SURMOUNT-CN (NCT05024032). The analysis excluded participants who received anti-obesity medications or bariatric procedures during the 26-week follow-up. Key outcomes were the changes in body weight and waist circumference after 26 weeks, from treatment cessation (Week 52) and trial baseline (Week 0), by the SURMOUNT-CN treatment groups (tirzepatide 10 or 15 mg, or placebo). Overall, 152 participants were included (tirzepatide 10 mg: n = 57; tirzepatide 15 mg: n = 51; placebo: n = 44). Following treatment cessation (Week 52), the mean (SD) percentage changes in body weight at Week 78 were 9.1% (7.4), 12.3% (9.9), and 1.8% (5.2), and the absolute changes in waist circumference were 2.9 cm (7.5), 5.5 cm (6.5) and -0.5 cm (5.6), in tirzepatide 10 and 15 mg, and placebo groups, respectively. From trial baseline to Week 78, the mean (SD) net percentage weight changes were -8.7% (6.9), -10.6% (10.2), and -2.5% (7.0), and the changes in waist circumference were -10.5 cm (8.1), -10.6 cm (9.3) and -4.0 cm (7.2), in the tirzepatide 10 and 15 mg, and placebo groups, respectively. At Week 78, residual improvements in multiple cardiometabolic indicators were evident in the tirzepatide groups. Despite weight gain following tirzepatide cessation, participants achieved a large net weight loss and reduction in waist circumference from trial baseline to Week 78, with residual improvements in several cardiometabolic indicators.

Exploring the off-label use of liraglutide in the treatment of obesity: a review.

Mol Cell Biochem

Carla Bruna Amorim Braga, João Paulo Viana Araújo Segundo, Carlos Alberto Alves Dias Filho

Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, has been used off-label for the treatment of obesity due to its considerable weight-reducing effects. This integrative review evaluated experimental studies in humans in order to explore the pharmacological mechanisms, metabolic effects, and the various clinical responses involved in the use of this drug. The research was conducted in the PubMed database, considering articles written in English and published in the last 10 years, with 9 studies included. The studies demonstrated that liraglutide is effective for weight loss and acts through gastric emptying, modulation of satiety, and influences on brain regions. Additionally, genetic polymorphisms may interfere with the clinical response. Regarding metabolic effects, improvements in glycemia and hepatic steatosis were observed, as well as possible anti-inflammatory action and improvement in blood pressure and lipid profile. The efficacy of liraglutide does not depend on variables such as BMI (Body Mass Index) or age; however, alcohol consumption and proper adherence to treatment may influence clinical outcomes. The main adverse effects, such as nausea and constipation, were well tolerated. Therefore, liraglutide can be considered a promising alternative in the management of obesity, especially in populations with multiple metabolic risk factors.

Glucagon-like Peptide-1 Receptor Agonists and Risk of Nonarteritic Anterior Ischemic Optic Neuropathy: Systematic Review and Meta-Analysis.

Neurology

Thanansayan Dhivagaran, Fahad Butt, Luckshann Arunasalam +7 more

Recent observational studies have reported conflicting evidence regarding an association between glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly semaglutide, and nonarteritic anterior ischemic optic neuropathy (NAION). We aimed to synthesize the pooled evidence assessing the association between GLP-1RA use and NAION risk.

Mild hypothermia alleviates post-resuscitation cerebral injury in rats via modulating the balance of the renin-angiotensin system.

Resusc Plus

Yongjing He, Qianqian Wu, Sisi Huang +6 more

Cardiac arrest and cardiopulmonary resuscitation represent a major cause of mortality. Cerebral ischemia-reperfusion injury following Cardiac arrest and cardiopulmonary resuscitation leads to severe neurological deficits and significantly worsens patient prognosis. Current clinical guidelines recommend targeted temperature management as a standard therapeutic approach following cardiopulmonary resuscitation. Multiple animal studies have demonstrated that mild hypothermia treatment exerts definite neuroprotective effects. However, the precise mechanisms of hypothermic neuroprotection remain incompletely understood. The renin-angiotensin system, a critical humoral regulatory system, operates through two opposing axes: the Angiotensin Converting Enzyme-Angiotensin II-Angiotensin II Type 1 Receptor axis (pro-inflammatory) and the Angiotensin-Converting Enzyme 2-Angiotensin-(1-7)-Mas Receptor axis (cytoprotective). A brain renin-angiotensin system has been implicated in neurological disorders including Parkinson's disease and blood-brain barrier dysfunction. However, currently there are no studies that have explored the dynamic changes of the intracerebral renin-angiotensin system following resuscitation and the modulatory effects of hypothermia on it. Our study investigates that mild hypothermia treatment improves neurological outcomes in post-resuscitation rats by shifting the balance of local brain renin-angiotensin system activity toward the protective Angiotensin Converting Enzyme 2-Angiotensin-(1-7)-Mas Receptor axis, while suppressing the deleterious Angiotensin-Converting Enzyme-Angiotensin II-Angiotensin II Type 1 Receptor pathway through downregulation of Angiotensin II Type 1 Receptor expression. This demonstrates renin-angiotensin system involvement in post-resuscitation brain injury and suggests new directions for studying hypothermic neuroprotection mechanisms and clinical applications.

Adverse outcomes due to atrioventricular synchrony loss induced by temporary VVI pacing in patients with pre-existing DDD stimulation: insights from a device recall scenario.

Europace

Cristian Martignani, Giulia Massaro, Alberto Spadotto +5 more

Temporary reprogramming of dual-chamber (DDD) pacemakers to non-synchronous ventricular modes (VVI/VVIR) may be required in selected clinical scenarios, but short-term consequences of abrupt atrioventricular (AV) synchrony loss remain incompletely characterized.Leveraging a unique natural experiment, this study aimed to quantify the clinical and echocardiographic consequences of temporary VVI/VVIR pacing in patients in sinus rhythm chronically adapted to DDD stimulation.

Paternal Caffeine Exposure Programs Offspring Stress Vulnerability via Sperm Dlk1-Dio3 Imprinting-Directed Remodeling of a Novel Neural Circuit.

Adv Sci (Weinh)

Mengxi Lu, Gaole Dai, Sen Zhu +8 more

Paternal environmental exposures program offspring neurodevelopment via sperm epigenetics, yet mechanisms for intergenerational hypothalamic-pituitary-adrenal (HPA) axis dysregulation, a core hub for stress disorders, remain elusive. Using a paternal preconception caffeine exposure (PPCE) rat model with in vitro fertilization to exclude maternal confounders, we uncover a novel pathway linking sperm epigenetics to offspring HPA axis hyperresponsivity. By elevating paternal corticosterone, PPCE induces hypomethylation at the intergenic differentially methylated region (IG-DMR) within sperm Dlk1-Dio3 domain. This epigenetic alteration evades postfertilization reprogramming, persists in offspring hippocampus, and derepresses the maternally expressed miRNA cluster, causing posttranscriptional downregulation of glutaminase (GLS). Hippocampal GLS deficiency impairs glutamatergic neurotransmission in a novel circuit: ventral hippocampal CA1 glutamatergic neurons (vCA1Glu) → piriform cortex γ-aminobutyric acid-ergic neurons (PirGABA) → paraventricular nucleus corticotropin-releasing hormone neurons (PVNCRH). Chemogenetic activation of this circuit rescues HPA axis hyperresponsivity and affective phenotypes. Clinically, sperm IG-DMR hypomethylation correlates with elevated plasma cortisol in prospective fathers. Importantly, paternal folic acid supplementation prevents these epigenetic alterations and restores offspring stress homeostasis. Our study delineates an intergenerational mechanism and identifies a potentially translatable prenatal intervention strategy.

Salivary responses to an experimental activation of the HPA axis in pigs: Effects of ACTH on analytes related to stress, immune system, inflammation, redox status and metabolism.

Vet Anim Sci

María Botía, José Joaquín Cerón, Silvia Martínez-Subiela +3 more

Non-invasive biomarkers are essential for assessing stress and welfare. Saliva is a suitable sample type because it can reflect endocrine, immune, inflammatory and redox responses without causing stress from handling. This study examined the impact of administering adrenocorticotropic hormone (ACTH) on a broad range of salivary analytes in pigs, to characterise the physiological response of saliva to the activation of the hypothalamic-pituitary-adrenal (HPA) axis. A total of twenty-two male Landrace x Large White pigs were randomly assigned to receive either ACTH (10 µg/kg; n = 11) or saline solution (n = 11). Saliva samples were collected before and after injection (at 20, 40, 60, 90 and 120 min, and after 24 h) and analysed for biomarkers of stress (cortisol, cortisone, chromogranin A, alpha-amylase, total esterase activity, butyrylcholinesterase and oxytocin), inflammation (haptoglobin, C-reactive protein and calprotectin), immunity (adenosine deaminase and total proteins), redox status (cupric reducing antioxidant capacity), and metabolism (urea and creatinine). ACTH administration induced significant increases in cortisol, cortisone, and total esterase activity, confirming HPA axis activation. However analytes related to sympathetic activation (chromogranin A and alpha-amylase) or positive welfare (oxytocin) remained unchanged. Regarding inflammatory markers, haptoglobin and calprotectin, but not C-reactive protein, increased. No significant changes were observed in redox and metabolism biomarkers. These data contribute to a better understanding of the physiological response of saliva components to ACTH administration, which is one of the major mechanisms involved in acute stress.

Peri-Arterial Neural Dissection During Adrenal Surgery Provides a Denervation-Like Benefit in Hypertension Control.

Hypertension

Liqi Yi, Yibang Cheng, Hai Huang +7 more

Peri-arterial neural tissue surrounding the renal artery contributes to sympathetic overactivity in hypertension. During adrenal surgery, surgical peri-arterial neural dissection may interrupt these fibers and exert a renal denervation-like effect. Whether this maneuver improves postoperative blood pressure control remains unclear.

When hidden steroids cause harm: Secondary adrenal insufficiency from unrecognised exposure.

Malays J Pathol

N A Absul, S C Thambiah, A D Masiman +2 more

Adrenal insufficiency is a life-threatening condition that often presents with non-specific symptoms, complicating diagnosis in elderly patients.

Activity dynamics in the NPY neuronal signaling of mPFC in response to an air puff.

Stress

Eugene Dimitrov, Ted Usdin, Janice H Urban

These studies were designed to elucidate the role of NPY in modulating the responses of mPFC to acute stress in mice. Fiberoptic photometry recorded a robust increase in the NPY fluorescent signal in the mPFC during exploration of the elevated O-maze (EOM). An application of a single air puff (stressor) increased anxiety-like behavior and was associated with a decreased NPY signal in the mPFC. Antagonism of Y1 receptors (Y1r) in the mPFC with BIBO3304 decreased time spent in the open compartments of the EOM, identifying a role for endogenous NPY in modulating anxiety-like behavior. While the chemogenetic actuation of local parvalbumin neurons (PVs) increased anxiety-like behavior, an injection of NPY into the mPFC decreased the Ca2+ signal detected from PVs in response to the stressor, an indication of NPY-mediated inhibition of PVs. Injection of NPY into the mPFC increased, while injection of BIBO3304 decreased, the Ca2+ signal detected from mPFC→BLA projections in response to the air puff stress. Viral tracing demonstrated that, while NPY neurons in the mPFC receive monosynaptic input from many brain regions, their axonal output is restricted to layers of the mPFC, with one of the targets being local PVs. These results demonstrate that ongoing inhibition of PV activity in the mPFC by NPY via Y1r influences anxiety-like activity in mice, likely through strengthening mPFC output to the BLA. Subjecting animals to an acute stress disrupts this circuitry, providing further and new support for a role of NPY in the mPFC and the modulation of stress-related behaviors. These studies were designed to elucidate the role of NPY in modulating the responses of mPFC microcircuitry to acute stress in mice. Using an NPY biosensor in the mPFC, fiberoptic photometry recorded a robust increase in the NPY fluorescent signal during exploration of the elevated O-maze (EOM). An application of a single air puff (stressor) increased anxiety-like behavior in the EOM and was associated with a decreased NPY signal in the mPFC, supporting a possible link between NPY signaling and levels of anxiety. Antagonism of Y1 receptors (Y1r) in the mPFC with BIBO3304 decreased time spent in the open compartments of the EOM, identifying a role for endogenous NPY in modulating anxiety-like behavior. The chemogenetic actuation of local parvalbumin neurons (PVs) increased anxiety-like behavior. Conversely, an injection of NPY into the mPFC decreased the Ca2+ signal detected from PVs in response to the stressor, an indication of NPY-mediated inhibition of PVs. Injection of NPY into the mPFC significantly increased, while injection of BIBO3304 decreased, the Ca2+ signal detected from mPFC→BLA projections in response to the air puff stress. Viral tracing demonstrated that, while NPY neurons in the mPFC receive monosynaptic input from many brain regions, their axonal output is restricted to layers of the mPFC, with one of the targets being local PVs. These results demonstrate that ongoing inhibition of PV activity in the mPFC by NPY via Y1r influences anxiety-like activity in mice, likely through strengthening mPFC output to the BLA. Subjecting animals to an aversive air puff acute stress disrupts this circuitry, providing further and new support for a role of NPY in the mPFC and the modulation of stress-related behaviors.

CircMAPK1-encoded micropeptide circMAPK1-110aa inhibits proliferation and differentiation of goat skeletal muscle satellite cells by suppressing MAPK1/3 phosphorylation.

Int J Biol Macromol

Qianqian Pan, Mengyu Lou, Mengkang Zhu +4 more

Skeletal muscle development directly determines growth efficiency and meat quality in livestock. Circular RNAs (circRNAs) and their encoded micropeptides are emerging regulators of this process, yet their roles in goats remain poorly understood. Through integrated ribosome profiling (Ribo-seq) and circRNA-seq of goat skeletal muscle satellite cells (SMSCs), we identified a MAPK1-derived protein-coding circRNA, circMAPK1 (novel-circ-0039015). Functional analyses revealed that circMAPK1 overexpression suppressed SMSCs proliferation and myogenic differentiation. Mechanistically, circMAPK1 encodes a 110-amino-acid micropeptide (circMAPK1-110aa) that binds Mitogen-Activated Protein Kinase Kinase 1 (MAP2K1) and reduces MAPK1/3 phosphorylation, thereby attenuating Mitogen-Activated Protein Kinase (MAPK) signaling. Importantly, pharmacological activation of the MAPK pathway with C16-PAF partially restored muscle cell growth and differentiation. These findings establish circMAPK1 as a negative regulator of goat skeletal muscle development and highlight its encoded micropeptides as a potential molecular target. By uncovering a new regulatory mechanism of muscle growth, this study provides valuable insights for breeding strategies aimed at enhancing meat yield and quality in goats.

Pervasive and programmed nucleosome distortion on single chromatin fibres.

Nature

Marty G Yang, Hannah J Richter, Simai Wang +19 more

Despite decades of biochemical and structural studies of the nucleosome1, researchers lack genome-scale methods to determine variability in nucleosome structure along individual chromatin fibres. To address this, here we present Iteratively Defined Lengths of Inaccessibility (IDLI), a computational method that maps the single-molecule co-occupancy of structurally distinct nucleosomes, subnucleosomes and other protein-DNA interactions through long-read single-molecule footprinting2,3. IDLI classifies methylase-inaccessible footprints on individual chromatin fibres into (i) linker-histone-associated nucleosomes; (ii) nucleosomes with focal DNA accessibility along the nucleosome wrap; (iii) unwrapped nucleosomes; and (iv) subnucleosomal species such as hexasomes, tetrasomes and other short DNA protections. Applying IDLI to chromatin from mouse embryonic stem cells, we discover that more than 85% of nucleosomes exhibit intranucleosomally accessible DNA (nucleosome 'distortion'). We observe epigenomic-domain- and expression-level-specific patterns of distortion, including at promoters and mouse satellite repeat sequences. Transcription factor (TF) motif occurrence correlates significantly with distinct types of distortion, and degron experiments provide evidence of direct regulation by TFs. We apply IDLI to in vitro endoderm differentiation in human induced pluripotent stem cells and primary mouse hepatocytes. In both cases, we observe distortion at pioneer TF FOXA2 binding sites, demonstrating that distortion is developmentally encoded and present in vivo. Finally, genetic experiments in mice show that a nucleosome-binding domain of FOXA2 directly affects nucleosome structure in vivo, implicating these protein-nucleosome interactions as direct mediators of distortion. Our work suggests extreme but regulated nucleosome structural variability at the single-molecule level. Furthermore, our approach offers opportunities to model TF binding, nucleosome remodelling and cell-type-specific chromatin regulation across biological contexts.

GLP-1R-GIPR-PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice.

Nature

Daniela Liskiewicz, Aaron Novikoff, Ahmed Khalil +50 more

There are increasing numbers of effective drugs to improve obesity-linked metabolic dysfunction; GLP-1R-GIPR co-agonism is effective in the management of obesity and type 2 diabetes1,2, and lanifibranor-a nuclear-acting small-molecule triple agonist of PPARα, PPARγ and PPARδ-is in clinical phase 3 trials for the treatment of metabolic dysfunction-associated steatohepatitis3. Here, seeking to further improve the metabolic efficacy of GLP-1R-GIPR co-agonism, we report the development of a unimolecular quintuple agonist that combines the body weight-reducing and blood glucose-lowering effects of GLP-1R-GIPR co-agonism with the insulin-sensitizing and anti-inflammatory effects of lanifibranor via its targeted delivery into GLP-1R- and GIPR-expressing cells. In vitro, GLP-1-GIP-lanifibranor is indistinguishable from GLP-1-GIP in relation to incretin receptor signalling and shows equal stimulation of insulin secretion in isolated mouse islets. In vivo, however, GLP-1-GIP-lanifibranor outperforms GLP-1R-GIPR co-agonism and semaglutide, further decreasing body weight, food intake and hyperglycaemia in obese and insulin-resistant mice through synergistic incretin and PPAR action. The metabolic action of GLP-1-GIP-lanifibranor is blunted in mice with genetic or pharmacological inhibition of GLP-1R, GIPR or PPARδ and is absent in DIO double incretin receptor-knockout mice, collectively suggesting that GLP-1-GIP-lanifibranor has substantial therapeutic value in the treatment of obesity and diabetes.

Impact of Tirzepatide on FIB-4 in Patients with Type 2 Diabetes: A Comparison between GLP-1RA-naïve and GLP-1RA Switch Initiation in a Retrospective Cohort.

Intern Med

Hiroyuki Ito, Chiaki I, Mizuki Matsushita +6 more

Objective Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to improve hepatic inflammation and steatosis in patients with type 2 diabetes. However, whether its effects on Fibrosis-4 (FIB-4), a surrogate marker of liver fibrosis, differ between patients naїve to GLP-1 receptor agonists (GLP-1RAs) and those who have switched from a GLP-1RA remains unclear. Methods In this single-center retrospective study, 65 Japanese patients with type 2 diabetes received tirzepatide for ≥6 months (GLP-1RA-naïve: n=15; GLP-1RA-treated: n=50). The primary outcome was change in the FIB-4. The secondary endpoints included changes in glycated hemoglobin (HbA1c), body weight, urinary protein, and estimated glomerular filtration rate (eGFR). Multivariable analyses were performed to identify the predictors of FIB-4 improvement. Results FIB-4 significantly decreased in the GLP-1RA-naïve group (from 1.55±1.01 to 1.25±0.74, Δ-0.26±0.32, p<0.01) but not in the GLP-1RA-treated group (Δ-0.02±0.23), with a significant between-group difference (p<0.05). HbA1c decreased in both groups, with a greater reduction in GLP-1RA-naïve patients (Δ-2.0±1.3% vs. -1.0±1.3%, p<0.01). Body weight decreased significantly in both groups (-3.5±5.5 kg vs. -2.2±3.5 kg), with no between-group difference. A multivariable analysis identified age, baseline FIB-4, and GLP-1RA-naïve status as independent predictors of FIB-4 reduction. Conclusion Tirzepatide significantly reduced FIB-4, particularly in patients who were GLP-1RA-naïve, and produced substantial reductions in HbA1c and body weight. As an exploratory and hypothesis-generating analysis, these findings suggest that initiating tirzepatide in GLP-1RA-naïve patients may be associated with favorable changes in fibrosis-related risk markers in patients with type 2 diabetes at a high risk of liver fibrosis.

Angiotensin-(1-7) suppresses pyroptosis in cerebral endothelium to decrease blood-brain barrier permeability and cognitive impairments in sepsis.

J Int Med Res

Yongli Han, Hongguang Ding, Yirun Chen +5 more

ObjectiveThis study aimed to explore the influence of the angiotensin-(1-7)/Mas receptor and angiotensin II/angiotensin II type 1 receptor pathways on pyroptosis during sepsis and their subsequent effects on cognitive function.MethodsAdult C57BL/6 mice were subjected to cecal ligation and puncture to induce sepsis. Brain microvascular endothelial cells were treated with angiotensin II and angiotensin-(1-7) to evaluate their impact on pyroptotic processes. Cognitive performance was assessed using the Morris water maze method, and blood-brain barrier permeability was quantified using Evans blue staining.ResultsCompared with the sham group, sepsis induced sustained activation of the angiotensin II/angiotensin II type 1 receptor pathway, whereas the angiotensin-(1-7)/Mas receptor pathway was progressively suppressed. Genetic ablation of cysteine-dependent aspartate protease-1 significantly attenuated pyroptosis in brain endothelial cells, decreased blood-brain barrier permeability, and enhanced cognitive function in septic mice compared with that in the cecal ligation and puncture group. Angiotensin-(1-7) treatment improved cognitive function in septic mice and significantly suppressed angiotensin II-induced pyroptosis, with these effects reversed by the Mas receptor antagonist A-779.ConclusionsThis study identified a novel mechanism in which angiotensin-(1-7) selectively suppresses angiotensin II-induced pyroptosis in brain endothelial cells, consequently ameliorating cognitive deficits during sepsis.

Euthyroid Sick Syndrome Precipitated By Rapid Weight Loss Following Semaglutide Initiation: A Case Report.

Clin Med Insights Endocrinol Diabetes

Ziad W Elmezayen, Farah Qrareya, Abdallah Abdallah +2 more

Euthyroid sick syndrome (ESS) is characterized by abnormal thyroid function tests, most notably a low triiodothyronine (T3) level, occurring in the absence of intrinsic thyroid disease. A 54-year-old woman presented to the endocrinology clinic with a 4-month history of progressive fatigue, lethargy, and new-onset cold intolerance after initiation of semaglutide for weight management. The dose was titrated monthly over 4 months, during which she experienced significant weight loss of 22 kg. Laboratory evaluation revealed a thyroid function profile classic for ESS, with low free T3, low-normal free T4, and a normal thyroid-stimulating hormone (TSH) level that was inappropriately low relative to the reduced T3. After exclusion of primary thyroid and pituitary disorders, a diagnosis of ESS secondary to the catabolic state induced by rapid weight loss was made. The patient was counseled that this represented a physiological adaptation rather than intrinsic thyroid disease. Semaglutide was continued given its metabolic benefits, and nutritional optimization with adequate caloric and protein intake was advised.