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[Liraglutide improves cardiac structure and function in mice with advanced diabetic nephropathy and massive proteinuria].
Nan Fang Yi Ke Da Xue Xue Bao
Yanzhen Yan, Wen Yang, Wangwang Li +3 more
To investigate the effects of liraglutide on cardiac structure and function in a mouse model of diabetic nephropathy at the massive proteinuria stage.
The Emerging Role of Glucagon-like Peptide 1 (GLP-1)-Based Medications in the Treatment of Heart Failure, with a Focus on Heart Failure with Preserved or Mildly Reduced Ejection Fraction.
Medicina (Kaunas)
Rachel Su Min Lee, Jas-Mine Seah, Sara Baqar +6 more
Glucagon-like Peptide 1 (GLP-1)-based medications have been extensively studied for the management of type 2 diabetes, obesity, chronic kidney disease, and atherosclerotic cardiovascular disease. More recently, their potential role in preventing and treating heart failure has gained increasing attention. Given the strong pathophysiological links among diabetes, obesity, and heart failure, GLP-1-based medications represent a promising therapeutic option to improve morbidity and mortality across these interconnected conditions. In this review, we summarise and discuss recent studies involving GLP-1-based medications that have reported on HF-related outcomes. There is increasing evidence that these medications have beneficial effects on HF outcomes in patients with heart failure with preserved ejection fraction and possibly in those with mildly reduced ejection fraction. The usefulness of GLP-1-based medications in reduced ejection fraction HF remains to be defined.
Searching for New Pharmacological Treatments of Alcohol Use Disorder (AUD): Focus on GLP-1 Receptor Agonists.
Int J Mol Sci
Jolanta B Zawilska, Ewa Zwierzyńska, Jakub Wojcieszak
Alcohol use disorder (AUD) remains a crucial public health challenge worldwide. The currently available medications for AUD remain limited in the number and efficacy, meaning that the development of new treatments is of critical importance. Agonists of glucagon-like peptide-1 receptor (GLP-1RAs) have recently received attention as a potential anti-addiction treatment, particularly in AUD. This review presents data from preclinical studies in rodents and non-human primates, registered clinical trials, observational studies, and social media posts, investigating the effects of GLP-1RAs on alcohol-related behaviors and consumption. Several GLP1-RAs and tirzepatide (a dual agonist of GLP-1R and glucose-dependent insulinotropic polypeptide receptor; GIP-R) reduced alcohol consumption and alcohol-seeking behaviors, alcohol-induced locomotor stimulation and memory of alcohol reward, and suppressed relapse drinking in rodents. In addition, they prevent acute alcohol from activating the mesolimbic dopamine system. There are limited human data on the role of the GLP-1 system in AUD. In registered clinical trials, exenatide, semaglutide, and dulaglutide reduced alcohol consumption. Pharmacoepidemiologic studies documented a decreased risk of alcohol-related events in AUD patients using various GLP-1RAs and tirzepatide. Together, existing preclinical and clinical data suggest that GLP-1 is involved in the AUD process and imply the role of GLP1-RAs as a tentative treatment for AUD.
Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer's Disease: Current Evidence and Future Directions.
Biomedicines
Klara Kopp, Patricia Silva, Frederik Damm +1 more
Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition affecting over 10-20% of individuals older than 70 years, characterized by the expansion of hematopoietic stem cell clones carrying somatic mutations in leukemia-associated driver genes in the absence of overt hematologic disease. Initially recognized as a precursor to hematologic malignancies, CHIP has since been implicated in diverse non-malignant disorders, notably increasing the risk of cardiovascular events by 40%. Recent epidemiological and experimental evidence suggests a potential disease-modifying influence of CHIP in neurodegenerative diseases, particularly Alzheimer's disease (AD), although findings remain heterogeneous and sometimes contradictory. This review synthesizes recent evidence linking CHIP to AD risk, neuropathology, and disease progression. In this study, we summarize population-based cohort studies reporting a 36 to 54% reduction in the odds of clinical AD among CHIP carriers, alongside emerging data indicating that DNMT3A and TET2 mutations may exert divergent effects on neurodegeneration. Mechanistic insights from experimental models are examined, highlighting the ability of mutated myeloid cells to infiltrate the central nervous system and modulate neuroinflammation and amyloid clearance. We discuss conflicting findings and analyze how CHIP-driven vascular disease and stroke confound neuroprotective signals. We propose that CHIP may differentially influence AD and vascular contributions to cognitive impairment and dementia, shaping mixed dementia phenotypes. Methodological challenges, including survivor bias, competing risks, variable mutation detection thresholds, and incomplete Apolipoprotein E stratification, are discussed. Ultimately, our review clarifies that CHIP is not a simple protective factor, but a complex systemic modulator that reshapes the neurodegenerative and vascular drivers of cognitive decline, necessitating cross-disciplinary neuro-hematology collaboration to establish its role as a novel risk stratificator for improving diagnostic precision and personalizing clinical outcomes in Alzheimer's disease.
Ceramic-Integrated Eddy Current Sensor for Blade Tip Clearance Measurement: Design and Performance Evaluation.
Sensors (Basel)
Qiang Miao, Zhichun Liu, Qijian Liu
Blade tip clearance (BTC) is a critical parameter for the thrust, fuel consumption, and operational safety of aero-engines, and its accurate monitorinfg is of significant engineering importance. Traditional eddy current sensors (ECS) in BTC measurement often employ wound coil structures, which suffer from issues such as poor consistency and limited geometric shapes, restricting further optimization of electromagnetic performance. This paper proposes a novel ECS based on ceramic-integrated printed coils. The ECS uses screen printing technology to directly print metal coils onto ceramic substrates and integrate them into a single unit, allowing the coils to be designed with high precision into any topology structure, with high consistency, structural stability, and high temperature tolerance. Performance studies indicate that the sensor can be manufactured with an accuracy of 0.2 mm or better, and the sensor with a line width and spacing of 0.2 mm performed the best in the test. Not only does it exhibit the best electromagnetic performance at room temperature, but it also shows an electromagnetic performance variation of less than 1% after a 24 h aging test at 800 °C. Additionally, it provides stable peak-to-peak and periodic responses to changes in BTC within the range of 0 to 600 rpm for the fan motor. This study provides a promising method for accurate and stable BTC measurement at high temperatures.
Kindlin-2 functional restoration through methylmalonic acid clearance by Coenzyme A counteracts osteoporosis.
Mol Ther
Xuling Li, Guixing Ma, Fen Wang +6 more
Old blood can induce senescence in young mice, yet the underlying mechanisms remain unclear. Here, we demonstrate that non-protein components (NP) of aged human serum (ONP) induce skeletal aging in young mice, with methylmalonic acid (MMA) identified as a key driver capable of independently recapitulating the skeletal aging phenotypes observed in ONP-treated mice. Photoaffinity labeling confirms Kindlin-2 as a direct intracellular MMA receptor. MMA binds directly to Kindlin-2 via a positively charged motif in its UBL domain, promoting Kindlin-2 ubiquitination and degradation, which accelerates skeletal aging. Notably, endogenous MMA scavenger coenzyme A (CoA), a clinically approved molecule, effectively reverses MMA- and ONP-induced skeletal aging. Furthermore, CoA treatment effectively protects against skeletal aging and bone mass loss in aged or estrogen-deficient mouse models. Our study establishes MMA as a central aging factor and Kindlin-2 as its intracellular receptor, offering a potential therapeutic strategy for age-related diseases, such as osteoporosis.
Beyond antioxidation: Retinal neuroprotection by Lycium barbarum polysaccharides via multiple signaling pathways.
Neural Regen Res
Yirong Ni, Jingping Li, Kwok-Fai So
Age-related macular degeneration, glaucoma, retinitis pigmentosa, and diabetic retinopathy are the major retinal degenerative disorders, and each ultimately leads to irreversible vision loss. In this context, single-target therapies aimed at isolated pathways have delivered only modest benefits. Lycium barbarum polysaccharides, the predominant bioactive components of goji berries, emerge as far more than simple antioxidants, functioning instead as orchestrators of interconnected signaling networks. Growing evidence shows that Lycium barbarum polysaccharides engages pathways well beyond redox control to interrupt disease-driving cascades: it limits cellular senescence through the SIRT1/p53 axis, preserves blood-retinal barrier integrity by maintaining aquaporin-4 at astrocytic endfeet, and biases microglia from proinflammatory M1 toward reparative M2 states. Beyond immunomodulation, Lycium barbarum polysaccharides promotes clearance of pathogenic protein aggregates and suppresses pathological neovascularization via the miR-15a-5p/ VEGFR2 axis. While antioxidant effects may predominate in early disease, the actions of LBP become more targeted as pathology advances, a stage-dependent selectivity that helps explain its cross-disease efficacy. In age-related macular degeneration, Lycium barbarum polysaccharides sustains metabolic homeostasis in retinal pigment epithelium by tuning autophagic flux through the miR-181/BCL-2 axis. In glaucoma, it safeguards mitochondrial membrane potential in retinal ganglion cells, supporting energy metabolism and survival. Collectively, these properties position Lycium barbarum polysaccharides as a pleiotropic regulator capable of reshaping multiple disease trajectories. Realizing its clinical potential will require precise identification of active metabolites, rigorous in vivo pharmacokinetic profiling, and rational combination with current standard-of-care therapies.
Sebum-Selective 1,726-nm Laser Therapy for Papulopustular Rosacea Associated with Demodex Mite Proliferation: A Case Report.
Clin Cosmet Investig Dermatol
Anon Paichitrojjana
Papulopustular rosacea is a chronic inflammatory condition of the pilosebaceous unit, with an unclear exact cause, but it is thought to involve an exaggerated immune response, persistent inflammation, and possibly an increased presence of Demodex mites on the skin. This is a case report of a 22-year-old woman with papulopustular rosacea treated with a 1,726-nm sebum-selective laser over three sessions. Progressive clinical improvement was observed, with a reduction of inflammatory lesions from 234 at baseline to complete clearance, along with improvement in erythema, flushing, and patient-reported symptoms. Demodex density decreased from 58 mites/cm2 to 12 mites/cm2. Treatment was well tolerated, with no adverse events and high patient satisfaction. These findings suggest that sebum-selective laser therapy may offer a non-pharmacologic treatment option for papulopustular rosacea, potentially by modulating sebaceous gland activity. Further studies are needed to confirm efficacy and clarify mechanisms.
Pharmacological Effects of Angiotensin 1-7 on Venous Vascular Tone.
Biomedicines
Armond Daci, Hygerta Berisha, Era Rexhbeqaj +3 more
Background/Objectives: The ACE2/Ang-(1-7)/Mas receptor axis is a protective, counter-regulatory component of the RAAS that opposes Ang II/AT1R-mediated vasoconstriction. The present study evaluated the pharmacological effects of Ang-(1-7) in the rat inferior vena cava (IVC), a venous capacitance vessel involved in the regulation of venous return and cardiac preload. We hypothesized that Ang-(1-7) exerts anti-contractile effects in the rat inferior vena cava through activation of potassium channel-dependent mechanisms in venous smooth muscle. Methods: Isolated IVC rings from Wistar rats were studied using organ bath assays. Ang-(1-7) effects were assessed on pre-constriction induced by angiotensin II (Ang II), phenylephrine (PE), endothelin-1 (ET-1), and thromboxane A2 analog (U46619). Responses were recorded and quantified. Mechanistic involvement of nitric oxide (NO), prostaglandins, soluble guanylate cyclase (sGC), and K+ channels was evaluated using specific pharmacological inhibitors. Results: Ang-(1-7) attenuated Ang II-induced contraction. The effect was markedly reduced by tetraethylammonium (TEA), indicating a predominant role of potassium channel-dependent mechanisms in venous smooth muscle. In contrast, inhibition of nitric oxide synthase, soluble guanylate cyclase, or cyclooxygenase had minimal influence. Ang-(1-7) also produced concentration-dependent relaxation in PE-, ET-1-, and U46619-precontracted vessels, demonstrating agonist-dependent anti-contractile activity. Conclusions: Ang-(1-7) exerts significant anti-contractile effects in the rat inferior vena cava primarily through activation of TEA-sensitive K+ channels in venous smooth muscle. These findings demonstrate functional activity of the ACE2/Ang-(1-7)/Mas axis in a major venous capacitance vessel and provide mechanistic insight into Ang-(1-7)-mediated modulation of venous tone, supporting further investigation in in vivo models.
Risk Stratification in Pulmonary Embolism: The Expanding Role of Biomarkers.
Biomedicines
Cyrus Moini, Piseth Lay, Sebastien Jochmans +4 more
Pulmonary embolism (PE) remains a frequent and potentially fatal condition, with early mortality largely driven by (RV) failure and hemodynamic collapse. Rapid and accurate prognostic assessment is therefore central to management. Current European Society of Cardiology (ESC) strategies rely first on hemodynamic status to identify high-risk patients requiring urgent reperfusion consideration, and then-when patients are normotensive-on a stepwise approach combining clinical risk scores, RV imaging, and circulating biomarkers. Clinical tools such as HESTIA and the Pulmonary Embolism Severity Index (PESI)/simplified PESI (sPESI) enable early identification of low-risk patients suitable for outpatient pathways and stratify 30-day mortality risk, but do not integrate biological data. Consequently, biomarkers have an expanding role in refining prognosis, particularly within the heterogeneous intermediate-risk group. This review provides a practical overview of established and emerging biomarkers for PE risk stratification. Conventional cardiac biomarkers-troponins and natriuretic peptides (BNP/NT-proBNP)-reflect RV myocardial injury and strain and, when combined with imaging evidence of RV dysfunction, allow discrimination between intermediate-low- and intermediate-high-risk PE, guiding monitoring intensity and escalation strategies. D-dimer, while essential in diagnostic algorithms because of its high negative predictive value, has only an adjunctive and indirect prognostic role. Beyond these markers, growing evidence supports additional biomarkers capturing complementary pathways: neurohormonal stress (copeptin), early myocardial injury (H-FABP), inflammation and hypoxia (GDF-15), tissue hypoperfusion (lactate), and molecular regulation (circulating microRNAs). Readily available inflammatory indices derived from blood counts (NLR, PLR, LMR), red cell distribution width, and hs-CRP may further contribute within multimarker models, although specificity and validation remain limitations. Future directions include multimodal and omics-driven biomarker profiling integrated with advanced imaging to enable more precise, dynamic, and personalized PE care, from acute risk prediction to long-term follow-up and prevention of chronic thromboembolic complications.
Early detection value of miR-29a in patients with acute myocardial infarction.
Front Cardiovasc Med
Yanqing Wang, Peng Gao, Yawei Duan +12 more
Early detection of myocardial remodeling, a critical precursor to heart failure in acute myocardial infarction (AMI), remains inadequate with current biomarkers. Preclinical studies suggest miR-29a plays a role in these processes, yet its diagnostic value in early AMI remains unclear. This study evaluates the diagnostic and prognostic potential of miR-29a as a marker for myocardial remodeling in AMI patients.
Neuroinflammation and Prefrontal Cortical Microcircuits: A Narrative Review of Hints from Experimental Models.
Cells
Maria Concetta Geloso, Gabriele Di Sante, Alberto Granato
Neuroinflammation is increasingly recognized as a major contributor to cognitive and neuropsychiatric dysfunction. The prefrontal cortex (PFC), a key substrate for executive functions and emotional behaviors, appears particularly vulnerable to inflammatory insults due to its high metabolic demand, prolonged developmental trajectory, and specialized microcircuit organization. In this narrative review, we focus on evidence from experimental models of neuroinflammation affecting the PFC. In particular, we approach the topic from the novel perspective of how neuroinflammation affects PFC microcircuitry, exploiting evidence from experimental models. The impact of neuroinflammatory processes on PFC microcircuit players, namely pyramidal neurons and different classes of inhibitory interneurons, will be examined and discussed. We also examine regional features that may underlie PFC susceptibility. Although available findings support the idea that neuroinflammation destabilizes PFC microcircuits, marked heterogeneity across models, timing, inflammatory burden, and readouts still limits direct comparison across studies. A more mechanistic and longitudinal understanding of these changes will be essential to clarify how inflammatory insults reshape PFC computation and contribute to cognitive dysfunction.
Metabolic Dysfunction-Associated Steatotic Liver Disease and Incretin Receptor Agonists: A Metabolic Approach to Halting Liver Disease Progression.
Medicina (Kaunas)
Ludovico Abenavoli, Anna Giulia Loricchio, Ivo Lopez +4 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with metabolic abnormalities, shares pathophysiological pathways with metabolic syndrome, and has become a leading cause of chronic liver disease in industrialized nations. In the absence of approved pharmacological treatments and due to its high risk of progression to advanced fibrosis, MASLD represents a significant clinical challenge. Incretin-based therapies, originally developed for the treatment of type 2 diabetes mellitus and obesity, have recently gained attention as promising therapeutic strategies in hepatology. Among them, GLP-1 receptor agonists have shown efficacy in reducing hepatic steatosis, inflammation, and fibrosis-related biomarkers, primarily through weight loss and enhanced insulin sensitivity. Dual agonists targeting both GLP-1 and GIP receptors, such as tirzepatide, have demonstrated superior outcomes in improving hepatic and metabolic parameters. Emerging agents like cotadutide (a GLP-1/glucagon receptor agonist) and retatrutide (a GLP-1/GIP/glucagon triagonist) represent a novel therapeutic frontier, with early clinical data indicating potent hepatoprotective effects and favorable metabolic remodeling. This narrative review examines the hepatoprotective potential of incretin-based therapies, highlighting how targeted intervention on the underlying metabolic dysfunction may lead to significant improvements in MASLD. These therapies may also exert beneficial effects on fibrosis progression; however, the currently available evidence remains limited.
Insulin and Incretin Receptor Agonists Reciprocally Alter Their Blood-Brain Barrier Permeabilities.
Int J Mol Sci
Angeline Fry, Alexis Rose, Riley Weaver +4 more
Incretin receptor agonists (IRAs) such as GLP-1-based therapies improve metabolic and cognitive outcomes and enhance brain insulin signaling. One way that IRAs could have these actions is by affecting the blood-brain barrier (BBB); however, IRA-BBB interactions are poorly studied. Here, we examined the ability of insulin and IRAs to affect each other's transport across the BBB in lean mice. We found that intracerebroventricular (ICV) administration of the insulin receptor antagonist S961 did not affect the blood-to-brain transport of the bioactive fragment of the IRA, 125I-dulaglutide (BAF). In contrast, 125I-dulaglutide (BAF) co-administered with intravenous (IV) insulin significantly enhanced 125I-dulaglutide (BAF) BBB transport into whole brain, olfactory bulb, parietal cortex, and pons, demonstrating insulin-dependent modulation of IRA BBB transport. Regional transport rates for 125I-dulaglutide (BAF) across the brain varied by ~2.5-fold, with the fastest transport into the olfactory bulb, frontal cortex, cerebellum, and pons. Co-administration of IV dulaglutide (BAF) did not alter 125I-insulin BBB transport rates (Ki) but did reduce reversible insulin binding (Vi) at the BBB by >50%, suggesting rapid effects on BBB insulin receptors. To explore the effects of chronic IRA administration, lean mice were treated with semaglutide for two weeks. Body weight and food intake were unchanged, but female mice showed reduced fasting levels of serum insulin and GLP-1 and decreased insulin transport into whole brain, while male mice showed a reduction in insulin binding at the BBB. Chronic semaglutide also reduced 125I-insulin BBB transport in female mice when studied with in situ perfusion, a procedure that removes the immediate influence of serum factors. Together, these findings demonstrate reciprocal and female-selective interactions between IRAs and insulin at the BBB. Acute insulin enhances the BBB transport of an IRA in female mice, whereas chronic IRA exposure selectively impairs insulin BBB transport in females, highlighting the BBB as a dynamic and hormone-sensitive interface with implications for long-term treatment in mouse models and potential for translation impact in humans.
Oral GLP-1-Based Therapeutics in the Obesity-Metabolic Syndrome-Diabetes Continuum: Translational Advances, Clinical Barriers, and Emerging Strategies.
Pharmaceuticals (Basel)
Syed Arman Rabbani, Manita Saini, Mohamed El-Tanani +5 more
The obesity-metabolic syndrome-diabetes continuum is driven by interconnected mechanisms including insulin resistance, dysfunctional adiposity, chronic inflammation and progressive cardio-renal-metabolic injury. This triggered a need for therapies that extend beyond glucose lowering alone. The benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as disease-modifying drugs include weight loss, cardiovascular risk reduction, glycemic control and renal protection. However, treatment burden, adherence issues and access restrictions may limit the long-term effects of injectable formulations. One significant translational development that aims to close this gap is oral GLP-1-based treatments. In this review, we examine the mechanistic rationale, formulation science and clinical development of oral GLP-1 RAs. Oral semaglutide is presented as the first validated proof of concept for systemic peptide delivery by the gastrointestinal route. The biological barriers to oral peptide absorption, including enzymatic degradation, low epithelial permeability, pharmacokinetic variability and epithelial safety constraints, are critically discussed. Enabling technologies such as SNAC-based gastric absorption, nanocarriers, mucoadhesive systems and stability-optimization platforms are evaluated. Evidence from the PIONEER program and related studies demonstrating meaningful glycemic and weight-loss efficacy, acceptable safety and clinical utility in patients with type 2 diabetes and chronic kidney disease is further synthesized. Beyond first-generation oral peptide platforms, we discuss the emerging landscape of non-peptide oral GLP-1 RAs, dual and triple incretin agonists, precision dosing strategies and model-informed drug development. Oral GLP-1-based therapeutics are shifting from a formulation breakthrough to a broader translational strategy for disease modification across the obesity-metabolic syndrome-diabetes continuum. Long-term renal outcomes, access and implementation barriers remain important priorities for future research.
Tirzepatide in Obesity-Related Obstructive Sleep Apnea: Beyond Weight Loss Toward Disease Modification?
Life (Basel)
Florin-Dumitru Mihălțan, Corina Ioana Borcea, Ancuța Alina Constantin
Obesity is a major driver of obstructive sleep apnea (OSA), traditionally managed as a mechanical disorder of upper airway collapse. However, growing evidence supports a broader pathophysiological model involving metabolic dysfunction, systemic inflammation, and ventilatory instability. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial weight loss and cardiometabolic benefits, raising the possibility of a paradigm shift in OSA management.
Multidimensional Predictors of Tirzepatide Efficacy: Clinical, Genetic, and Molecular Biomarkers for Glycemic, Weight, and Organ Protection.
Pharmaceuticals (Basel)
Min Hyeok Shin, Jin Woo Jeong, Se Eun Ha +4 more
Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates robust efficacy in glycemic control and weight reduction. However, substantial interindividual variability in treatment response is observed in clinical practice. In this narrative review, we summarize current evidence on clinical, genetic, and molecular predictors of tirzepatide response and discuss their implications for a precision medicine framework. Data from pivotal clinical trials, post hoc analyses, and relevant preclinical and clinical studies were evaluated to identify determinants of glycemic and weight loss responses, as well as hepatic and renal protective effects. Key clinical predictors include tirzepatide dose, duration of diabetes, β-cell function, baseline glycated hemoglobin, sex, age, race, concomitant therapies, and early treatment response. Genetic factors implicated in treatment variability include variants in GLP-1 receptor, GIP receptor, β-arrestin 1, transcription factor 7-like 2, fat mass and obesity-associated protein, and melanocortin 4 receptor, although tirzepatide-specific validation remains limited. Molecular biomarkers such as branched-chain amino acids, insulin-like growth factor-binding protein-1 and -2, the adiponectin-to-leptin ratio, high-sensitivity C-reactive protein, and interleukin-6 show potential as pharmacodynamic indicators of metabolic response. For organ-specific outcomes, procollagen type III N-terminal peptide and magnetic resonance imaging-proton density fat fraction are supported for assessing hepatoprotective effects, while cystatin C-based estimated glomerular filtration rate and urine albumin-to-creatinine ratio are validated markers of renoprotection. Additional candidates-including tumor necrosis factor receptor 1/2, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin-are promising but require prospective validation. Overall, predicting response to tirzepatide's multifaceted therapeutic effects necessitates an integrated, multidimensional approach that incorporates clinical characteristics, genetic variation, and molecular profiling. Ongoing validation and harmonization of these predictors may help establish a precision medicine framework for optimizing tirzepatide therapy.
Reduced CAG Repeats in the Androgen Receptor Gene May Independently Cause Polycystic Ovarian Syndrome.
Curr Issues Mol Biol
Rhea Sharma, Daniel H Shain
Polycystic ovarian syndrome (PCOS) affects over 116 million women globally and is typically linked with excess androgens such as testosterone. Many patients, however, display classic PCOS symptoms despite normal serum androgen. One proposed mechanism for these cases involves a shortened CAG (i.e., encodes glutamine) repeat length in the androgen receptor (AR) gene, which increases AR activity without elevating testosterone. Fewer glutamine repeats alter the AR's N-terminal domain and may contribute to strengthened interactions with co-activators and enhanced transcription of androgen-regulated genes. Heightened AR activity in hypothalamus neurons stimulates increased pulsatile release of gonadotropin-releasing hormone (GnRH), which disrupts pituitary secretion dynamics and favors luteinizing hormone (LH) over follicle-stimulating hormone (FSH). This altered LH/FSH ratio leads to impaired folliculogenesis, anovulation and other hallmark PCOS symptoms. Targeting AR activity directly, for example by using compounds that covalently modify the AR N-terminal domain to suppress activity, may therefore offer a more precise treatment strategy for PCOS.
The Effect of 2.45 GHz Radiofrequency Electromagnetic Radiation on Components of the Hypothalamic-Pituitary-Gonadal Axis in Male Rats.
Int J Mol Sci
Sivasatyan Vijay, Siti Fatimah Ibrahim, Khairul Osman +6 more
The brain and testes are connected via the hypothalamic-pituitary-gonadal (HPG) axis. Both are vulnerable to radiofrequency electromagnetic radiation (RF-EMR). However, no comprehensive study had evaluated the effects of RF-EMR on key hormones along this axis. Hereby, this study evaluated the effect of RF-EMR on the hormonal changes along the axis, including the neuropeptide kisspeptin. A total of 18 (N = 18) adult Sprague-Dawley rats were divided into three groups (n = 6): Control, 4 h, and 24 h. The Control group was sham-exposed to an inactive router. The exposed groups were subjected to 2.45 GHz RF-EMR for 4 and 24 h daily, for 60 days at a 20 cm distance. The power density was 0.141 W/m2 with a whole-body specific absorption rate (SAR) of 0.41 W/kg. No significant changes were observed in hypothalamic Kiss1 gene expression or serum kisspeptin levels. GnRH levels increased significantly in both exposed groups, while FSH and LH remained unchanged. Testicular testosterone was significantly reduced in the 24 h group, while serum testosterone was elevated in the 24 h group compared to the 4 h group. In conclusion, prolonged 2.45 GHz RF-EMR exposure caused selective changes in components of the HPG axis, particularly involving GnRH and testosterone, suggesting potential endocrine effects on male reproductive regulation.
Genetic Determinants of Stress Reactivity in Pregnancy: A Systematic Review and Meta-Analysis: Implications for Maternal and Fetal Health.
Genes (Basel)
Socol Ioana Denisa, Socol Flavius George, Farcaș Simona Sorina +6 more
Background: Gestation is a period of significant biological plasticity where the intrauterine environment influences fetal development via "fetal programming". This study systematically reviews and meta-analyzes the association between genetic determinants-specifically the NR3C1, FKBP5, and CRHR1 genes, chosen for their pivotal role in the functional regulation and feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis-and stress reactivity during pregnancy. Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Scopus, and Web of Science, yielding an initial total of 1430 records. After removing duplicates and screening 669 studies, a total of 34 primary observational studies were included in the systematic review and qualitative synthesis. For the quantitative synthesis, 27 articles provided sufficient data, resulting in k = 39 independent effect sizes analyzed via a mixed-effects model to account for tissue-specific and cohort-specific outcomes. Results: Systematic analysis reveals that maternal psychosocial stress significantly correlates with NR3C1 hypermethylation, acting as a biological mediator for neonatal cortisol dysregulation and hippocampal volume reduction. The FKBP5 rs1360780 polymorphism emerged as a key moderator of structural vulnerability, showing a "double-hit" effect when combined with epigenetic alterations. Furthermore, the study identifies sex-specific susceptibility, with divergent placental trajectories for male and female fetuses. Meta-analytic estimates confirmed the robustness of these associations (Rosenthal Fail-Safe N = 431,000), despite a general trend toward statistical significance (p = 0.079) in heterogeneous cohorts. Conclusions: The findings underscore a stable link between genetic determinants and prenatal stress reactivity. The interaction between molecular predisposition and environmental factors defines the health of the mother-infant dyad. These results advocate for a transition toward Precision Prenatal Medicine, integrating polygenic risk scores and epigenetic monitoring to implement early, targeted preventive interventions.