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Antimicrobial Peptide BSN-37 Enhances Macrophage Immune Activation Through the circBptf-Rbm14-Mediated Regulatory Axis.
Probiotics Antimicrob Proteins
Xiaojing Xia, Xujie Zhao, Yanhe Lv +12 more
Antimicrobial peptides (AMPs) are increasingly recognized as regulators of immune cell function, yet whether they engage nuclear regulatory circuits to control macrophage activation remains unclear. Here, we report that the bovine cathelicidin BSN-37 promotes macrophage immune activation through a regulatory mechanism associated with the nuclear circRNA circBptf and the RNA-binding protein Rbm14. Transcriptomic profiling revealed that BSN-37 markedly remodels the circRNA landscape and consistently suppresses circBptf, a circular RNA derived from the chromatin-regulatory Bptf locus. circBptf is a stable nuclear RNA that functions as a negative regulator of macrophage activation, limiting cytokine production and antigen-presentation-related molecules. Mechanistically, circBptf physically associates with the nuclear RNA-binding protein Rbm14, a transcriptional co-regulator linked to immune gene expression. Functional perturbation analyses indicate that circBptf overexpression suppresses macrophage activation, whereas Rbm14 promotes the expression of cytokines and antigen-presentation-related molecules. Functional rescue experiments further support a circBptf-Rbm14-associated regulatory module involved in BSN-37-induced macrophage activation. Together, these findings support a nuclear circRNA-RBP-associated regulatory module linking an antimicrobial peptide to circRNA-mediated control of transcription and identify circBptf as a negative regulatory component of macrophage activation. This work expands the understanding of AMP-mediated immunoregulation by revealing how noncoding RNA-protein interactions contribute to coordinated immune gene expression.
Validation of a Pharmacist-Led Semaglutide Prescribing Algorithm for Type 2 Diabetes and Chronic Kidney Disease: Research Letter.
Can J Kidney Health Dis
Maneka Sheffield, Emma Phelan, Natalie Ratajczak +10 more
Diabetes is a leading cause of chronic kidney disease, yet gaps in the use of guideline-directed therapies persist in primary care. In 2025, our group developed and validated community pharmacist-led prescribing algorithms for individuals with an estimated glomerular filtration rate ≥30 mL/min/1.73 m2, targeting angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, sodium-glucose cotransporter-2 inhibitors, and nonsteroidal mineralocorticoid receptor antagonists. To address the evolving therapeutic landscape, we developed and validated a semaglutide-specific algorithm to complement this approach. Algorithm development and validation followed Lynn's method. A two-part questionnaire per algorithm item assessed content and face validity, with nephrology clinicians (nephrologists and kidney pharmacists) and community pharmacists rating items using Likert scales. Content validity was measured using item-level (I-CVI) and scale-level (S-CVI/Ave) indices, while face validity was assessed by level of agreement to five statements per round. The algorithm was iteratively revised between rounds. Ten nephrology clinicians (five per round for three rounds) and 12 community pharmacists (six per round for two rounds) participated. For clinicians, the I-CVI ranged from 0.6 to 1.0, with an overall S-CVI/Ave of 0.89 across three rounds. Among pharmacists, all items met the prespecified content validity threshold for both rounds (I-CVI ≥0.83; P < 0.05). Face validity exceeded the 70% consensus threshold for both validator groups. This study adds a validated semaglutide-specific algorithm to our existing pharmacist-led care model, expanding a suite of algorithms to support uptake of disease-modifying therapies for individuals with type 2 diabetes and chronic kidney disease in primary care. Implementation and evaluation in Nova Scotia community pharmacy clinics are underway.
GLP-1-based incretin therapy is associated with lower incident Alzheimer's disease and cardiorenal events in adults with documented neuropsychiatric, cognitive, or sensory risk.
Biol Methods Protoc
Karthik Murugadoss, A J Venkatakrishnan, Venky Soundararajan
Alzheimer's disease (AD) develops over years, creating an opportunity for interventions that target modifiable risk factors before the onset of clinical dementia. Here we applied a federated electronic health record (EHR) system encompassing over 29 million de-identified patients toward a target-trial emulation framework involving 153,412 adults aged 50 years or older with at least one documented AD risk factor. New users of glucagon-like peptide-1 (GLP-1)-based incretin therapy were compared with new users of non-GLP-1 antidiabetic medications after a 12-month washout, with 1:1 propensity-score matching on 30 baseline variables and additional exact matching on index year of therapy initiation and 5-year age band. In the primary matched cohort, 28,901 patients per arm, incretin initiation was associated with lower first recorded AD diagnosis (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.29-0.73, q = 0.003), all-cause dementia (HR 0.66 [0.55-0.79], q < 0.001), and all-cause mortality (HR 0.46 [0.37-0.58], q < 0.001), with directionally-lower Mild Cognitive Impairment (HR 0.76 [0.61-0.94], q = 0.135) and Alzheimer's-related medication initiation (HR 0.82 [0.65-1.03], q = 0.217). The AD diagnosis mitigation signal was independently reproduced for semaglutide (HR 0.56; N = 23,675 per arm; q = 0.02), with the directionally consistent tirzepatide point estimate (HR 0.60) not reaching significance. GLP-1 RA initiation was also associated with substantially lower (all q < 0.001) incidence of heart failure (HR 0.50 [0.45-0.55]), cardiomyopathy (HR 0.38 [0.31-0.47]), major adverse cardiovascular events (HR 0.74 [0.67-0.82]), acute kidney injury (HR 0.67 [0.67-0.74]), and chronic kidney disease (HR 0.68 [0.62-0.75]). Negative-control outcomes showed no significant separation (all q > 0.45), including allergic rhinitis (HR 0.96 [0.87-1.07]), hemorrhoids (HR 1.07 [0.95-1.21]), and inguinal hernia (HR 1.39 [0.89-2.18]). Stricter two-code ICD definitions supported lower first recorded AD diagnosis in the incretin arm (HR 0.51 [0.29-0.89], q = 0.018) and lower first recorded all-cause dementia diagnosis (HR 0.68 [0.54-0.85], q = 0.003). In 12-month landmark analyses among semaglutide initiators, ≥5% weight-loss responders had lower 3-year AD cumulative incidence than non-responders after matching (0.07% vs. 0.40%; incidence ratio 5.76; P = .036), although this was not significant in the hazard-ratio model (HR 0.54, P = .39). Sustained-dose stratification showed no comparable gradient (high-dose vs. low-dose 0.30% vs. 0.14%; HR 2.77; P = .38), with ≤12 AD events per group. The weight-loss-specific pattern did not extend to all-cause dementia: weight-loss responders and non-responders had similar 3-year cumulative incidence (1.54% vs. 1.70%; HR 0.87, P = .53). Initiation of GLP-1 receptor agonist therapy in adults with documented AD risk factors was associated with lower recorded incidence of AD, dementia, mortality, and multiple cardiovascular and renal outcomes in this observational target-trial emulation. These findings support the hypothesis that earlier incretin therapy may contribute to AD risk modification through upstream cardiometabolic pathways, while prospective randomized prevention studies will be required to determine causality, underlying biological mechanisms, and optimal treatment timing.
Real-world evaluation of the effectiveness and safety of tirzepatide in patients with obesity: A prospective study.
Clin Nutr ESPEN
Belén Pérez-Pevida, Mónica Santana Santana, Cristina Liaño Arriola +7 more
Recent randomised controlled trials have demonstrated the efficacy of tirzepatide in inducing weight loss among adults with overweight or obesity, irrespective of diabetes mellitus status. However, evidence from real-world settings remains limited. This study aimed to evaluate the effectiveness and safety of tirzepatide for weight management in routine clinical practice.
Effect of tirzepatide and semaglutide on blood pressure: A systematic review and meta-analysis.
Endocrine
Qing-Xin Chen, Xiao-Yu Zhou, Qi Wu +4 more
Tirzepatide and semaglutide are widely used for type 2 diabetes mellitus (T2DM) and obesity. However, the blood pressure-related adverse event profiles associated with tirzepatide and semaglutide remain unclear. This study systematically evaluated hypertension- and hypotension-related treatment-emergent adverse events (TEAEs) that occurred when using tirzepatide and semaglutide for the treatment of T2DM or obesity.
Long non-coding RNAs in glial cells: key drivers of neuroinflammation in cognitive disorders.
Front Aging Neurosci
Chiara Malatino, Ivana Raffaele, Angelo Quartarone +4 more
Neurodegenerative diseases (NDs) are characterized by the progressive deterioration of cognitive and motor functions. In this context, glial cell-mediated neuroinflammation is recognized as a key driver of disease progression. Long non-coding RNAs (lncRNAs) have emerged as key epigenetic regulators that modulate gene expression and inflammatory signaling pathways in this context. Due to their high cell-type specificity and dynamic regulation, lncRNAs are promising diagnostic biomarkers and therapeutic targets for NDs. The balance between the neuroprotective and proinflammatory functions of glial cells plays a crucial role in ND progression. LncRNAs act as multifunctional modulators of glial activity, influencing neuroinflammatory responses, astrocyte and microglia dysfunction, and the clearance of toxic protein aggregates. Several lncRNAs, including RMST, MALAT1, and NEAT1, regulate inflammatory pathways through various molecular mechanisms. For example, they act as competing endogenous RNAs that absorb microRNAs. These regulatory networks influence key signaling cascades involved in neuroinflammation, including Toll-like receptor (TLR)-mediated pathways, the NF-κB signaling axis, and NLRP3 inflammasome activation. In this review, we summarize and categorize glial lncRNAs according to their molecular interactions and functional roles in disorders related to cognitive decline. By integrating current evidence, we highlight the contribution of lncRNA-mediated regulatory networks to neuroinflammatory processes and discuss their potential as biomarkers and therapeutic targets. Our findings suggest that glial lncRNAs are crucial regulators of neuroinflammation in cognitive disorders. Their ability to modulate pathways such as the NLRP3 inflammasome makes them promising diagnostic biomarkers and therapeutic targets. Targeting these molecular networks provides new opportunities to halt neurodegeneration and improve clinical outcomes.
Development and Evaluation of a Clinical Prediction Model for Acute Kidney Injury Risk in Elderly Patients with Heart Failure with Reduced Ejection Fraction.
Glob Heart
Rui Yang, Qiqi Song, Haohan Ma +6 more
Acute kidney injury (AKI) is a significant complication among patients with heart failure with reduced ejection fraction (HFrEF). Once AKI occurs, therapeutic options are limited to supportive care, underscoring the clinical importance of early identification of patients at risk. This study sought to identify independent predictors of AKI development in geriatric HFrEF patients and subsequently establish a clinically applicable bedside risk quantification.
Glucagon-like peptide-1 and peptide YY multi-agonism with GEP44 to optimize weight loss and glycemic control while reducing gastrointestinal side effects: the future of anti-obesity pharmacotherapy?
Front Endocrinol (Lausanne)
Melissa A Burmeister, Skyler A Brown, Jakeem J Greer +2 more
Obesity is a chronic, multifactorial disease that has reached epidemic status. The glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) is a key therapeutic target to achieve weight loss and glycemic control in obesity and type 2 diabetes mellitus. Tirzepatide and retatrutide, the latest generation of GLP-1-incorporating multi-agonists, target multiple receptors in complementary systems to achieve marked and sustained weight loss. However, the associated gastrointestinal (GI) side effects (e.g., nausea, vomiting, diarrhea, abdominal pain) that often hinder patient compliance underscore a remaining need for therapies with better tolerability. GEP44, a novel, monomeric, chimeric peptide structurally based on native GLP-1, the GLP-1RA exendin-4 (Ex-4), and the gut-derived hormone peptide YY3-36 (PYY3-36), is an agonist at the GLP-1R and multiple neuropeptide Y (NPY) receptors. This review summarizes the design rationale for GEP44 and preclinical evidence supporting its beneficial metabolic effects and tolerability. Like GLP-1, PYY3-36 is associated with decreased food intake (FI), and co-administration of GLP-1RA and PYY3-36 elicits synergistic food intake (FI)- and body weight (BW)-reducing effects with similar or enhanced blood glucose (BG)-lowering effects. Studies examining the efficacy of GEP44 to promote weight loss and improve glucoregulation in lean vs. diet-induced obese rodents report that peripheral administration generally decreases BW, FI, and insulin resistance and increases EE at equivalent or greater magnitudes than those observed with single GLP-1RAs in a GLP-1R-dependent manner with improved GI tolerability. These beneficial actions reflect GEP44's potential to expand the mechanistic scope of anti-obesity medications.
Maximizing Metabolic Synergy: A Review of Dual Incretin Therapy as a Step-Up Strategy Following Glucagon-Like Peptide-1 (GLP-1) Monotherapy Failure or Optimization.
Cureus
Soroush Ansari Lari, Maya S Zumot, Manar A Alrashid
While single-pathway glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have transformed metabolic medicine, patients encounter therapeutic ceilings, glycemic plateaus, and weight-loss stagnation despite ongoing treatment. The emergence of dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor (GLP-1R) co-agonists offers a novel multi-receptor mechanism that can overcome these single-pathway limitations. This review synthesizes current clinical evidence supporting the transition from single-pathway GLP-1 monotherapy to dual-pathway co-agonism and outlines practical, evidence-based clinical strategies to safely and effectively implement this step-up therapy. A comprehensive literature search was conducted across the PubMed, Embase, and Google Scholar databases for peer-reviewed articles published from inception through June 15, 2026, focusing on the landmark SURPASS, SURMOUNT, and SUMMIT trial programs, relevant cardiorenal post hoc analyses, emerging body recomposition trials, and real-world cohort-switching protocols. Based on this review, evidence from head-to-head and insulin-comparator trials demonstrates that dual GIP/GLP-1 co-agonism consistently overcomes metabolic plateaus that result from single-pathway therapy, producing superior glycated hemoglobin reduction, bariatric-level weight loss (up to 25.3%), and robust macrovascular and heart failure protection, including a 38% reduction in composite cardiovascular risk among patients with heart failure with preserved ejection fraction (HFpEF). Furthermore, recent phase 2 data demonstrate that the lean mass loss associated with profound weight loss can be pharmacologically managed; when tirzepatide is paired with the anti-myostatin agent apitegromab, sarcopenic risk is mitigated by nearly halving lean mass loss compared with dual-incretin monotherapy (14.6% vs. 30.2%), though whether this muscle-sparing synergy extends to single-pathway GLP-1 agents remains unverified. The transition from single-pathway GLP-1R agonism to dual incretin therapy reflects a broader shift toward comprehensive metabolic risk reduction rather than glycemic control alone. To safely maximize therapeutic benefits while maintaining tolerability in patients with treatment plateaus, clinicians should use structured escalation protocols characterized by clear candidate phenotyping, direct next-dose conversion without prolonged washout periods, and conservative dose-reset titration schedules to proactively mitigate gastrointestinal adverse events.
Mechanisms and therapeutic potential of microglia-regulated remyelination in chronic cerebral hypoperfusion.
Exp Neurol
Zherui Yang, Xiaoli Qin, Yunsha Zhang +5 more
White matter injury after chronic cerebral ischemia is characterized by demyelination and impaired remyelination, representing a major contributor to neurological deficits and cognitive impairment. With the accelerating global aging population, the burden of cerebral small vessel disease and vascular cognitive impairment is increasing, and chronic cerebral ischemia has emerged as an important pathological basis for white matter damage and cognitive decline (Markus & Joutel, 2025). However, effective repair strategies for chronic cerebral hypoperfusion (CCH)-related white matter injury remain limited, highlighting the need to elucidate key mechanisms and develop targeted interventions (Rajeev et al., 2023). Persistent hypoperfusion induces oligodendrocyte dysfunction and impairs myelin repair through mechanisms involving metabolic disturbance, oxidative stress, and blood-brain barrier disruption. Microglia exert dual regulatory roles in this process: pro-inflammatory activation aggravates injury, whereas reparative responses promote remyelination through myelin debris clearance, neurotrophic factor secretion, and microenvironment modulation. In addition, interactions between microglia and astrocytes, endothelial cells, and immune cells collectively establish a cellular network regulating white matter repair. This review summarizes the molecular and cellular mechanisms underlying white matter injury after chronic cerebral ischemia, with particular emphasis on the dynamic regulation of microglia and their interactions with other cell types. Potential therapeutic strategies targeting microglial polarization, excessive inflammation, phagocytic function, and reparative transformation are also discussed. This review highlights the potential of microglia as therapeutic targets for promoting white matter repair and provides insights into future mechanistic studies and precision interventions.
Musculoskeletal degeneration in space: translational parallels with spaceflight-associated ocular pathology and surgical implications.
Life Sci Space Res (Amst)
Rohan Phadke, Samer Salman, Ananya Bansal +5 more
Prolonged exposure to microgravity leads to rapid and widespread physiological changes, most notably musculoskeletal degeneration and spaceflight-associated neuro-ocular syndrome (SANS), which are often considered separate clinical challenges. This opinion piece suggests that these conditions may share overlapping upstream mechanisms - particularly cephalad fluid shifts, oxidative stress, and mitochondrial dysfunction - that contribute to system-wide maladaptation with important implications for surgical risk, countermeasure design, and mission readiness during long-duration spaceflight. We highlight translational links between skeletal catabolism, muscle and tendon atrophy, spinal structural changes, and the high prevalence of SANS characterized by optic disc edema, globe flattening, and altered cerebrospinal fluid dynamics. Central to this perspective is the role of mitochondrial stress and redox imbalance as unifying biological hubs connecting impaired mechanotransduction, vascular and neural vulnerability, and disrupted glymphatic clearance. We propose that targeting these shared pathways through integrated strategies - such as lower body negative pressure, targeted resistive exercise, nutritional and antioxidant optimization, and emerging tele-robotic surgical platforms - may offer a more cohesive framework than organ-specific countermeasures alone. While acknowledging technical and evidentiary limitations, we argue that a systems-based perspective can enhance surgical preparedness in space and provide translational insights for terrestrial aging, orthopedic recovery, and complex surgical care.
Endoscopic endonasal approach for adrenocorticotropic hormone-producing pituitary neuroendocrine tumor causing Cushing's disease: multicenter retrospective study on 162 patients with early postoperative cortisol assessment.
J Neurosurg
Ilaria Bove, Jacopo Berardinelli, Robert Grady Briggs +7 more
Cushing's disease (CD) is a severe endocrine disorder that remains difficult to treat. The first-line treatment for confirmed CD is selective pituitary adenoma resection. Postoperative hormonal remission may not be achieved, though, despite surgical intervention. Effective postoperative monitoring of the hormonal response in CD remains challenging.
Endoscopic gastric remodeling and its histologic impact on metabolic dysfunction-associated steatohepatitis: a 12-month prospective study.
Gastrointest Endosc
Pichamol Jirapinyo, David J Papke, Guadalupe Garcia-Tsao +4 more
Weight loss through lifestyle modification or glucagon-like peptide-1 receptor agonists (GLP-1RAs) is first-line therapy for metabolic dysfunction-associated steatohepatitis (MASH). However, few subjects achieve sufficient weight loss with lifestyle changes, and long-term medication use limits GLP-1RA adoption. This study evaluated the effect of endoscopic gastric remodeling (EGR), a 1-time, minimally invasive intervention, on MASH histologic features.
Efficacy and safety of semaglutide injection in Indian patients with type 2 diabetes mellitus inadequately controlled on metformin: A phase 3, randomized, active-controlled, multicenter, non-inferiority trial (WIN-IND study).
Metabol Open
Ambrish C, Anurag Ranjan Kundan Lal Lila, Archit Parikh +31 more
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with a rapidly rising global burden. Present study established the non-inferiority and evaluated the safety of Intas semaglutide (test) compared to Innovator semaglutide (reference) in patients with T2DM inadequately controlled on metformin.
Treatment of obesity with liraglutide in bipolar disorder: a case report.
Front Psychiatry
Salvatore Cipolla, Giovanni Vasca, Daniele De Francesco +6 more
Bipolar disorder (BD) is a chronic, severe mental illness frequently complicated by metabolic disturbances such as obesity, insulin resistance and dyslipidaemia. We report the case of a 57-year-old man with Bipolar I Disorder and class III obesity (BMI 47.7 Kg/m²) whose mood episodes were tightly linked to weight fluctuations. patients' psychiatric history began in 1986 with a manic episode and recurrent depressive and manic relapses over nearly four decades, often provoked by weight-loss attempts. In February 2024, he was admitted for initiation of liraglutide under close psychiatric monitoring, given prior episodes of mania triggered by dietary interventions. At baseline, he exhibited moderate illness severity (CGI = 4), insulin resistance (HOMA-IR = 6.19), dyslipidaemia and sedentary habits. Liraglutide was titrated from 0.6 mg to 1.8 mg over three weeks. During the weight-loss intervention, and temporally after liraglutide titration to 1.8 mg/day, he developed a manic episode (YMRS = 30), prompting an increase in risperidone and addition of gabapentin alongside continuation of mood stabilizers. His manic symptoms remitted within one week, allowing discharge with liraglutide 1.8 mg, risperidone 3 mg, valproic acid and lamotrigine. Over subsequent outpatient follow-up at the target liraglutide dose (3 mg/day), he lost 6.5 kg more (total Δ weight = - 7 kg), his HOMA-IR improved to 5.78 and glycemic and lipid parameters stabilized without further mood destabilization. This case illustrates the bidirectional interplay between metabolic regulation and mood stability in BD, highlights the need for close psychiatric monitoring during structured weight-loss interventions in clinically vulnerable patients, and supports integrated multidisciplinary care when initiating anti-obesity treatments in patients with severe mental illness.
The Expression Profile of microRNA Genes and NT-proBNP as Possible Predictors of One-Year Mortality in Egyptian Adults with Acute Heart Failure: A Prospective Biomarker Study.
Genet Test Mol Biomarkers
Haidy Magdy, Radwa M Abdel Halim, May M Selim +3 more
Acute heart failure (AHF) is a prevalent and life-threatening condition that is associated with high morbidity and mortality, particularly in adults. MicroRNAs (miRNAs) have been identified as potential biomarkers in various cardiovascular diseases. Specifically, miR-302b-3p and miR-103 have demonstrated potential as biomarkers in heart failure.
Evaluating the use of GLP-1 receptor agonists in Wolfram syndrome patients.
Front Endocrinol (Lausanne)
Laura A Lee, Abby F Tang, Anna E Asako +8 more
Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene and characterized by early-onset, insulin-dependent diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration driven by chronic endoplasmic reticulum (ER) stress; no proven disease-modifying therapy currently exists. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) augment glucose-dependent insulin secretion and, in preclinical models, preserve β-cell mass, attenuate ER stress, and confer neuroprotection - properties of particular therapeutic relevance to Wolfram syndrome.
Beyond Weight Loss: Tirzepatide as a Metabolic Disease-Modifying Strategy for Metabolic Dysfunction-Associated Steatohepatitis: A Narrative Review.
Health Sci Rep
Zubaier Ahmed, Nashrah Mustafa, Tamanna Sarkar +1 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disease worldwide and a major contributor to liver-related morbidity and mortality. Its progressive subtype, metabolic dysfunction-associated steatohepatitis (MASH), is characterized by hepatocellular injury, inflammation, and fibrosis, which may ultimately progress to cirrhosis and hepatocellular carcinoma. Despite the rapidly increasing global burden of MASH, effective pharmacological therapies remain limited. Lifestyle modification remains the cornerstone of management; however, achieving and maintaining the degree of sustained weight loss required for meaningful histological improvement is challenging in routine clinical practice.
Role of KNDy neurons in the negative-feedback suppression of gonadotropin secretion in female rats.
Endocrinology
Ana C Campideli-Santana, Kaoma S C Silva, Roberta Araujo-Lopes +4 more
The hypothalamic neurons that coexpress kisspeptin, neurokinin B, and dynorphin (KNDy) play a crucial role in the control of gonadotropin-releasing hormone (GnRH) pulsatile release and, thereby, in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. However, the feedback mechanism of sex steroids on KNDy neurons is not fully understood. We selectively ablated KNDy neurons using intra-arcuate nucleus injections of neurokinin-3 receptor agonist conjugated with saporin (NK3-SAP) to investigate their role in gonadotropin secretion in female rats under different feedback conditions. NK3-SAP rats bearing submaximal (75%) ablation of KNDy neurons displayed estrous cycle irregularity, an increased number of preovulatory follicles, and similar occurrence of corpora lutea. LH pulse frequency and amplitude, and basal LH and FSH levels were elevated in NK3-SAP rats on diestrus. Ovariectomy increased pulsatile LH secretion and basal LH and FSH levels, abolishing the differences between NK3-SAP and blank-SAP. In estradiol (E2)-treated ovariectomized (OVX + E2) rats, NK3-SAP ablation of KNDy neurons increased the frequency of the LH pulses but not basal gonadotropin secretion. Thus, the submaximal loss of KNDy neurons potentiates pulsatile LH secretion and increases basal LH and FSH release during negative-feedback states, in which E2 is required for LH pulse modulation. Supporting a dynorphin role, treatment of OVX + E2 rats with kappa-opioid receptor agonist, nor-binaltorphimine, increased basal and surge LH secretion, associated with a higher c-Fos expression in KNDy and GnRH neurons. Our findings provide evidence that KNDy neurons play a role in limiting pulsatile and nonpulsatile gonadotropin secretion during negative feedback, possibly through a dynorphin output.
Liver cirrhosis is associated with altered glucocorticoid metabolism related to disease severity.
J Intern Med
Soyeon Park, Min Jeong Park, Hye Won Yang +6 more
Liver cirrhosis (LC) is frequently complicated by adrenal dysfunction; however, whether cirrhosis drives the coordinated, pathway-specific reprogramming of cortisol metabolism remains unclear.