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An Open-Label, Single-Center Proof of Concept Study Evaluating the Efficacy and Safety of Tirzepatide for Moderate to Severe Hidradenitis Suppurativa.
J Drugs Dermatol
Ana Sofia Acosta-Madiedo, Marcela Gutierrez, Martha Gutierrez +2 more
Hidradenitis suppurativa (HS) is a chronic inflammatory disease associated with obesity and metabolic dysregulation. Current therapies yield variable benefits and do not target metabolic drivers. Tirzepatide, a dual GLP-1/GIP receptor agonist, induces weight loss and exerts anti-inflammatory effects, offering a potential novel approach for the treatment of HS.
GLP1 and GIP Receptor Agonists: Effects on the Gastrointestinal Tract and Management Strategies for Primary Care Physicians.
Mayo Clin Proc
Bibek Saha, Vijayvardhan Kamalumpundi, Don C Codipilly
Type 2 diabetes and obesity drive significant morbidity, mortality, and health care costs in the United States. Clinicians increasingly prescribe glucagon-like peptide 1 (GLP1) receptor agonists (GLP1-RAs) and dual GLP1 and glucose-dependent insulinotropic polypeptide receptor agonists to treat these and other conditions. However, 40% to 70% of patients experience gastrointestinal adverse effects, such as nausea, vomiting, diarrhea, constipation, delayed gastric emptying, and biliary disease. High-quality studies have not yet confirmed an increased risk of pancreatitis. Management of gastrointestinal symptoms should start with dietary modifications-smaller, more frequent meals; adequate hydration; and avoidance of high-fat or high-sugar foods. If symptoms persist, patients can trial several medications for symptom relief. For patients undergoing elective endoscopy, clinicians should engage in shared decision-making to weigh the risks of continuing vs temporarily discontinuing incretin-based therapies. For endoscopy, GLP1-RA use is associated with a higher incidence of retained gastric contents but not with increased aspiration risk. Long-acting formulations (eg, semaglutide, dulaglutide, and tirzepatide, among others), high doses, procedures during dose escalation, and gastrointestinal comorbidities that delay gastric emptying raise risk of retained gastric contents. In most cases, clinicians can continue GLP1-RAs periprocedurally, although a 24-hour liquid diet may benefit high-risk patients. For colonoscopy, withholding GLP1-RAs may reduce the risk of inadequate bowel preparation, but further research should clarify the magnitude of this risk.
Outcomes of Patients With Familial Central Precocious Puberty due to Mutations of MKRN3 Gene After Treatment With Gonadotropin-Releasing Hormone Agonist.
Int J Endocrinol
Ziwei Chen, Wenying Li, Junqi Wang +7 more
To assess the therapeutic effects of gonadotropin-releasing hormone agonist (GnRHa) on children with familial central precocious puberty (FCPP) due to Makorin ring finger Protein 3 (MKRN3) gene mutations.
Dileucine-supplemented essential amino acids support whole-body anabolism after resistance exercise and serum-stimulated cell-based anabolism.
J Int Soc Sports Nutr
Jonathan A Aguilera, Cassidy T Tinline-Goodfellow, Matthew J Lees +9 more
Essential (EAA) and branched chain (BCAA) amino acid ingestion support whole-body anabolism after resistance exercise and can attenuate markers of postexercise myofibrillar protein breakdown (i.e. urinary 3-methylhistidine; 3MH). Leucine is often considered a primary anabolic EAA through its ability to activate the mechanistic target of rapamycin complex 1 (mTORC1) and stimulate muscle protein synthesis. The dipeptide leucine (dileucine) has been shown to more effectively stimulate myofibrillar protein synthesis than leucine in young males at rest. Therefore, we aimed to determine the effect of a dileucine-containing essential amino acid formula (DIEAA; 2 g dileucine, 1 g leucine, 9.15 g total EAA) on the anabolic and catabolic responses following resistance exercise in young recreationally active adults when compared with ingesting branched chain amino acids (BCAA; 3 g leucine, 1.5 g isoleucine, 1.5 g valine) or isonitrogenous (to DIEAA) collagen hydrolysate (COL).
Concurrent head and neck paragangliomas and pulmonary carcinoid tumor: A rare clinical entity.
Radiol Case Rep
Faria Nisar, Hoo Jung Rhim, Roman Finocchiaro +1 more
We report the first documented case of a 61-year-old female presenting with concurrent multiple head and neck paragangliomas (HNPGLs) and a pulmonary carcinoid tumor, representing an unprecedented association of synchronous neuroendocrine tumors (NETs). This rare coexistence presented unique diagnostic challenges requiring multimodal imaging, including FDG PET-CT, contrast-enhanced CT, MRI, and Cu-64 DOTATATE PET-CT for comprehensive tumor characterization. Management employed a tailored multidisciplinary approach: surgical resection of the dominant carotid body tumor with excellent local control, stereotactic radiation therapy for remaining cervical lesions (45 Gy), and active surveillance with octreotide therapy for the pulmonary carcinoid. At 24-month follow-up, all lesions remained stable with no evidence of progression or new neurological deficits. Despite declining genetic testing, the patient's multiple paragangliomas strongly suggest hereditary predisposition, emphasizing the critical importance of genetic counseling in such presentations. The successful management approach provides a framework for similar complex presentations and highlights the potential for shared molecular mechanisms underlying synchronous neuroendocrine tumorigenesis.
A Systematic Literature Review Exploring the Efficacy and Safety of Tadalafil and Sildenafil in Pulmonary Arterial Hypertension.
Pulm Circ
Rajan Saggar, Nora Rahhali, Assunta Senatore +7 more
Pulmonary Arterial Hypertension (PAH) is a rare, chronic and progressive disease affecting the heart and lungs. Endothelin receptor antagonist (ERA) + phosphodiesterase type 5 inhibitor (PDE5i) treatment is recommended for all PAH patients. The two approved PDE5is are tadalafil and sildenafil. To determine the efficacy and safety outcomes for tadalafil and sildenafil as monotherapies or in combination with ERAs for treating PAH, from randomized controlled trials (RCTs) and real-world evidence studies (RWEs) identified by a systematic literature review (SLR). MEDLINE, Embase and Cochrane Libraries were searched in May 2024. Relevant outcomes included 6-min walk distance (6MWD), pulmonary vascular resistance (PVR) and safety. This report includes studies where patients were treated with either sildenafil or tadalafil. Fifteen RCTs and three RWEs investigated tadalafil (tadalafil 40 mg or 20 mg once daily) or sildenafil (20 mg three times a day). Mean 6MWD change from baseline (CFB) in patients receiving tadalafil or sildenafil monotherapy were comparable, however, in combination with an ERA, tadalafil may be more effective. Generally, there was more data for tadalafil + ERAs, showing marked improvement in mean PVR CFB, compared with patients receiving sildenafil. Conclusions on safety were limited. Risk of bias in RCTs was generally low but moderate in RWEs. Two studies reported patients who switched from sildenafil to tadalafil treatment, treatment transition was feasible. Although comparable when used as monotherapy, this qualitative analysis suggests that tadalafil + ERA combination therapy may have more favorable 6MWD improvements than sildenafil + ERA combination therapy.
Oxytocin: a neglected hormone in pituitary disease - From function to the diagnosis of a deficiency, resulting clinical relevance, and potential treatment options in endocrinology.
Arch Endocrinol Metab
Svenja Leibnitz, Mirjam Christ-Crain, Cihan Atila
Oxytocin (OXT) is a neuropeptide hormone that plays a central role in numerous physiological and socio-emotional processes. Similar to arginine vasopressin (AVP), it is synthesized in the supraoptic and paraventricular hypothalamic nuclei and released both centrally and peripherally. Peripherally, OXT regulates uterine contractions during childbirth and milk ejection during lactation, metabolism, bone health, and cardiovascular functions. Centrally, it modulates social behavior, influencing trust, empathy, stress regulation, and emotional processing. Despite its close connection to AVP, the clinical significance of OXTDeficiency has only recently gained attention, particularly in patients with hypothalamic or pituitary damage with concomitant AVP-Deficiency. OXT-Deficiency may contribute to various neuropsychological symptoms seen in these patients, including social dysfunction, anxiety disorders, and reduced quality of life. However, a major challenge lies in accurately measuring OXT and thereby diagnosing a potential OXT-Deficiency. Basal plasma levels are unreliable, and most studied provocation tests only stimulate to a limited degree; hence, stronger provocation tests (e.g., using MDMA) and new surrogate parameters such as neurophysin I (NP-I) are gaining traction. Preliminary evidence from case reports and one small study suggests that intranasal OXT administration in patients with hypothalamic disorders may have beneficial effects on social behavior and emotion recognition. However, there is a clear need for larger, well-designed clinical trials, and several trials are currently underway to investigate the therapeutic potential of OXT in patients with AVP-Deficiency. OXT is also being explored as a possible treatment option in psychiatric conditions such as autism spectrum disorder, borderline personality disorder, and social anxiety disorder, with controversial results so far.
The Clinical Application of GLP-1RAs and GLP-1/GIP Dual Receptor Agonists Based on Pharmacological Mechanisms: A Review.
Drug Des Devel Ther
Zhao Liu, Shanshan Yu, Xinyan Jin +5 more
This review provides a comprehensive examination of the clinical pharmacological mechanisms and broad therapeutic applications of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual receptor agonists targeting both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. GLP-1RAs exert their effects by stimulating insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite through the activation of the GLP-1 receptor. These agents have demonstrated significant efficacy in the management of type 2 diabetes mellitus (T2DM) and obesity. Moreover, emerging evidence suggests that GLP-1RAs may confer cardiovascular protection, neuroprotective benefits, and positive effects on mental health. Dual GLP-1/GIP receptor agonists, such as tirzepatide, simultaneously activate both receptors, thereby potentiating glycemic control, promoting weight loss, and ameliorating metabolic dysfunction. This review also addresses recent advances in the development of other dual and triple receptor agonists. Distinct from prior reviews that predominantly focus on a single drug class or limited clinical indications, this article systematically contrasts the mechanistic pathways, therapeutic efficacy, and safety profiles of GLP-1RAs versus GLP-1/GIP dual receptor agonists. Notably, it integrates the most current evidence pertaining to novel domains, such as perioperative management, neuropsychiatric outcomes, and the innovation of multi-receptor agonists. This synthesis offers a timely and practical resource to inform clinical precision medicine and to guide future investigative efforts.
The Sustained Effects of Bioactive Collagen Peptides on Skin Health: A Randomized, Double-Blind, Placebo-Controlled Clinical Study.
J Cosmet Dermatol
Yu Wang, Weixing Zhu, Wenyu Luo +2 more
Collagen is a fundamental component of the skin's extracellular matrix, yet its low oral bioavailability raises questions about its efficacy in improving skin health. Bioactive collagen peptides (BCP), as hydrolyzed forms of collagen, offer enhanced absorption and functionality. However, evidence regarding their sustained effects and the impact of molecular weight distribution is still limited.
Efficacy and Safety of PRaG Therapy in Elderly Patients with Advanced Malignant Tumors: A Prospective, Multicenter Clinical Study Protocol (PRaG 9.0 Study).
Technol Cancer Res Treat
Xiangrong Zhao, MengMeng Yang, Junjun Zhang +8 more
Background: Current evidence from evidence-based medicine is limited regarding the efficacy and safety of immunotherapy in elderly patients aged 75 years and older with malignant solid tumors. PRaG therapy, which combines PD-1/PD-L1 inhibitors, radiotherapy, and granulocyte-macrophage colony-stimulating factor (GM-CSF), aims to treat patients with advanced, refractory tumors. Preliminary findings indicate that patients aged 75 years and older can benefit from this treatment and can tolerate it well. Objective: This study aims to evaluate the efficacy and safety of the PRaG regimen in elderly patients with advanced malignant solid tumors to provide evidence-based support for immunotherapy in this population. Methods and Analysis: This study involves a multicenter, prospective, single-arm phase II clinical trial designed to enroll 29 patients aged 75 years and older with either newly diagnosed or recurrent metastatic advanced solid tumors that are histologically confirmed. All of the eligible patients will have had to receive at least two cycles of PRaG therapy until disease progression or intolerable adverse effects occurred. The study protocol was approved on September 12, 2023, by the Ethics Committee of the Second Affiliated Hospital of Soochow University (JD-LK-2023-082-I01) and by the ethics committees of all of the participating centers (Trial Registration Number: NCT06112041).
Dietary Copper on the Onset of Puberty in Rats: Possible Mechanism.
Nutrients
Rui Sun, Zhongshen Wang, Cheng Li +3 more
Background/Objectives: Copper is an essential trace element for physiological processes related to reproduction, but its impact on the hypothalamic-pituitary-ovarian (HPOA) axis and its specific mechanism remain unclear. Methods: In vivo study: 21-day-old female Sprague Dawley (SD) rats were randomly assigned to five groups (n = 10 per group), with all groups fed a basal diet and supplemented with CuSO4·5H2O to achieve copper ion concentrations of 0, 15, 30, 45, or 60 mg/kg in the diet. During the second phase of proestrus, blood samples, hypothalamic tissues, pituitary tissues, and ovarian tissues were collected. In vitro study: Primary mixed hypothalamic neurons were isolated and cultured from fetal SD rats on embryonic day 17. After identification by NSE immunofluorescence staining, six copper ion concentration groups (0, 15.6, 31.2, 46.8, 62.4, and 78 μmol/L) were established. The optimal copper concentration for cell viability and GnRH secretion was screened using CCK-8 assay (Sangon, Shanghai, China) and ELISA (Mlbio, Shanghai, China). On this basis, the cells were treated with different concentrations of PKC agonist (PMA) and PKC inhibitor (chelerythrine). Cell viability was evaluated by CCK-8 assay, the expression level of PKC was detected by Western blot, and the optimal concentration with no obvious toxicity was selected for subsequent mechanism research. Results: Dietary copper dose-dependently regulated rat puberty onset; the 45 mg/kg copper group had the earliest onset, and showed significantly increased levels of reproduction-related hormones (GnRH, FSH, LH, E2) in serum and HPOA axis. Hypothalamic transcriptomics revealed significantly enriched GnRH signaling pathways and GABAergic synaptic pathways. Mechanistically, this copper dose upregulated hypothalamic KISS-1, GPR54, and PKC (mRNA/protein), and downregulated GABA/GABA-R. Adding 46.8 μmol/L copper (as Cu2+, equivalent to optimal in vivo level) could activate the KISS-1/GPR54-GnRH system in hypothalamic neurons; regulating PKC activity could synchronously affect the expression of KISS-1, GPR54, GnRH, and GABA/GABA-R, with additional copper enhancing this effect in vitro experiments. Conclusions: This study demonstrates for the first time that dietary copper at 45 mg/kg promotes puberty onset in SD rats. The mechanism involves activation of the hypothalamic PKC pathway, which inhibits GABAergic neurotransmission while activating the KISS-1/GPR54-GnRH system, thereby enhancing HPOA axis activity and gonadotropin secretion.
Nutritional Supplements for Muscle Hypertrophy: Mechanisms and Morphology-Focused Evidence.
Nutrients
Andreea Maria Mănescu, Simona Ștefania Hangu, Dan Cristian Mănescu
Nutritional supplementation is widely used in resistance training, yet assessment of "hypertrophy" is often confounded by body-composition surrogates. This narrative review, anchored in mechanistic plausibility, integrates trials reporting morphology-direct outcomes (ultrasound/MRI). Across 46 eligible trials, protein/essential amino acids (EAA) showed consistent benefits when daily intake was <1.6 g·kg-1·day-1 or when per-meal leucine provision was <2-3 g; effects plateaued once intakes exceeded ~2.0 g·kg-1·day-1. Creatine monohydrate (3-5 g·day-1, with or without loading) produced measurable increases in muscle thickness or cross-sectional area in interventions lasting ≥8-12 weeks, mediated by enhanced training volume and quality. β-hydroxy-β-methylbutyrate (HMB, 3 g·day-1) demonstrated conditional utility during high training stress or caloric deficit, but was largely neutral in well-fed, resistance-trained cohorts. Adjuncts such as omega-3 fatty acids (1-2 g·day-1), citrulline (6-8 g pre-exercise), and collagen (10-15 g·day-1 plus vitamin C) primarily facilitated training tolerance, recovery, or connective-tissue adaptation, rather than driving hypertrophy directly. A tiered model is proposed: protein/EAA as the foundation, creatine as amplifier, HMB as conditional agent, and adjuncts as facilitators. Methodological heterogeneity, short intervention length, and inconsistent imaging protocols remain limiting factors, underscoring the need for standardized ultrasound/MRI and adequately powered, preregistered trials.
Burden of illness and unmet needs in patients with erythropoietic protoporphyria and X-linked protoporphyria: A large US nationwide claims analysis.
J Manag Care Spec Pharm
Maral DerSarkissian, Chelsea Norregaard, Hela Romdhani +5 more
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare genetic disorders caused by the accumulation of the toxic metabolite protoporphyrin IX, which results in painful phototoxicity upon sunlight exposure. Despite their significant impact on quality of life and potential for serious complications, treatment options for EPP/XLP are limited and real-world burden of illness and unmet needs have been understudied in this population.
Octreotide ameliorates Bisphenol A-induced testicular toxicity via autophagy-inflammation pathway modulation.
Hum Exp Toxicol
Basma B Morad, Ola M Salem, Rasha Osama El-Esawy +1 more
IntroductionTesticular toxicity commonly manifests as impaired spermatogenesis and testicular atrophy. Bisphenol A (BPA), a commonly used organic plasticizer, negatively affects sperm parameters, hormonal levels, and fertility. Octreotide (OCT), a somatostatin analog, was originally used to treat acromegaly, carcinoid tumors, vasoactive intestinal peptide-secreting, and growth hormone-secreting tumors. OCT has demonstrated potential therapeutic properties beyond its traditional use in endocrine disorders. We hypothesized that OCT would attenuate BPA-induced testicular damage through its anti-inflammatory, anti-oxidant, and anti-autophagic properties. This study aimed to assess the mechanisms of BPA-induced testicular toxicity and evaluate the ameliorative effects of OCT.MethodsForty adult male Sprague Dawley (SD) rats were randomly assigned to four equal groups: group1: saline control, group2: dimethyl sulfoxide (DMSO) vehicle, group3: BPA-treated, and group4: BPA + OCT-treated. Treatments were administered for 4 weeks. Sperm count, testicular weight, serum testosterone, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), total antioxidant capacity (TAC), testicular levels of malondialdehyde (MDA), tumor necrosis factor-alpha (TNFα), Beclin-1 (BECN-1), Microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A/LC3), mammalian target of rapamycin (M-TOR), histopathological examination, apoptotic index, and Johnson's score were assessed.ResultsBPA administration significantly impaired spermatogenesis, reduced serum testosterone and TAC, and increased MDA, TNFα, and autophagy-related markers, along with histopathological damage of testis. Co-treatment with OCT mitigated these effects by improving sperm parameters, hormone levels, oxidative stress markers, inflammatory cytokines, and testicular histology.DiscussionThe findings suggest that OCT exerts a protective effect against BPA-induced testicular toxicity, through its anti-inflammatory, antioxidant, and autophagy-modulating properties. OCT may offer therapeutic potential in mitigating BPA-induced testicular toxicity.
Prevalence, associated factors, and prognostic value of P wave abnormality in patients with coronary artery disease.
Int J Cardiol Cardiovasc Risk Prev
Kazutoshi Hirose, Hiroyuki Kiriyama, Shun Minatsuki +13 more
P-wave terminal force in V1 (PTFV1) on electrocardiography is an easily available and cost-effective surrogate marker reflecting myocardial electrical and structural remodeling. An abnormal PTFV1 was recently suggested to be a reliable predictor of adverse cardiovascular events, whereas its performance in the setting of coronary artery disease (CAD) remains unknown.
Thyrotropin-releasing hormone protects hippocampal neurons against glutamate toxicity via phosphatidylinositol 3-kinase/AKT pathway and new protein synthesis.
bioRxiv
Yina Dong, Deborah J Watson
Thyrotropin-releasing hormone is best known as a neuropeptide that stimulates the release of thyroid-stimulating hormone and prolactin in hypothalamic-pituitary-thyroid (HPT) axis. Independent from its activity in the HPT axis, TRH also exerts strong neuroprotective activity against neurodegenerative diseases such as Alzheimer's disease, epilepsy and traumatic brain injury. Although multiple factors have been linked to its neuroprotective action, the cellular mechanism of TRH neuroprotection is still not clear. Here we show that TRH protects hippocampal neurons against glutamate toxicity via phosphatidylinositol 3-kinase (PI3K)/AKT pathway and new protein synthesis. Both adeno-associated virus (AAV) mediated TRH transduction and TRH peptide given exogenously over 24 hours period of time inhibit glutamate-induced lactate dehydrogenase (LDH) release. This effect is not mediated by the decreased intracellular calcium response as TRH treatment (24 hours) has no effect on glutamate-induced increase in intracellular calcium nor the calpain activity. While TRH treatment (10 minutes) significantly inhibits glutamate-induced increase in intracellular calcium, no protective effect is observed when TRH is applied 30 minutes before or after glutamate stimulation. Instead, PI3K inhibitor LY294002 but not mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 completely inhibits the protective effect of TRH. LY294002 also blocks TRH induced AKT activation. In addition, protein synthesis inhibitor cycloheximide inhibits the protective effect of TRH. Taken together, these results suggest PI3K/AKT signaling pathway and new protein synthesis are involved in the protective effect of TRH against glutamate toxicity, thereby providing mechanistic support for its action in neurodegenerative diseases.
An overview of oxytocin integrative mechanisms in autism spectrum disorder.
Discov Ment Health
Nand Lal, Bin Song, Chi Zhang +8 more
Autism Spectrum Disorder (ASD) is a multifaceted neurodevelopmental condition characterized by impairments in social interaction, communication, and repetitive behaviors. Its etiology involves a complex interplay of genetic, environmental, and neurobiological factors. The oxytocin (OT) system, central to social behavior and emotional regulation, has emerged as a key area of interest in ASD research. This review synthesizes current evidence, highlighting that dysregulation of OT and its receptor (OTR) signaling, often characterized by lower baseline OT levels and altered OTR expression due to genetic and epigenetic factors, contributes to the social and behavioral deficits observed in ASD. While aberrant OT/OTR signaling presents a potential target for therapeutic intervention, the narrative has evolved beyond simple peptide replacement. Critical analysis reveals that intranasal OT administration, as a standalone treatment, yields inconsistent results due to its non-specific delivery and inability to address core circuit-level dysfunctions established during neurodevelopment. Promising future avenues include the development of selective OTR agonists, epigenetic modulation to correct OTR expression, and the use of OT as a targeted adjunct to enhance behavioral therapy efficacy. This paper provides a comprehensive and critical overview of the integrative mechanisms linking OT/OTR signaling to ASD, evaluates the therapeutic potential of correcting this pathway, and emphasizes the necessity for personalized, biomarker-driven approaches to improve social cognition and neural connectivity in individuals with ASD.
Intestinal fructose metabolism triggers a glucagon-like peptide-1-β-cell axis to prevent post-fructose hyperglycaemia.
J Physiol
Naoya Murao, Yusuke Seino, Risa Morikawa +10 more
Fructose ingestion increases circulating glucagon-like peptide-1 (GLP-1) and insulin, yet the specific contributions of these hormonal responses to glycaemic control remain incompletely defined. We hypothesised that fructose metabolism in intestinal L-cells triggers GLP-1 secretion, which then potentiates insulin secretion and counteracts fructose-induced hyperglycaemia. To test this hypothesis, we systematically characterised metabolic responses across multiple mouse strains after 24 h ad libitum fructose ingestion. In both lean (NSY.B6-a/a) and obese diabetic (NSY.B6-Ay/a) mice, fructose elevated plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). The insulin response was preserved in GIP receptor-deficient mice (Gipr-/-) but was abolished in proglucagon-deficient mice (Gcg-/-) by pharmacological GLP-1 receptor antagonism, indicating a requirement for GLP-1, but not GIP. Across strains, fructose-induced insulin response correlated with attenuation of post-fructose glycaemia, consistent with insulin being essential for suppressing fructose-induced hyperglycaemia. To explore the mechanism underlying fructose-induced GLP-1 secretion, we combined ATP-sensitive potassium channel-deficient mice (Kcnj11-/-), the GLUTag L-cell line, and metabolic tracing of 13C-labelled fructose in freshly isolated intestinal crypts. These complementary approaches support a model in which fructolysis increases the ATP/ADP ratio in L-cells, closes KATP channels and stimulates GLP-1 secretion. In obese diabetic mice, increased fructolytic flux and a higher ATP/ADP ratio were associated with elevated GLP-1 levels, further corroborating this model. Collectively, our findings indicate that intestinal fructose metabolism drives GLP-1 secretion required to potentiate insulin secretion, thereby establishing a gut-pancreas axis that counter-regulates fructose-induced hyperglycaemia. KEY POINTS: Fructose ingestion acutely increases plasma insulin levels, but the underlying mechanisms and physiological significance remain elusive. Our study demonstrates that short-term (24 h) fructose ingestion in mice elevates both insulin and glucagon-like peptide 1 (GLP-1) levels in the blood, with the plasma insulin response being GLP-1-dependent. We found that fructose metabolism in intestinal L-cells triggered GLP-1 secretion by increasing the ATP/ADP ratio and closing ATP-sensitive K+ (KATP) channels. This intestinal fructose metabolism-GLP-1-β-cell axis plays a crucial role in preventing fructose-induced hyperglycaemia, an effect that is compromised in obese diabetic mice. These insights highlight the previously unclear metabolic responses following short-term fructose ingestion and their importance in glucose homeostasis.
Chronic stress and the IL-10-mediated immunoregulatory loop in the pathogenesis of periodontitis.
Clin Sci (Lond)
Maksym Skrypnyk, Axel Spahr, Shlomo Berkovsky +9 more
Periodontitis is a chronic inflammatory condition that gradually destroys the tissues supporting the teeth, including the gingiva, periodontal ligament, and alveolar bone. Emerging evidence suggests that psychological stress plays a significant role in the initiation and progression of periodontal disease, primarily through its impact on immune regulation. Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of corticotropin-releasing hormone (CRH) from the hypothalamus and, in turn, adrenocorticotropic hormone (ACTH) from the pituitary gland. Activation of the HPA axis and the sympathetic-adrenal-medullary (SAM) system during stress triggers the systemic release of cortisol, epinephrine, norepinephrine, and cytokines. The HPA, SAM, and cytokines interact in both direct and indirect ways. Not only does stress induce interleukin-10 (IL-10), but IL-10 also helps regulate the stress response and cortisol levels. IL-10 can stimulate the release of CRH and ACTH, while concurrently inhibiting cortisol secretion from the adrenal glands. IL-10 has drawn increasing attention within the oral cavity owing to its dual role in modulating immune responses and maintaining periodontal tissue homeostasis. This review outlines the current understanding of stress-related neuroendocrine pathways and their relevance to periodontal health. It explores the involvement of HPA axis effectors-cortisol and IL-10-in modulating the inflammatory milieu associated with periodontitis. This includes recent insights into IL-10-expressing regulatory B cells and the potential role of IL-10 in mitigating alveolar bone loss. By integrating recent advances in neuroendocrinology, immunology, and oral biology, this review clarifies how systemic stress responses contribute to local inflammatory changes in the periodontium. Understanding the mechanisms linking psychological stress, cortisol dynamics, and IL-10-mediated regulation may offer new opportunities for early diagnosis and intervention in stress-exacerbated periodontitis.
Thymosin β4 released by mast cells under stress conditions impairs intestinal epithelial barrier via IL22RA1/JAK1/STAT3 signaling in irritable bowel syndrome.
World J Gastroenterol
Yue-Shan Sun, Xiao-Qin Bai, Kai-Di Sun +6 more
Mast cells (MCs) under stress conditions contribute to the development of irritable bowel syndrome (IBS), yet their precise mechanisms in IBS remain unclear.