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Emerging risk factors for stroke and bleeding in patients with atrial fibrillation and heart failure-a narrative review.
Curr Probl Cardiol
Jan Zabierowski, Bartosz Hudzik, Jolanta Nowak +1 more
Atrial fibrillation (AF) and heart failure (HF) frequently coexist, which leads to adverse clinical outcomes and a significant increase in the risk of both ischemic stroke and major bleeding. Although still valuable due to their widespread adoption, traditional risk scores (e.g. CHA2DS2-VASc, HAS-BLED) may not adequately capture group-specific differences in the context of substantial therapeutic and demographic changes that have occurred in recent years. This review summarizes emerging risk factors for stroke and bleeding, focusing on clinical and structural markers, and highlighting the novel biomarker-based approach. Factors such as chronic kidney disease, poor nutritional status, metabolic-associated fatty liver disease, frailty, and polypharmacy appear to substantially modify the risk. Biomarkers, including natriuretic peptides, high-sensitivity cardiac troponins, and growth differentiation factor-15, along with various markers of inflammation and hypercoagulability, provide valuable prognostic information. Incorporating echocardiographic measures, such as left atrial size, morphology, and appendage flow, together with electrocardiographic factors, including AF type and episode duration, may further refine stroke and bleeding prediction. New risk models, such as those based on novel biomarker strategies and machine learning, offer promising results in predicting stroke and bleeding when compared to traditional and well-validated risk scores. A better understanding and integration of these emerging risk factors can enhance existing risk stratification tools, guiding clinicians toward a more individualized decision-making process, while improving strategies for preventing stroke and major bleeding in this specific and vulnerable population.
JAK4D, a first-in-class thyrotropin-releasing hormone analogue, reverses scopolamine-induced memory deficits.
Brain Commun
Roisin McMackin, Smita Price, Gillian R Slator +2 more
There is a pressing unmet clinical and health economic need for effective drugs to treat cognitive impairment that occurs in neurodegenerative diseases. JAK4D is a first-in-class thyrotropin releasing hormone (TRH) analogue that overcomes the pharmacological limitations of thyrotropin releasing hormone and enables delivery of the long-recognized multifactorial neurotherapeutic actions of thyrotropin releasing hormone without inducing endocrine side effects. JAK4D is demonstrated to be neuroprotective and significantly reduce excitotoxic-induced hippocampal-dependent memory deficits in rat. In the present study, we used the scopolamine challenge test coupled with the novel object recognition test to evaluate the effect of JAK4D on scopolamine-induced recognition memory deficits in the male, Lister-Hooded rat. Scopolamine administration has been shown by others to mimic cholinergic and brain network disruption in neurodegenerative diseases. Although the scopolamine challenge test does not fully replicate the pathophysiology of neurodegenerative disease, such as Alzheimer's disease, it is a well-recognized acute pharmacological model for assessing the ability of pharmacological interventions to counteract memory deficits relevant to neurodegenerative diseases. In this model of cholinergic dysfunction, we also assessed the effects of thyrotropin releasing hormone, taltirelin (a degradation-stabilized thyrotropin releasing hormone analogue) and the acetylcholinesterase inhibitor, donepezil, as a positive reference compound. The discrimination (d2) index was used as the primary measure to assess the effect of treatment on scopolamine-induced performance deficit in the novel object recognition test. d2 is a standard well-recognized measure of discrimination between a novel and familiar object in the novel object recognition test, which advantageously takes into account individual differences in exploration levels. Across all investigations, JAK4D (1 mg/kg i.p.) significantly reversed scopolamine-induced recognition memory impairment (P = 0.0274, P = 0.0002, P < 0.0001). The degree of reversal of scopolamine-induced memory deficits by JAK4D (1 mg/kg i.p.) was indistinguishable from that observed for donepezil (0.1 mg/kg p.o.) (P = 0.026). Subcutaneously administered JAK4D (0.3-10.0 mg/kg) also significantly reversed this deficit (P = 0.0432-0.0021). Furthermore, similar pro-cognitive effects were exerted by thyrotropin releasing hormone (5 mg/kg i.p., P = 0.0055) and taltirelin (10 mg/kg p.o., P = 0.0002). Together, these results underscore the relevance of the central thyrotropin releasing hormone signalling system for the treatment of memory impairment. Data from the current study provide further evidence in support of the potential of JAK4D as a novel therapeutic for cognitive deficits in neurodegenerative diseases.
Correlation between life satisfaction, pleasure level, and negative emotion in patients with chronic renal failure.
World J Psychiatry
Lin-Lin Zhang, You-Li Zhang, Ting Liu +3 more
Anxiety, depression, and other negative emotions are common among patients with chronic renal failure (CRF). Analyzing the factors related to negative emotions is necessary to provide targeted nursing care.
Mitochondrial Targeting by Elamipretide Improves Myocardial Bioenergetics Without Translating into Functional Benefits in HFpEF.
Int J Mol Sci
Antje Schauer, Daniela Jahn, Beatrice Vahle +6 more
Mitochondrial dysfunction contributes to impaired myocardial energetics and performance in heart failure with preserved ejection fraction (HFpEF). Elamipretide (Ela) enhances mitochondrial bioenergetics in preclinical models, yet its relevance in HFpEF remains unclear. This study examined the effects of Ela on cardiac mitochondrial function, structure, and cardiovascular performance in a rodent HFpEF model. Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls. Cardiac function and hemodynamics were assessed by echocardiography and pressure-volume analysis. Mitochondrial respiration was measured in permeabilized fibers and ultrastructure evaluated by transmission electron microscopy. Molecular and histological analyses included cardiolipin lipidomics and mRNA/protein profiling of hypertrophic, fibrotic, and inflammatory markers. Ela modestly improved complex I and II respiration, whereas mitochondrial ultrastructure, cardiolipin composition, and tafazzin expression were unchanged. Diastolic dysfunction persisted, reflected by unchanged E/é, ventricular stiffness factor β, and titin phosphorylation. Compared to untreated HFpEF, systolic performance showed a mild decline, with small reductions in LV ejection fraction and end-systolic elastance. Accordingly, cardiac remodeling, including hypertrophy, fibrosis, and inflammatory activation, remained unaltered. Vascular stiffness slightly increased, while carotid reactivity and morphology were preserved. In conclusion, despite enhanced mitochondrial respiration following Ela treatment, no functional or structural benefits were observed in experimental HFpEF, suggesting limited therapeutic efficacy once HFpEF is established.
Tracheocutaneous Fistula Resolved by Pentadecapeptide BPC 157 Therapy Through the NO-System-Triple NO-Agent Approach in Rats.
Pharmaceuticals (Basel)
Goran Madzarac, Tomislav Becejac, Toni Penovic +20 more
Background/Objectives: This 7-day rat tracheocutaneous fistula study considered the not-studied issues of tracheocutaneous fistula course, wound healing, and fistula in the NO-system relations. Therefore, we focused on fistulas' severe course, tracheocutaneous fistula → air leak → compensatory diaphragmatic/abdominal "heaving", NO-system failed relations, and therapy resolution. Stable gastric pentadecapeptide BPC 157 was proposed. Methods: Tracheocutaneous fistula rats received daily medication (/kg), alone or combined, BPC 157 therapy (10 µg, 10 ng, in drinking water or intraperitoneally) along with a triple NO-agent approach (L-NAME 5 mg, L-arginine 100 mg, and L-NAME+L-arginine, intraperitoneally). Results: Tracheocutaneous fistulas occurred as specific and NO-system-related as follows: NO system: blockade (L-NAME-aggravation) over-activity (L-arginine-amelioration) or immobilization (L-NAME+L-arginine oppose each other's effects). Controls presented severe clinical signs of respiratory distress, failed healing, skin and tracheal defects, a not-healed and open, macro/microscopically, and fistulous tract that was well-formed and wide, tracheal shrinking below the fistula, and clinically, open-mouth breathing, "heaving abdomen", cyanosis (bluish snout, ears, extremities), abundant secretion through the fistula, and weight loss. Fistula tissue NO level decreased, and the malondialdehyde (MDA) level increased. The BPC 157 therapy (both application routes) resulted in rapid recovery. Healing of defects (skin and trachea) and fistula closure, macro/microscopically, corresponded with clinical findings, avoiding observable clinical signs of dyspnea, reducing weight loss, and avoiding any sign of "heaving abdomen". BPC 157-treated rats displayed regular breathing movements without observable signs of respiratory distress. Finally, when combined, BPC 157 therapy upgrades L-arginine amelioration, abolishes L-NAME-induced worsening, and restores full healing after NO immobilization (L-NAME+L-arginine). BPC 157 counteracted increase in NO level and counteracted increase in MDA level. Conclusions: Thus, first, acting systemically, BPC 157 reverses tracheocutaneous fistula course in rats. It acts through the NO system.
Fourier Transform Infrared Spectroscopic Characterization of Aortic Wall Remodeling by Stable Gastric Pentadecapeptide BPC 157 After Unilateral Adrenalectomy in Rats.
Pharmaceuticals (Basel)
Ivan Maria Smoday, Vlasta Vukovic, Katarina Oroz +19 more
Background: No Fourier transform infrared (FTIR) spectroscopy studies have directly evaluated adrenalectomy vessels, the technique's established ability to probe collagen/elastin-associated spectral features and lipid peroxidation-related signatures, and protein structural damage. Stable gastric pentadecapeptide BPC 157 therapy was found to maintain the vascular function under severe stress, as FTIR spectroscopy recently demonstrated rapid peptide-induced molecular changes in healthy rat blood vessels, particularly in lipid content and protein secondary structure. Methods: To extend these findings and highlight the BPC 157 vascular background in the special circumstances of the course following unilateral adrenalectomy, abdominal aortas were collected at 15 min, 5 h, and 24 h after unilateral adrenalectomy for the FTIR spectroscopy assessment. Results: FTIR spectra were acquired, preprocessed, and analyzed using principal component analysis (PCA), support vector machine discriminant analysis (SVMDA), and band-specific statistics. BPC 157 (10 ng/kg intragatrically immediately after unilateral adrenalectomy) produced a clear, reproducible separation of aortic spectra from control samples at all time points. The main discriminatory spectral signatures were observed in three regions, including amide I and amide II (protein-related bands, consistent with collagen/elastin contributions) and lipid C-H stretching bands. These spectral signatures are consistent with early extracellular matrix reinforcement and membrane preservation in the vascular wall and align with the recovering effect on the lesions in counteraction of the severe vascular and multiorgan failure, attenuation/elimination of thrombosis and blood pressure disturbances in various occlusion/occlusion-like syndromes. Conclusions: Together, after unilateral adrenalectomy, the FTIR data provide molecular-level spectral signatures consistent with rapid remodeling of the aortic wall toward a more structurally stable and functionally favorable state.
Pharmacologic Treatments for the Preservation of Lean Body Mass During Weight Loss.
J Clin Med
Gunjan Arora, Katherine R Conde, Cyrus V Desouza
Introduction: Overweight and obesity are becoming increasingly prevalent. Incretin-based obesity treatments-glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor agonists (GIP/GLP-1 RAs or dual agonists)-are a major stride in the evolution of obesity management. However, like weight loss with other means, they are associated with an inadvertent significant loss of lean body mass, including muscle. This has led to a resurgence in research for the preservation of lean body mass, the loss of which occurs with weight loss. The purpose of this narrative review is to discuss the mechanisms involved with lean body loss and capture the research landscape of the different classes of pharmacological agents being developed to address this problem. Methodology: We queried PubMed, Medline, and Scopus for randomized controlled trials and phase II or phase III trials using key words to capture the breath of this topic-obesity, weight loss, muscle loss, lean mass, and muscle preservation. Animal studies were excluded. We analyzed the studies conducted to date. Results: Weight loss, regardless of the method used to achieve it, is inadvertently accompanied by lean body mass loss, to varying degrees. There are several mechanisms that govern the loss of lean body mass and, more specifically, the loss of muscle mass; as such, several classes of medications have been explored, targeting different pathways and receptors-including bimagrumab (activin receptor agonist), tesamorelin (growth hormone releasing hormone agonists), and enobosarm (selective androgen receptor modulator). Most of these drugs are in the early phases of research development, but some show great promise. Conclusion: This narrative review attempts to detail the physiology of muscle mass loss when accompanied by weight loss and identify pharmacological targets that can be utilized to minimize it with mechanisms, effects, side effects, and research developmental progress.
Natural and Synthetic Peptides as Alternatives to Antibiotics in Intestinal Infections-A Review.
Antibiotics (Basel)
Lala Stepanyan, Monika Israyelyan, Alessandro Gori +7 more
Antimicrobial peptides (AMPs), evolutionarily conserved components of innate immunity characterized by their broad-spectrum efficacy and minimal resistance development, are increasingly recognized as promising therapeutic candidates. This review aims to integrate current knowledge concerning natural and synthetic antimicrobial peptides and their therapeutic effectiveness in addressing gastrointestinal infections.
Strategies for Treating Sexual Health Concerns After Breast and Gynecologic Cancer.
J Minim Invasive Gynecol
Olivia Mihulka, Melissa Curran, Raksha M Narasimhan +2 more
Sexual dysfunction is a common but underrecognized sequelae of breast and gynecologic cancer treatment. Many patients experience symptoms of genitourinary syndrome of menopause, including vaginal dryness, dyspareunia, and diminished sexual desire. Addressing these challenges requires a comprehensive, evidence-based approach to management.
Dual Inhibition of the Renin-Angiotensin-Aldosterone System and Sodium-Glucose Cotransporter-2: Mechanistic and Clinical Evidence for Cardiorenal Protection.
Biomedicines
Reem F M Aazar, Rayan Arzouni, Persoulla A Nicolaou
Overactivation of the renin-angiotensin-aldosterone system (RAAS) promotes haemodynamic overload, inflammation, and fibrosis in the heart and kidneys. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone therapy in cardiorenal protection. Emerging data indicate that adding SGLT2 inhibitors to angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, or angiotensin receptor-neprilysin inhibitors confers additional cardiorenal protection, yet their mechanistic basis and optimal clinical use in cardiovascular (CV) disease remain unclear. This review will integrate pre-clinical and clinical evidence on dual RAAS/SGLT2 modulation in CV disease, providing mechanistic insight into dual therapy. The review will finally outline priorities for future translational and outcome studies. Clinically, adding SGLT2 inhibitors to RAAS-based therapy reduces heart failure hospitalizations and slows kidney disease progression without new safety liabilities in type 2 diabetes, heart failure, and chronic kidney disease. Mechanistically, SGLT2 inhibition restores tubuloglomerular feedback and constricts the afferent arteriole; RAAS blockade dilates the efferent arteriole, and together, they lower intraglomerular pressure. Both classes also reduce oxidative stress, inflammatory signalling, and pro-fibrotic pathways, with SGLT2 inhibitors in several settings shifting RAAS balance toward the protective ACE2/angiotensin-(1-7)/Mas receptor axis. Key gaps include the scarcity of adequately powered trials designed to test combination therapy versus either component alone, limited evidence on timing and sequencing, incomplete characterization in high-risk groups, and mechanistic insight limited by study design in animal and cell models. Collectively, current data support layering SGLT2 inhibitors onto RAAS-based therapy, while definitive evidence from dedicated clinical trials is awaited.
Use, efficacy, and safety of desmopressin for congenital nephrogenic diabetes insipidus in children: a nationwide survey.
Endocr J
Kento Ikegawa, Masanobu Fujimoto, Kohei Aoyama +12 more
Congenital nephrogenic diabetes insipidus (CNDI) is characterized by resistance of the distal nephrons and collecting ducts to arginine vasopressin (AVP). High doses of 1-deamino-8-D-arginine vasopressin (DDAVP), a V2-receptor-selective agonist, are effective in some cases. The present study aimed to demonstrate the use, efficacy, and safety of DDAVP and the characteristics of patients who responded to this treatment. The present, retrospective, multicentric, observational survey of patients with CNDI receiving DDAVP was based on a previous, nationwide survey conducted by the Japanese Society for Pediatric Endocrinology (JSPE) and collected data on the use (formulation, dosage, and treatment duration), efficacy (change in urine output and height SDS), and safety of DDAVP. In the initial survey, 43 of 123 JSPE council members (35.0%) observed the patients. The secondary survey of 13 patients found DDAVP to be effective in five patients (38.5%), as evidenced by a 12.6-31.6% decrease in urine output. The maximum urine osmolality on a water deprivation test and urine osmolality after vasopressin injection were lower in patients who were unresponsive to DDAVP than in those who were responsive to the drug (106 vs. 206 mOsm/H2O/kg, 140 vs. 525 mOsm/H2O/kg). The AVPR2 variants identified in the DDAVP-responsive group were p.Ala37Pro, p.Leu44Phe, p.Arg104Cys, and p.Tyr128Ser. DDAVP was effective against CNDI with residual V2R function. The water deprivation test with vasopressin injection and genetic testing may be useful for predicting responsiveness to DDAVP.
Release of Bioactive Peptides from Whey Protein During In Vitro Digestion and Their Effect on CCK Secretion in Enteroendocrine Cells: An In Silico and In Vitro Approach.
Molecules
Anaís Ignot-Gutiérrez, Orlando Arellano-Castillo, Gloricel Serena-Romero +4 more
During gastrointestinal digestion, dietary proteins are hydrolyzed into peptides and free amino acids that modulate enteroendocrine function and satiety-related hormone secretion along the gut-brain axis, thereby contributing to obesity prevention. We investigated whey protein concentrate (WPC) as a source of bioactive peptides and evaluated the effects of its digests on cholecystokinin (CCK) secretion in STC-1 enteroendocrine cells by integrating the standardized INFOGEST in vitro digestion protocol, peptidomics (LC-MS/MS), and in silico bioactivity prediction. In STC-1 cells, the <3 kDa intestinal peptide fraction exhibited the strongest CCK stimulation, positioning these low-molecular-weight peptides as promising bioactive components for satiety modulation and metabolic health applications. Peptidomic analysis of this fraction identified short sequences derived primarily from β-lactoglobulin (β-La) and α-lactalbumin (α-La), enriched in hydrophobic and aromatic residues, including neuropeptide-like sequences containing the Glu-Asn-Ser-Ala-Glu-Pro-Glu (ENSAEPE) motif of β-La f(108-114). In silico bioactivity profiling with MultiPep predicted antihypertensive, angiotensin-converting enzyme (ACE)-inhibitory, antidiabetic, dipeptidyl peptidase-IV (DPP-IV)-inhibitory, antioxidant, antibacterial, and neuropeptide-like activities. Overall, digestion of WPC released low-molecular-weight peptides and amino acids that enhanced CCK secretion in vitro; these findings support their potential use in nutritional strategies to enhance satiety, modulate appetite and energy intake, and improving cardiometabolic health.
Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: Current Therapeutic Strategies and Future Prospects.
Biomolecules
Yukina Mizuno Yokoyama, Ryu Watanabe, Tomohiro Yamaguchi +8 more
Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a severe form of pulmonary hypertension with poor prognosis. It most commonly arises in systemic sclerosis (SSc), followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Its pathogenesis involves a complex interplay of immune dysregulation, chronic inflammation, endothelial injury, vascular remodeling, and fibrosis. Although vasodilators targeting the endothelin, nitric oxide, and prostacyclin pathways remain the therapeutic backbone, newer agents-including the activin signal inhibitor sotatercept and inhaled treprostinil-have expanded treatment options. Immune-targeted therapies such as glucocorticoids, cyclophosphamide, mycophenolate mofetil, rituximab, and IL-6 receptor inhibitors may benefit inflammation-dominant PAH phenotypes, while fibrotic phenotypes continue to demonstrate limited responsiveness. In addition to brain natriuretic peptide (BNP), N-terminal (NT)-proBNP and disease-specific autoantibodies, emerging biomarkers show promise for early detection, risk stratification, and personalized treatment, though validation in CTD-PAH is lacking. Advances in animal models replicating immune-mediated vascular injury and fibrosis have further improved mechanistic understanding. Despite these developments, substantial unmet needs remain, including the absence of disease-specific therapeutic strategies, limited biomarker integration into clinical practice, and a scarcity of large, well-designed trials targeting individual CTD subtypes. Addressing these gaps will be essential for improving prognosis in patients with CTD-PAH.
Sotatercept in Pulmonary Arterial Hypertension: Molecular Mechanisms, Clinical Evidence, and Emerging Role in Reverse Remodelling.
Int J Mol Sci
Ioan Tilea, Dragos-Gabriel Iancu, Ovidiu Fira-Mladinescu +2 more
Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials-PULSAR, STELLAR, ZENITH, and HYPERION-demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept's therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management.
Possible Involvement of Hypothalamic Dysfunction in Long COVID Patients Characterized by Delayed Response to Gonadotropin-Releasing Hormone.
Int J Mol Sci
Yuki Otsuka, Yoshiaki Soejima, Yasuhiro Nakano +12 more
Long COVID (LC) may involve endocrine dysfunction; however, the underlying mechanism remains unclear. To examine hypothalamic-pituitary responses in patients with LC, we conducted a single-center retrospective study of patients with refractory LC referred to our University Hospital who underwent anterior pituitary stimulation tests. Between February 2021 and November 2025, 1251 patients with long COVID were evaluated, of whom 207 (19%) had relatively low random ACTH or cortisol levels. Ultimately, 16 underwent anterior pituitary stimulation tests and were included. All tests were performed in an inpatient setting without exogenous steroids. Fifteen patients (six women, mean age 35.6 years) underwent corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH) tests. All patients had mild acute COVID-19, eight had ≥2 vaccinations, and the mean interval from infection was 343 days. Frequent symptoms included fatigue (100%), insomnia (66.7%), headache (60.0%), anorexia/nausea (40.0%), and brain fog (40.0%). Mean early-morning cortisol and 24 h urinary free cortisol were 7.5 μg/dL and 41.0 μg/day, respectively. MRI showed an empty sella in one case. Peak hormonal responses were preserved (ΔACTH 247%, ΔTSH 918%, ΔPRL 820%, ΔFSH 187%, ΔLH 1150%); however, peaks were delayed beyond 60 min in ACTH (13%), LH (33%), and FSH (87%). Notably, significantly delayed elevations remained at 120 min in the responses of TSH (4.1-fold), PRL (1.8-fold), LH (9.3-fold), and FSH (2.8-fold), suggesting possible hypothalamic involvement, particularly in the gonadotropin responses. Additionally, serum IGF-I was lowered (-0.70 SD), while GH response (mean peak 35.5 ng/mL) was preserved by growth hormone-releasing peptide (GHRP)-2 stimulation. Low-dose hydrocortisone and testosterone were initiated for three patients. Although direct viral effects and secondary suppression have been proposed, our findings may suggest that, at least in part, the observed response characteristics are consistent with functional secondary hypothalamic dysfunction rather than irreversible primary injury. These findings highlight the need for objective endocrine evaluation before initiating hormone replacements.
The role of dopamine release and D2 dopamine receptor in GHRH and somatostatin cells in controlling growth hormone secretion.
Front Endocrinol (Lausanne)
Gabriel O de Souza, Daniela O Gusmao, Maria E de Sousa +3 more
Pituitary growth hormone (GH) secretion is primarily controlled by GH-releasing hormone (GHRH) and somatostatin (SST), peptides produced by hypothalamic neurons. Evidence indicates that dopamine also modulates GH secretion, potentially via D2 dopamine receptor (D2R). Additionally, a subset of GHRH neurons in the arcuate nucleus of the hypothalamus expresses tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine biosynthesis. However, the role of dopamine release from GHRH neurons and the neuronal population that expresses D2R to regulate GH secretion remain currently unknown.
Exogenous MOTS-c mitigates myocardial ischemia-reperfusion injury: experimental and in silico evidence from rat heart models.
Naunyn Schmiedebergs Arch Pharmacol
Saranya Sri Santhanam, Srijan Jayaraman, Gino A Kurian
The mitochondrial-derived peptide MOTS-c regulates metabolic and cellular stress responses, but its dose-response profile and direct cardioprotective mechanisms in myocardial ischemia-reperfusion injury (MIRI) remain undefined. This proof-of-concept study aimed to identify the optimal cardioprotective dose of exogenous MOTS-c and delineate its multi-pathway mechanisms using an ex vivo rat heart IR model with in silico support. Isolated Langendorff-perfused rat hearts underwent 30-min global ischemia and 60-min reperfusion with or without MOTS-c (0.25-0.7 mg/kg) delivered via Krebs-Henseleit buffer during the first 10 min of reperfusion. Hemodynamics, infarct size (TTC), oxidative stress markers, inflammation, and apoptotic gene expression were quantified. Peptide-protein interactions with survival pathways were predicted computationally. MOTS-c at 0.5 mg per kg conferred maximal protection, producing a 73% reduction in infarct size compared with ischemia-reperfusion alone, improving heart rate, left ventricular developed pressure, and rate-pressure product, and lowering end-diastolic pressure. Lactate dehydrogenase release decreased by 65%. Antioxidant defenses improved with increased superoxide dismutase, catalase, and glutathione redox ratio, along with reduced lipid peroxidation. Myeloperoxidase activity normalized, pro-apoptotic genes including caspase 3, caspase 7, caspase 9, BAX, and PARP were downregulated, while cytoprotective genes including BCL2, GPX4, and FOXO were increased. Molecular docking demonstrated high-affinity interactions of MOTS-c with MAPK, mTOR, AMPK, NRF2, PI3K, and caspase 3. This ex vivo study identifies 0.5 mg/kg as the optimal dose within the tested range, producing coordinated anti-apoptotic, antioxidant, and anti-inflammatory effects. Although the isolated heart model isolates direct myocardial actions, the lack of systemic influences and limited dose range necessitate broader dosing and pharmacokinetic studies before translational application.
Transcatheter Valve Replacement in Carcinoid Heart Disease: A Potential Change of Paradigm.
Interdiscip Cardiovasc Thorac Surg
Marie-Anne Barbier, Laura Gerard, Daniel Grinberg +4 more
To evaluate the feasibility and early clinical outcomes of transcatheter valve replacement in high-surgical-risk patients with carcinoid heart disease.
Structural insights, immunomodulatory functions, and therapeutic potential of host defense peptides in avoiding antimicrobial resistance.
Adv Protein Chem Struct Biol
Gisele Regina Rodrigues, Michel Lopes Leite, Octavio Luiz Franco
Antimicrobial resistance (AMR) undermines the effectiveness of antibiotic treatment, and due to this, it now worldwide health concern. In general, antibiotics are used to control or combat bacteria, their widespread and irresponsible has contributed to the development bacterial resistance to some microbial drug. Due to this, treating patients identified with resistant bacteria is burdensome and, expensive, and success rates are low. Among the more successful tools are host defense peptides (HDPs), which represent a beneficial alternative due to their unique mechanisms of action and low toxicity toward host cells. HDPs are crucial innate immune system components, exhibiting antibacterial, antifungal, antiviral, and anti-inflammatory activities. Some peptides, such as human cathelicidin LL-37, exhibit direct pathogen-killing activity and the ability to modulate innate immune responses. HDPs also interact with various pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs), influencing downstream pathways essential for microbial clearance and inflammation regulation. These interactions damage the microbial membrane, stimulating cytokine production and immune cell recruitment. Furthermore, HDPs can modulate chemokine receptor signaling to coordinate leukocyte migration and enhance host protection. Despite these promising aspects, there are challenges to overcome, such as potential immunotoxicity, proteolytic instability, and low receptor specificity, which hinder clinical application. This review highlights the complex interaction between HDPs and immune receptors, which can be used to overcome AMR and inform next-generation anti-infective therapy development.
Hypoxic microenvironment and pulmonary hypertension.
Respir Res
Tiantian Mu, Boshuo Guo, Chuqi Xiang +4 more
Pulmonary hypertension (PH) is a serious pulmonary vascular disease characterized by a progressive increase in pulmonary vascular resistance and abnormally high pulmonary arterial pressure. The hypoxic microenvironment plays an important role in its development. Studies have indicated that early exposure of pulmonary vasculature to hypoxia in the hypoxic microenvironment triggers an adaptive response in the organisms and has a homeostatic regulatory effect. However, under prolonged hypoxic stimulation, pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs) can be induced to abnormally proliferate and migrate through endothelial cell dysfunction and endothelial-mesenchymal transition. This leads to irreversible pulmonary vascular remodeling, which ultimately results in PH formation. Core components of the hypoxic microenvironment include hypoxia-inducible factors (HIFs) through a complex regulatory network, metabolic reprogramming in the microenvironment (glucose metabolism, lipid metabolism, and amino acid metabolism), an overabundance of reactive oxygen species and redox imbalance, reprogramming of the immuno-inflammatory microenvironment, regulation of cell death patterns (apoptosis resistance, iron death, and autophagy imbalance), mechanical stress and cytoskeletal dynamics, non-coding RNA regulatory networks (miRNA, IncRNA, and circRNA), microbial-host interactions (gut flora metabolites), epigenetic regulation (DNA methylation, histone modification, and RNA modification) and Transient Receptor Potential (TRP) Channels and Calcium Signaling Regulation. These processes are interconnected in the organisms to induce or promote aberrant proliferation and migration of PASMCs and PAECs, which are the pathogenic mechanisms resulting in PH. Current clinical treatments for PH include endothelin receptor antagonists, drugs targeting cyclic guanosine monophosphate production, phosphodiesterase-5 inhibitors, and prostacyclin analogs. However, novel targeted drugs against HIF-1ɑ remain under development. Oxygen therapy and mechanical ventilation, gene therapy, and molecularly targeted interventions (modulation of the RhoA/ROCK pathway or non-coding RNAs) can improve hypoxemia. Future studies must integrate multi-omics data, incorporate artificial intelligence to accelerate drug development, and focus on gender and individualization to achieve precision therapy. In conclusion, an in-depth analysis of the mechanism of the hypoxic microenvironment in PH will provide the fundamental basis for developing more effective therapeutic strategies.