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Cardioprotective Effects of Apelin in Myocardial Ischemia/Reperfusion Injury: A Systematic Review and Meta-Analysis.
J Cardiovasc Pharmacol
Seyedhesamoddin Khatami, Mohammadsadegh Faghihi, Amirali Zarrin +3 more
Myocardial ischemia/reperfusion (I/R) injury remains a major clinical challenge, because blood flow restoration can exacerbate tissue damage. Apelin, an endogenous peptide acting through the APJ receptor, has demonstrated cardioprotective effects in experimental models. The APJ receptor, a G-protein-coupled receptor widely expressed in cardiovascular tissues, mediates vasodilation, cardiac contractility, and angiogenesis. This systematic review and meta-analysis evaluates its efficacy in myocardial I/R injury. A systematic search in Medline (PubMed), Embase, Scopus, and Web of Science was conducted up to 2024, identifying rodent studies of cardiac I/R injury (Langendorff/in vivo) treated with apelin. Studies on pretreatment or chronic ischemia were excluded. A random-effects meta-analysis reported standardized mean differences with 95% confidence intervals, assessing heterogeneity using the I 2 statistic. From 1765 records, 26 preclinical studies met inclusion criteria. Apelin significantly improved +LVdp/dtmax, -LVdp/dtmax, left ventricular end-diastolic pressure, left ventricular end-systolic pressure, left ventricular ejection fraction, left ventricular developed pressure × heart rate, cardiac output, stroke volume, coronary flow, and left ventricular developed pressure, but did not affect heart rate, mean arterial pressure, left ventricular end-diastolic volume, or left ventricular end-systolic volume. It reduced infarct size, fibrosis, lactate dehydrogenase, malondialdehyde, and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay), while also reducing creatine kinase-MB and improving adenosine triphosphate, energy charge, and phosphocreatine. Meta-regression indicated most outcomes were dose independent, although a few (eg, mean arterial pressure, terminal deoxynucleotidyl transferase dUTP nick end labeling) showed dose-related responses. The risk of bias was high in most studies, and publication bias was observed for some outcomes. Apelin exerts cardioprotective effects in rodent I/R models, enhancing cardiac function and metabolism while reducing infarct size, oxidative stress, and apoptosis. Further standardized preclinical and clinical studies are warranted to optimize dosing protocols and define therapeutic applicability.
Correlation of anxiety/depression status with stress-related markers and cancer-related fatigue in patients with colon cancer.
World J Psychiatry
Ling Zhao, Bin Jian, Duan-Hong Chen
Anxiety and depression are significant contributors to adverse outcomes in patients with colon cancer (CC). Therefore, investigating the key determinants of this psychological distress in such patients is essential.
Transcription Factor SP1 Drives Myocardial Ischemia/reperfusion Injury By Transcription Activation-mediated GADD45G Upregulation.
J Cardiovasc Transl Res
Yaping Wang, Jianying Xue, Mingliang Cui +2 more
Myocardial ischemia-reperfusion injury (MIRI) is an unresolved clinically fatal complication in the management of acute myocardial infarction (AMI). Growth arrest and DNA damage-inducible gene 45 Gamma (GADD45G) plays a vital role in the regulation of MIRI. However, the underlying mechanisms remain unclear. GADD45G and SP1 expression were upregulated in hypoxia/reoxygenation (H/R)-treated H9C2 cells. H/R treatment repressed H9C2 cell viability, and induced apoptosis, oxidative stress, and inflammatory response. Moreover, GADD45G deficiency could relieve H/R-triggered H9C2 cell injury. In mechanism, SP1 was a transcription factor of GADD45G and activated the transcription of GADD45G via binding to its promoter region. Besides, SP1 knockdown alleviated MI/R-induced pathological damage in the myocardial tissue of rats by regulating GADD45G. In conclusion, SP1 could promote H/R-induced cardiomyocyte injury and MI/R-caused rat myocardial tissue pathological injury by increasing GADD45G, providing a promising therapeutic target for MIRI treatment.
Sleep, wake, and signaling: Functional profiling of orexin agonists and antagonists using newly developed orexin β-arrestin 2 and miniGαq recruitment assays.
Eur J Pharmacol
Marie H Deventer, Silvia Mori, Marcus Angermann +2 more
The excitatory neuropeptides orexin-A and -B interact with their target G protein-coupled receptors (GPCRs), the orexin 1 and orexin 2 (OX1 and OX2) receptors, which are widely expressed throughout the central nervous system. The orexin system plays a critical role in regulating several physiological processes such as sleep-wake cycles, feeding behaviour, and arousal, and is implicated in a variety of (neurological) disorders. In particular dysregulation of the orexin system is linked to sleep disorders such as narcolepsy (often associated with orexin deficiency) and insomnia (characterized by an overactivity of sleep-wake regulation). This has prompted a growing interest in orexin-targeting therapeutics. This study is the first to report the development of four OX1 and OX2 receptor luminescence bioassays based on functional complementation of a split-nanoluciferase enzyme, capable of monitoring β-arrestin 2 (βarr2) and Gαq recruitment to activated OX1 and OX2 receptors. These assays were successfully applied to evaluate the pharmacological profiles of both agonists and antagonists, including the endogenous ligands orexin-A and -B, the clinically approved small molecule antagonists suvorexant and daridorexant, as well as EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) and four other compounds described in literature to act at orexin receptors. The obtained receptor activation patterns and selectivity profiles were consistent with literature data, indicating the reliability and robustness of the assay systems. Overall, the newly developed assays expand the toolkit for orexin receptor research by allowing the characterization of both agonists and antagonists, thereby contributing to the functional characterization of potential new drug candidates for various pathological conditions.
Regulation of virulence factors of Pseudomonas aeruginosa by Scutellaria baicalensis, Prunella vulgaris and antimicrobial peptide LL-37.
J Med Microbiol
Qian Xiao, Kaiwen Du, Li Luo +6 more
Introduction. The increasing resistance and the pathogen's complex multi-drug resistance mechanisms made the selection of effective antimicrobial treatments more challenging for Pseudomonas aeruginosa (P. aeruginosa). The study aimed to explore the effect of Scutellaria baicalensis, Prunella vulgaris and antimicrobial peptide LL-37 on the virulence factors of P. aeruginosa.Hypothesis. Previous studies have shown that extracts from traditional Chinese medicines, Scutellaria baicalensis and Prunella vulgaris, can also enhance the effects of antibiotics and reduce antibiotic resistance in P. aeruginosa. Antimicrobial peptide LL-37 shows the potential as a new-generation candidate for treating multi-drug-resistant bacteria, which has advantages over traditional antibiotics, whilst the combination role between Scutellaria baicalensis, Prunella vulgaris and LL-37 in P. aeruginosa remains unknown.Aim. We explored whether the combined use of Scutellaria baicalensis, Prunella vulgaris and LL-37 can exert antibacterial effects through the quorum sensing (QS) system.Methodology. The minimal inhibitory concentrations of Scutellaria baicalensis, Prunella vulgaris and LL-37 were determined for PAO1 and PA-ΔlasI/rhlI using micro broth dilution. The antibacterial activity of Scutellaria baicalensis combined with LL-37 and Prunella vulgaris combined with LL-37 was also assessed. The growth abilities of PAO1 were analysed after being treated with Scutellaria baicalensis, Prunella vulgaris and LL-37, respectively. Elastase secretion was measured using Congo red-elastic proteinase assays. And the expressions of QS genes (lasI, rhlR) were analysed by real-time PCR.Results. Single or combined treatments of Scutellaria baicalensis and LL-37 and Prunella vulgaris and LL-37 would significantly reduce elastase secretion. There were no significant differences in proliferation between the groups at any timepoint. All treatments downregulated lasI and rhlR gene expressions.Conclusion. Scutellaria baicalensis, Prunella vulgaris and antimicrobial peptide LL-37 all down-regulate the QS system-related genes of P. aeruginosa, inhibiting the secretion of virulence factors and reducing bacterial toxicity.
IGF-I bioavailability in congenital isolated growth hormone deficiency.
Eur J Endocrinol
Viviane C Campos, Manuel H Aguiar Oliveira, Martin Bidlingmaier +8 more
The Itabaianinha cohort in Brazil carries a homozygous growth hormone-releasing hormone (GHRH) receptor (GHRH-R) gene mutation, causing congenital isolated GH deficiency (GHD). Affected individuals present with severe short stature, central obesity, hypercholesterolemia, and marked reductions in serum GH, IGF-I, and IGFBP 3 concentrations yet show no premature atherosclerosis and maintain a normal lifespan. IGF-I mostly circulates bound to IGFBPs and requires proteolytic cleavage for IGF-I receptor activation. Pregnancy-associated plasma protein A (PAPP-A) is an important IGF-dependent cleavage enzyme, binding to IGFBP 4 and releasing IGF-I. PAPP-A activity is inhibited by stanniocalcin-2 (STC2). The IGFBP 4-STC2-PAPP-A axis (ISPa) has emerged as a key regulator of IGF-I bioactivity.
Isolated Follicle-Stimulating Hormone (FSH) Deficiency in Male Sex: A Case Report.
Cureus
Daniela M Soares, Jorge Diogo Silva, Ana Rita Soares +1 more
Follicle-stimulating hormone (FSH) is a glycoprotein hormone produced in the anterior pituitary, essential in the regulation of gonadal functions. Isolated FSH deficiency (IFD) is a rare inherited disorder, usually caused by β-subunit alterations. In men, it is frequently detected during infertility evaluation, commonly associated with spermatogenesis impairment and testicular atrophy with normal testosterone levels. We present the case of a 30-year-old male patient who was referred for breast pain and bilateral gynecomastia. Laboratory evaluation displayed primary hypothyroidism with positive thyroid autoantibodies and decreased FSH levels, with normal total testosterone and adequate luteinizing hormone (LH) levels. A gonadotropin-releasing hormone (GnRH) stimulation test demonstrated inadequate FSH response, highly suggestive of IFD. Genetic testing for FSHB mutations was negative, and whole exome sequencing revealed no recognized pathogenic variants. Semen analysis was postponed by the patient's choice. Although rare, IFD should be considered when evaluating patients with symptoms suggestive of hypogonadism. The overall prevalence of FSH-β mutations is unknown but probably underdiagnosed in male patients.
The Ly6ghigh Neutrophil Subset Dictates Breast Cancer Lung Metastasis via CD8+ T Cell Death.
Cancer Commun (Lond)
Rui Wang, Xiaoqi Liu, Yixuan Hou +10 more
Background: Lung metastasis is a leading cause of breast cancer (BC)-related mortality, driven by the immunosuppressive traits of the metastatic tumor microenvironment. However, the mechanisms underlying cell-cell crosstalk in shaping immune evasion within the metastatic niche remain poorly defined. Neutrophil extracellular traps (NETs) and their associated proteins, such as cathelicidin, have emerged as key mediators of metastatic regulation in cancer. Here, we aimed to decipher the interaction between a neutrophil subset characterized by high expression of lymphocyte antigen 6 complex locus g (Ly6ghigh) and cluster of differentiation 8-positive T lymphocytes (CD8+ T cells), mediated via cathelicidin embedded in NETs, as well as their synergistic mechanism and cooperative role in promoting lung metastasis of BC. Methods: We characterized neutrophil heterogeneity and functional dynamics by performing single-cell RNA sequencing and flow cytometry on lung tissues derived from murine models of BC lung metastasis. We utilized cathelicidin-related antimicrobial peptide (Cramp) knockout mice to dissect the role of cathelicidin in NETs. The spatial colocalization of apoptotic CD8+ T cells and NETs was analyzed using multiplex immunofluorescence, and the molecular interactions were probed by protein binding assays. Results: Neutrophils in the lung metastatic niche were classified into 2 subsets based on the Ly6g expression: Ly6ghigh and Ly6glow neutrophils. Ly6glow neutrophils, which were recruited in the macrometastatic stage, exhibited myeloid-derived suppressor cell-like characteristics. Notably, Ly6ghigh neutrophils induced CD8+ T cell apoptosis through NET formation, with apoptotic CD8+ T cells spatially clustered within NET-rich areas. Mechanistically, NET-derived cathelicidin (Cramp in mice) directly bound to mitochondrial adenine nucleotide translocator 1 (Ant1) in CD8+ T cells, triggering conformational changes and complex formation with voltage-dependent anion channel 1 (Vdac1). These events resulted in the opening of the mitochondrial permeability transition pore and loss of mitochondrial membrane potential. Conclusions: Our study demonstrates that Ly6ghigh neutrophils play a critical role in immunosuppression and immune evasion through NET-induced apoptosis of CD8+ T cells. These findings underscore the importance of NETs and cathelicidin in BC lung metastasis, suggesting their potential as therapeutic targets in restoring antitumor immunity and in preventing metastatic progression.
Hormonal Modulation of Fat Mass Induced Insulin Resistance.
Metab Syndr Relat Disord
Humam Emad Rajha, Ahmed Arabi, Dima Nasrallah +12 more
This study examines the impact of body mass index (BMI) on homeostatic model assessment for insulin sensitivity (HOMA-S) and homeostatic model assessment for pancreatic β-cell function (HOMA-B) in adults with obesity but without diabetes. Additionally, the association of key hormones, leptin and gastric inhibitory peptide (GIP), with HOMA indices and BMI has been investigated.
Lugol's solution for preoperative management of a TSH/GH-secreting pituitary adenoma with suboptimal response to octreotide: a case report.
Front Endocrinol (Lausanne)
Guiliang Peng, Xiaotian Lei, Weiling Leng +4 more
Thyroid-stimulating hormone pituitary adenomas (TSHomas) are a rare cause of central hyperthyroidism, characterized by abnormally high TSH levels, and typically respond to somatostatin analogue (SSA). We report a young patient with SSA-insensitive TSHoma where Lugol's solution facilitated surgical preparation.
Multi-target incretin-based therapeutics: The rise of dual and triple agonists for metabolic disorders.
Eur J Med Chem
Seyed Ebrahim Alavi, Reza Boshrouyeh, Aun Raza +1 more
Dual and triple incretin-based therapies are transforming treatment for type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease. By targeting glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon receptors, these agents enhance glycemic control, reduce body weight, and improve liver outcomes. Drugs like tirzepatide and retatrutide have shown unprecedented efficacy and tolerability. This review summarizes their mechanisms, clinical progress, and limitations, highlighting how dual and triple incretin agonists may extend or refine the therapeutic benefits established by current GLP-1-based therapies. While challenges remain in safety, accessibility, and long-term use, multi-target agonists represent a promising future in metabolic disease management.
Exploring the relationship between adherence and outcomes in pulmonary arterial hypertension: A retrospective cohort study in the United States.
Respir Med
Teresa De Marco, Carly J Paoli, Hayley D Germack +6 more
Pulmonary arterial hypertension (PAH) is a rare, progressive disease with significant morbidity and mortality. New medications have improved outcomes, but adherence is crucial.
Protective effect of pituitrin combined with norepinephrine on cardiopulmonary injury in patients with septic shock diagnosed by critical care ultrasound evaluation.
Pak J Pharm Sci
Henghao Cui, Xiaochun Yuan, Kai Lu +2 more
Septic shock is a life-threatening complication of sepsis, often accompanied by cardiopulmonary dysfunction, which significantly increases the mortality of patients. Norepinephrine (NE) is a commonly used vasopressor in the treatment of septic shock, but single-drug therapy may not fully achieve cardiopulmonary protection. Antidiuretic hormone (ADH) has potential regulatory effects on hemodynamics and inflammation, but its combined efficacy with NE in cardiopulmonary protection for septic patients remains to be further verified.
Idebenone protects against doxorubicin-induced cardiac injury by inhibiting ferroptosis in cardiomyocytes.
Exp Gerontol
Jie Mao, Zhiyi Zhou, Yuting Xu +3 more
Heart failure (HF) remains a global health challenge with limited efficacious therapies, necessitating novel strategies targeting its underlying pathological mechanisms. Emerging evidence implicates dysregulated iron metabolism and ferroptosis-an iron-dependent form of regulated cell death-as critical drivers of cardiomyocyte attrition in heart failure pathogenesis. This study investigates the therapeutic potential of idebenone (IDE), a clinically approved mitochondrial-targeted antioxidant and short-chain analog of coenzyme Q10, in modulating ferroptosis-mediated cardiac dysfunction. We confirmed that idebenone significantly attenuated pathological markers of cardiac stress, reducing expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cardiomyocytes. Furthermore, idebenone treatment suppressed lipid peroxidation and mitochondrial iron overload. In the HF animal model, idebenone administration improved left ventricular ejection fraction, restored redox homeostasis and reduced cardiac iron deposition. These findings establish idebenone as a promising strategy to mitigate ferroptosis-driven myocardial injury, providing a translational framework for developing idebenone-based therapies for heart failure management.
A coral-derived neuropeptide suppresses pentylenetetrazol (PTZ)-induced epileptic seizures and improves recognition memory deficits by modulating NPY-Y1R.
Arch Toxicol
Qian Chen, Congshuang Deng, Xiaoshan Huang +8 more
Epilepsy is a prevalent neurological disorder characterized by recurrent and unprovoked seizures. Despite the availability of anti-epileptic drugs (AEDs), a significant number of patients are still suffering from drug-resistant epilepsy. Neuropeptide Y (NPY) signaling system has emerged as a potential target for the development of anti-epileptic drugs due to its modulation of epileptic activity. In this study, we investigated the therapeutic potential of our previously discovered Scleractinia-derived NPY-like peptide (TpNPY) in seizure disorders. The anticonvulsant effects of TpNPY were evaluated using PTZ-induced seizures in zebrafish and mice in vivo. Furthermore, the underlying molecular mechanisms of TpNPY were assessed using glutamate-induced excitotoxicity models in HT22 mouse hippocampal cells in vitro. Our findings indicated that TpNPY could alleviate PTZ-induced seizure behavior, reduce the expression of seizure-associated immediate-early genes and the production of Reactive Oxygen Species (ROS) in zebrafish. In mice, TpNPY improved seizure behaviors, decreased inflammatory cytokine levels, and ameliorated abnormal glial activation in a PTZ kindling epileptic model. Besides, the administration of TpNPY could attenuate the PTZ-induced anxiety levels and improve recognition memory deficits. Moreover, TpNPY promotes neurogenesis and neural synaptic plasticity through the BDNF/TrkB signaling pathway. Additionally, TpNPY restored cell injury and attenuated oxidative stress in glutamate-challenged HT22 cells through the Nrf2/HO-1 signaling pathway. These results highlight the potential therapeutic efficacy of TpNPY in the treatment of seizures and provide new insights into the development of coral-derived anti-epileptic peptide-based drugs.
Efficacy and safety of fibroblast growth factor 21 analogs in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis: A systematic review and network meta-analysis.
J Pharmacol Exp Ther
Marwa Muhammed Abdeljawad, Mohammed Tarek Hasan, Areeba Fareed +7 more
Metabolic dysfunction-associated steatotic liver disease has emerged as a global public health concern. Fibroblast growth factor 21, a liver hormone, is gaining interest because of its ability to regulate metabolism and improve metabolic dysfunction-associated steatotic liver disease. In this network meta-analysis, we investigated the efficacy of these treatments in treating metabolic dysfunction-associated steatotic liver disease. A comprehensive search was conducted across electronic databases, including PubMed, Scopus, the Cochrane Library, and Web of Science, till August 2025. We used R software to analyze data using a random effects model. Heatmaps were used to visualize the included interventions' ranking. We included 9 clinical trials comprising 1277 patients. Among them, 284 received efruxifermin, 263 received pegbelfermin, 151 received pegozafermin, 65 received efimosfermin, 139 received MK-3655, and 375 received a placebo. Pegozafermin and efruxifermin were effective in improving liver fibrosis (RR, 3.89-3.93, P < .05; RR, 2.23-1.91, P < .05, respectively), whereas the other interventions did not yield statistical significance. Efimosfermin α, efruxifermin, and pegozafermin improved different metabolic parameters, including adiponectin, hemoglobin A1c, and non-high-density lipoprotein. However, no significant differences were observed in body weight and low-density lipoprotein. For liver enzymes, efimosfermin α had the greatest reduction of alanine aminotransferase and aspartate aminotransferase, whereas efruxifermin was most effective in reducing γ-glutamyl transferase levels. The odds of adverse events were higher in pegozafermin, efimosfermin, and efruxifermin groups, mainly attributed to mild to moderate gastrointestinal adverse events. In conclusion, efruxifermin and pegozafermin are promising therapeutic options with a tolerable adverse event profile; meanwhile, efimosfermin α showed promising results in improving metabolic parameters, with histologic results yet to be published. SIGNIFICANCE STATEMENT: This meta-analysis evaluates the efficacy of fibroblast growth factor 21 analogs in improving metabolic dysfunction-associated steatotic liver disease. Efruxifermin and pegozafermin were the most significant in improving liver fibrosis; moreover; significant improvements in some metabolic parameters were observed with efimosfermin α, efruxifermin, and pegozafermin.
Therapeutic Approaches Involving Mitochondria in the Treatment of Acute Kidney Injury.
Semin Nephrol
Prisha S Patel, Navjot S Pabla, Amandeep Bajwa
Acute kidney injury (AKI) continues to pose a significant clinical burden, characterized by high morbidity and mortality rates. Emerging evidence has established mitochondrial dysfunction as a central driver in the pathogenesis of AKI, encompassing deficits in bioenergetics, excessive production of reactive oxygen species, and disruption of mitochondrial dynamics. Therapeutic interventions targeting mitochondrial pathways-most notably peptide-based agents such as SS-31-have demonstrated promising results in preclinical models. Recent discoveries have identified phospholipid scramblase 3 (PLSCR3) as an essential mediator of SS-31's mitochondrial protective effects, positioning it as a novel therapeutic target. This review synthesizes current mitochondrial-directed approaches for AKI, with a particular emphasis on the mechanistic role of PLSCR3 in maintaining mitochondrial homeostasis and injury responses. Despite encouraging data, mitochondrial therapies face several translational hurdles, including limited bioavailability, challenges in establishing effective dosing regimens, incomplete mechanistic understanding, and variability in efficacy across different experimental models. Moreover, concerns regarding cost, accessibility, and long-term safety remain unresolved, contributing to inconsistent outcomes in clinical trials. Herein we evaluate the emerging role of PLSCR3 as a potentially druggable mitochondrial target, supported by recent genetic, biochemical, and in vivo evidence, and discuss translational strategies that may bridge the gap between experimental promise and clinical application.
Growth hormone releasing peptide-6 (GHRP-6) ameliorates acute lung injury and its subsequent evolvement to interstitial fibrosis.
Int Immunopharmacol
Linlin Wang, Jorge Berlanga-Acosta, Haoying Yu +6 more
Acute lung injury/acute respiratory distress syndrome is a complex, characterized by acute onset, alveolar damage, and progressive hypoxemia. The subsequent proliferative phase drives to pulmonary fibrosis. Lipopolysaccharide (LPS) and zymosan (ZYM) induced lung injury are commonly used biomodels that recapitulate multiple pathogenic hallmarks. We examined the ability of growth hormone releasing peptide 6 (GHRP-6) to attenuate the pulmonary damages associated with intratracheal instillation of LPS or ZYM combined injection with platelet activating factor (PAF) in mice. For the acute scenario, mice received LPS challenge and 6 h later, assigned to normal saline (Control) or to a single administration of each GHRP-6 dose and evolved for 24 h; or mice received four ZYM tracheal instillations and 6 h after, one PAF injection assigned to normal saline (Control) or to five administrations of each GHRP-6 dose and evolved for 15 days. For the chronic scenario, mice were terminated 28 days after receiving a single LPS instillation and seven subsequent daily administrations of GHRP-6; or mice were terminated 28 days after receiving five GHRP-6 therapeutic interventions after four ZYM tracheal instillations and one PAF injection. The acute scenario, GHRP-6 reduced neutrophilic alveolitis, attenuated lung compliance failure, contributed to improve alveolar-capillary permeability, and reduced interleukin-1 beta serum levels. The chronic scenario, GHRP-6 preserved lung parenchymal integrity accounted for meager collagen accumulation. This is the first assessment on the potential protective of GHRP-6 in model of lung damages. This study therefore paves the way for future research on the potential pneumoprotective effects of GHRP-6.
Amylin Revisited: A 5-Year Perspective on Its Emerging Role in the Treatment of Diabesity.
J Obes Metab Syndr
Chae Won Chung, Jaetaek Kim
Amylin is a pancreatic peptide hormone that regulates blood glucose levels and appetite. This review outlines the physiological role of amylin and highlights recent clinical studies exploring its therapeutic potential in diabetes and obesity. Amylin lowers postprandial glucose levels by delaying gastric emptying and suppressing glucagon secretion, while promoting satiety via central nervous system pathways. Preclinical research has driven the development of long-acting amylin analogs with enhanced pharmacokinetics and reduced aggregation, resulting in significant weight loss and metabolic benefits in animal models. Clinically, the synthetic analog pramlintide has been shown to modestly improve glycemic control and induce weight loss in patients with diabetes. More recently, cagrilintide, a long-acting analog, has produced substantial weight reduction in individuals with obesity. Combination therapy with glucagon like peptide-1 receptor agonists has achieved synergistic effects, with weight loss exceeding 15%, positioning amylin analogs as a promising approach for treatment of diabesity-the co-existence of diabetes and obesity. This review summarizes recent advancements and discusses their implications for future therapeutic applications in diabesity management.
Modulating neuropeptide Y pathways to combat nicotine addiction through emerging evidence and future directions.
Neuropeptides
Sameer Khidkikar, Divya Malode, Brijesh Taksande +5 more
Nicotine addiction constitutes a significant global health burden, primarily driven by the substance's capacity to dysregulate the brain's reward and stress systems. This chronic relapsing disorder is characterized by robust dependence and high rates of relapse, underscoring the limitations of current therapeutic strategies. Neuropeptide Y (NPY), a 36-amino acid neuromodulator abundantly expressed in the central nervous system, has emerged as a critical regulator of emotional behavior, stress responses, and reward pathways. Its role in the pathophysiology of nicotine addiction is of increasing interest. NPY exerts its pleiotropic effects via G-protein-coupled receptors (Y1, Y2, and Y5), which are strategically positioned to modulate stress-related circuits and attenuate the hyper-dopaminergic state induced by nicotine in the mesolimbic system. Chronic nicotine exposure disrupts endogenous NPYergic signaling in key neuroanatomical loci such as the amygdala and prefrontal cortex, a neuroadaptation that heightens stress sensitivity and addiction vulnerability. The consequent reduction in NPY tone during withdrawal exacerbates the negative affective states of anxiety and stress, precipitating relapse. Preclinical evidence indicates that therapeutic strategies targeting NPY pathways including receptor-specific agonists, gene therapy for region-specific overexpression, and advanced peptide delivery systems show considerable promise for mitigating withdrawal symptomatology and reducing nicotine-seeking behavior. This review synthesizes the compelling preclinical and emerging human evidence supporting the NPY system as a therapeutic target, highlighting the critical need to develop novel, brain-penetrant NPY receptor agonists and biomarkers to bridge the translational gap and improve clinical outcomes for nicotine dependence.