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Body composition, hepatic fat, metabolic, and safety outcomes of Tesamorelin, a GHRH analogue, in HIV-associated lipodystrophy: A meta-analysis of randomized controlled trials.
Obes Res Clin Pract
Ahmed Samy Badran, Abdulrhman Helal, Karim Samir Shata +1 more
HIV-associated lipodystrophy leads to visceral fat accumulation, metabolic complications, body image concerns, medication non-adherence, and increased cardiovascular risks. We thought to assess the effects of Tesamorelin, a synthetic growth hormone-releasing hormone analogue, that has been proposed as a targeted therapy.
Magnetic resonance imaging-based adenohypophyseal volume for diagnosing hypothalamic-pituitary-gonadal axis activation in pre- and at-puberty children.
Quant Imaging Med Surg
Sikang Gao, Yunyun Zhao, Weiyin Vivian Liu +9 more
Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. Although the gonadotropin-releasing hormone (GnRH) stimulation test remains the diagnostic standard for evaluating HPG axis activation, its invasive nature limits clinical utility. Magnetic resonance imaging (MRI)-derived pituitary measurements offer a promising alternative, yet previous studies on two-dimensional measurements have reported limited accuracy. This study aimed to assess the value of adenohypophysis volume (aPV) and height (aPH) precisely measured with the three-dimensional (3D) CUBE T1 sequence (GE HealthCare) in diagnosing HPG axis activation.
Aster yomena Alleviates Chronic Unpredictable Mild Stress (CUMS)-Induced Depressive Cognitive Dysfunction by Regulating the HPA Axis and TLR4/NF-κB Pathway.
J Microbiol Biotechnol
In Young Kim, Jong Min Kim, Hyo Lim Lee +4 more
The purpose of this study was to assess the effects of a 60% ethanolic extract of Aster yomena (EAY) on chronic unpredictable mild stress (CUMS)-induced depressive cognitive dysfunction. The results showed that EAY mitigated CUMS-induced depressive-like behaviors, as confirmed by the sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swimming test (FST). In addition, EAY showed protective effects on cognitive function in the Y-maze and the Morris water maze (MWM) tests. In this regard, EAY alleviated hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis through regulation of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cytochrome P450 family 11 subfamily B member 1 (CYP11B1), thereby improving the levels of serum cortisol. It suppressed neuroinflammation, oxidative stress, and mitochondrial dysfunction by inhibiting the Toll-like receptor 4 (TLR4)/nuclear factor κ-light-chain-enhancer of the activated B cells (NF-κB) pathway. As a result, cognitive dysfunction was ameliorated through modulation of the cholinergic system, including acetylcholinesterase (AChE), acetylcholine (ACh), and choline acetyltransferase (ChAT), and synaptic plasticity-related factors such as postsynaptic density protein 95 (PSD-95) and growth-associated protein 43 (GAP-43). Based on these results, EAY could potentially be used as a natural therapeutic for prevention of major depressive cognitive impairment.
The impact of radioligand therapy on prognosis in patients with lung neuroendocrine tumors.
Front Endocrinol (Lausanne)
Katarzyna Jóźwik-Plebanek, Marek Saracyn, Adam Daniel Durma +7 more
Evidence on the efficacy and safety of radioligand therapy (RLT) in lung neuroendocrine tumors (LNETs) remains scarce. The limited data available, derived mainly from retrospective analyses are based on small patient cohorts and heterogeneous treatment protocols. The objective of this study was to assess the efficacy and safety of RLT in patients with SSTR-positive LNETs treated with either [¹77Lu]Lu-DOTA-TATE or tandem therapy with [90Y]Y-DOTA-TATE/[¹77Lu]Lu-DOTA-TATE at Polish ENETS Center of Excellence.
Recent Advances in Pharmacological Management of Autism: A Narrative Review.
Cureus
Pallavi Abhilasha, Monika Sharma
Autism Spectrum Disorders (ASD) are a highly heterogeneous neurodevelopmental conditions defined by impairments in social communication, reciprocal interaction, and the presence of restricted or repetitive behaviors. While its "spectrum" nature highlights variability in symptom severity and presentation, ASD often coexists with conditions like attention deficit hyperactivity disorder (ADHD), anxiety, depression, epilepsy, digestive, metabolic, and immune disorders. No pharmacological treatments currently address the core deficits of ASD; instead, behavioral and educational interventions remain central. Medications, including US Food and Drug Administration (FDA)‑approved antipsychotics such as risperidone and aripiprazole, are used to manage comorbid irritability and aggression, stimulants and non‑stimulants (e.g., methylphenidate, atomoxetine, clonidine, guanfacine) to treat ADHD-like symptoms, and melatonin for sleep disturbances. Other off‑label agents like selective serotonin reuptake inhibitor (SSRIs) for anxiety/obsessive compulsive disorder (OCD), anticonvulsants or mood stabilizers for mood dysregulation. Emerging compounds such as intranasal oxytocin and N‑acetylcysteine are under investigation but have not yet been formally approved. The future of ASD care hinges on the development of objective, biologically based diagnostic tools ranging from EEG and neuroimaging biomarkers to proteomic and metabolomic panels that could enable early, precise identification and guide personalized treatment strategies.
Glucose-dependent insulinotropic polypeptide reduces postprandial glucose excursions but does not protect from hypoglycaemia in persons with type 1 diabetes-A randomised placebo-controlled study.
Diabetes Obes Metab
Bjørn Hoe, Sebastian M N Heimbürger, Lærke S Gasbjerg +13 more
In type 1 diabetes, glucose-dependent insulinotropic polypeptide (GIP) increases glucagon secretion during low plasma glucose and improves time in the glycaemic range during daytime. To explore the glucose-stabilising potential of GIP in type 1 diabetes, we evaluated the effects of exogenous and endogenous GIP on plasma glucose excursions in a setting of excess prandial insulin and physical activity after meal ingestion.
Therapeutic Efficacy of HPβ-CD-Angiotensin-(1-7) Oral Formulation in Muscle Injury Recovery in Rat.
J Cell Mol Med
Nádia Lúcia Totou, Ana Maria Sampaio Rocha, Samara Silva de Moura +8 more
To evaluate the therapeutic effect of oral treatment with HPβ-CD-angiotensin-(1-7) (Ang-(1-7)) on muscle recovery after laceration injury. Wistar rats were divided into four groups: Control (n = 10); HPβ-CD-Ang-(1-7) (n = 10); muscle injury + HPβ-CD (MI + Placebo) (n = 24); and muscle injury + HPβ-CD-Ang-(1-7) (MI + Ang-(1-7)) (n = 24). After 7-21 days of treatment, physical performance, histological features and the expression of pro- and anti-fibrotic genes were evaluated. The MI + Ang-(1-7) group showed improved control of the inflammatory phase and reduced deposition of collagen types I and III compared to MI + Placebo. CTGF gene expression analysis revealed lower levels of pro-fibrotic markers and higher expression of proteins involved in blocking fibrotic pathways. In treadmill tests, MI + Ang-(1-7) animals also showed superior physical performance at all evaluated time points. Oral treatment with Ang-(1-7) is effective in promoting recovery from muscle injuries, particularly fibrotic lesions, while preserving muscle function and enhancing physical performance.
Thymosin beta 4: An emerging therapeutic candidate for kidney diseases.
Peptides
Huajie Di, Jiaxin Huang, Dexin Zhang +3 more
Over the past decades, the escalating global burden of kidney disease has underscored an urgent need for innovative therapeutic strategies. Thymosin β4 (Tβ4), a highly conserved 43-amino-acid peptide encoded by the X-linked TMSB4x gene, is the predominant β-thymosin in mammalian cells and a multifunctional regulator of cellular homeostasis. Once considered mainly an actin-sequestering molecule, Tβ4 and its N-terminal metabolite N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) now emerge as dynamic mediators of renal injury and repair. In this review, we synthesize current evidence on the Tβ4-Ac-SDKP axis. We map intra- and extracellular mechanisms and relevant signaling pathways, delineate cell-type and spatial expression across glomerular and tubular compartments, and critically evaluate its renoprotective efficacy-including cytoprotection, anti-inflammatory and antifibrotic actions-across models of acute and chronic kidney injury. To reconcile disparate findings, we propose conceptual frameworks that consider bidirectional effects on fibrosis and model-dependent mechanisms. Finally, translational opportunities are appraised with attention to pharmacokinetics, peptide stability and delivery strategies. Key challenges moving forward include validating efficacy in additional clinically relevant models, overcoming peptide instability and completing comprehensive safety assessments.
Oral salmon acylated ghrelin increases food intake in common carp (Cyprinus carpio) via ghrelin receptors, likely through sensory nerves rather than systemic absorption.
Peptides
Minoru Kihara, Teppei Yamagiwa, Hidekazu Katayama +1 more
This study clarified the local mechanism of action and assessed the aquaculture potential of orally administered salmon acylated ghrelin (sAG) on feed intake in common carp (Cyprinus carpio). Experimental diets containing sAG (ranging from 0.001 to 13.04 µg/g) were prepared and fed to carp at 2.0 % of body weight (BW) in single-shot trials. Fish receiving diets of 0.64 µg/g (1.3 µg/100 g BW) or higher exhibited a significant, dose-dependent increase in additional feed intake, plateauing at 1.20 µg/g (2.4 µg/100 g BW). Despite this behavioral effect, plasma ghrelin levels remained unchanged, as measured by both N-terminal and salmon-specific C-terminal radioimmunoassays, confirming that sAG was not systemically absorbed. The orexigenic effect was abolished by pretreatment with the ghrelin receptor antagonist [D-Lys3]-GHRP-6 or with capsaicin, demonstrating local sAG action via growth hormone secretagogue receptor signaling and peripheral sensory neurons (likely vagal afferents). These findings provide the first evidence that fish ghrelin exerts biological activity via a non-circulatory neuroendocrine pathway. This advances our understanding of the vertebrate gut-brain axis and highlights the potential of harnessing locally acting peptides for physiological modulation in aquatic species.
Identification and characterization of novel antimicrobial peptides from Camelus dromedarius: a combined bioinformatics and experimental study.
Front Immunol
Wafa Al-Mamari, Yasmin Elhag, Samir Al Bulushi +5 more
There is an urgent need for new antimicrobial agents to address the emerging antimicrobial resistance and the lack of novel antibiotics on the market. Antimicrobial peptides (AMPs) have gained significant interest as potential antibiotics over the past 30 years due to their broad activity against bacteria. So far, the presence, characteristics, and function of AMPs in camel immunity remain to be explored. Therefore, this study aims to identify and functionally characterize AMPs in Camelus Dromedarius using in-silico and experimental approaches. In-silico identification and prediction of cathelicidin peptides properties were conducted using Blastp, Conserved Domain, Signal P-5.0, Peptide Cutter-Expasy, and the Antimicrobial Sequence Scanning System (AMPA) database. Physicochemical and biological properties were characterized using bioinformatics analysis tools. The experimental assays of synthetic AMPs were performed using circular dichroism (CD) spectroscopy, colony-forming assay, sytox green uptake assay, transmission and scanning electron microscopy, and hemolysis assay. Three cathelicidin peptides were identified from Camelus Dromedarius which were designated as CdPMAP-23, Cdprotegrin-3 (CdPG-3), and Cdcathelin-like (CdCATH). CdPG-3 and CdCATH demonstrated significant antibacterial effects against all tested Gram-negative and Gram-positive strains, including Escherichia. coli (Multidrug resistant) and Methicillin-Resistant Staphylococcus aureus (ATCC 700699). These two peptides caused significant membrane leakage and damage to Escherichia. coli (ATCC 25922), with CdPMAP-23 showing a lesser effect. Lower concentrations of CdPMAP-23, CdPG-3 and CdCATH exhibited low to moderate lytic activity against red blood cells in humans, camels, and chickens. This study identified novel AMPs from dromedary camels with potential therapeutic value against multidrug-resistant strains. The results show that AMPs are present in dromedary camels, setting out a foundation for further studies on the unique features of their innate immune system.
Investigation of the stability profile of therapeutic α-MSH analogue: Insights from liquid chromatography-high resolution mass spectrometry analysis of afamelanotide.
J Pharm Biomed Anal
Ashwini Chawathe, Nitish Sharma
Afamelanotide, also known as melanotan-1, is a synthetic 13-amino acid peptidomimetic of α-melanocyte stimulating hormone (α-MSH), and is a critical peptide orphan drug used for the management of erythropoietic protoporphyria. It contains norleucine and D-phenylalanine at positions 4 and 7, in place of methionine and L-phenylalanine, respectively as found in endogenous peptide. Therapeutic peptide stability profiling is crucial in drug development because chemical and physical degradation during storage alters structural properties, potentially reducing efficacy and compromising safety by preventing target engagement. Stability testing for synthetic peptides is performed by following the International Council for Harmonisation (ICH) guidelines Q1A(R2) and Q5C. The current work endeavours to explore afamelanotide's degradation pathways under various chemical and physical stress conditions: acidic, basic, neutral, and oxidative stress, UV light exposure, and increased temperature at 60⁰C. The study demonstrated that afamelanotide undergoes degradation under all applied stress conditions with the generation of fourteen different degradation products (DPs) which were separated by gradient reversed-phase HPLC on a Zorbax SB C18 column (300 Å, 4.6*150 mm, 3.5 µm) and the method was validated according to the ICH Q2(R1) guideline. To enable comprehensive characterization, the analysis was coupled with ultra-high-performance liquid chromatography-high resolution tandem mass spectrometry (UHPLC-HRMS/MS), where collision-induced dissociation yielded abundant and accurate fragmentation patterns, enabling the detailed structural elucidation of the products. While this work has identified several degradation pathways such as truncation, methylation, deacetylation, and oxidation, it also establishes complete stability profile of α-MSH analogue, thus offering key insights for the rational design of robust drug formulations.
Tissue-Slice Organ-on-Chip Culture of Hypothalamic and Pituitary of Lambs─The Role of Phoenixin-20 as a Modulator of Gonadotrophic Axis.
ACS Biomater Sci Eng
Michał Szlis, Bartosz Jarosław Przybył, Anna Wójcik-Gładysz
This study aimed to reconstruct the hypothalamic-pituitary axis using an organ-on-a-chip (OOC) model and to evaluate the modulatory role of phoenixin-20 (PNX) in the regulation of the gonadotrophic axis in sheep. Sixteen female Polish Merino lambs were used as tissue donors to create microfluidic chips containing paired hypothalamic and pituitary slices connected via perfused channels. This system enabled continuous medium flow and maintenance of functional neuroendocrine interactions under ex vivo conditions. The OOC platform was used to analyze changes in the expression of gonadotropin-releasing hormone (GnRH), kisspeptin (Kiss), neurokinin B (NKB), and prodynorphin (pDYN) in the hypothalamus, as well as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) expression and secretion in the pituitary. PNX treatment significantly increased hypothalamic GnRH expression, while the blockade of neuropeptide Y receptors (NPY1R and NPY5R) diminished this response, suggesting that PNX effects are at least partially mediated through NPY-dependent pathways. Moreover, PNX altered the transcription of Kiss, NKB, and pDYN, key components of the GnRH pulse generator, and modulated LHβ mRNA expression in the pituitary. Changes in the LH and FSH concentrations further supported a receptor-specific mechanism of PNX action. The developed hypothalamo-pituitary OOC model proved valuable for studying neuroendocrine control of reproduction. This system offers a physiologically relevant and ethically sustainable alternative to in vivo experiments, enabling precise investigations of molecular and hormonal mechanisms within the gonadotrophic axis.
Influence of the angiotensin-(1-7) on the vascular effects of the endothelin-1 in normotensive and hypertensive rats.
Peptides
Jaqueline Moura da Costa, Amanda de Sá Martins de Bessa, Lara Marques Naves +4 more
Angiotensin-(1-7) [Ang-(1-7)] exerts cardioprotective effects through Mas receptor activation. Endothelin-1 (ET-1) is implicated in cardiovascular pathologies. Previous studies indicate a cross-talk between angiotensin and endothelin pathways; however, it remains unclear whether Ang-(1-7) differentially modulates vascular responses to ET-1 in normotensive and hypertensive conditions. This study investigated the influence of Ang-(1-7) on ET-1-induced pressor and vascular responses in normotensive and hypertensive rats (SHR). Blood pressure was recorded in conscious animals. Vascular reactivity was assessed in isolated aortic rings, and coronary effects were assessed in isolated hearts using the Langendorff technique. ET-1 increased blood pressure and reduced heart rate only in Wistar rats, effects abolished by Ang-(1-7). In normotensive rats, Ang-(1-7) potentiated ET-1-induced vasoconstriction in endothelium-intact aortas independently of Mas receptors, but had no effect in the aorta without endothelium. In hypertensive rats, Ang-(1-7) attenuated ET-1 responses in endothelium-intact aorta via Mas receptor, whereas in endothelium-denuded vessels it potentiated the vasoconstriction. In isolated hearts, ET-1 produced a biphasic response in normotensive rats (vasodilation followed by vasoconstriction) but only vasoconstriction in hypertensive rats. Ang-(1-7) potentiated vasoconstriction in normotensive but attenuated it in hypertensive hearts, which was abolished by Mas receptor blockade. These findings demonstrate that Ang-(1-7) differentially modulates ET-1 actions in normotensive and hypertensive conditions, reinforcing RAS-endothelin cross-talk. Its counter-regulatory effect in hypertension highlights Ang-(1-7) as a promising therapeutic target in cardiovascular disease.
Menstrual cycle phase and hormonal contraceptive use influence circulating proforms of atrial natriuretic peptide, adrenomedullin, and the vasopressin proxy copeptin in healthy women.
Peptides
Anne Sophie Broholt Jensen, Janne Gasseholm Bentzen, Jens P Goetze +6 more
Cardiovascular disease is the main cause of mortality among women. However, the menstrual cycle and hormonal contraception are often overlooked in research. This study investigates whether concentrations of common cardiovascular biomarkers (natriuretic peptides, adrenomedullin, and copeptin) change during a menstrual cycle and with hormonal contraception use.
Ameliorative effects of Atractylodes macrocephala insoluble dietary fiber on loperamide-induced functional constipation in rats.
Food Res Int
Senye Wang, Wenjing Feng, Suxing Tu +5 more
In this study, loperamide hydrochloride (LOP) was used to establish a rat model of functional constipation (FC) to explore the mechanism of Atractylodes macrocephala insoluble dietary fiber (AMDF) in improving FC. The results showed that AMDF could increase the fecal water content and small intestinal advancement rate of FC rats, raise the levels of gastrin (GAS), vasoactive intestinal peptide (VIP), and substance P (SP) in serum, reduce the level of somatostatin (SS), reduce the levels of IL-6, TNF-α, and NO in serum, and alleviate the pathological state of colon tissue. The 16S rDNA sequencing results revealed that AMDF could enhance the diversity of the intestinal microbiota and restore the ratio of Firmicutes/Bacteroides (F/B). Metabolomics results show that AMDF treatment can regulate bile secretion, primary bile acid biosynthesis, amino acid metabolic signaling pathways, etc. Meanwhile, AMDF could inhibit the activation of the NF-κB signaling pathway in colon tissue and alleviate intestinal inflammation in FC rats. In conclusion, the research results showed that AMDF can improve the intestinal microbiota and metabolism, and inhibit the intestinal inflammatory response, achieving the effect of relieving FC.
Bioactive peptides-incorporated photo-crosslinking hydrogel for suture-free repair of corneal injuries.
J Colloid Interface Sci
Wei Wu, Shuo Huai, Chenhao Li +9 more
The development of new biomaterials for suture-free repair of corneal stromal injuries holds promise, especially given the shortage of donor corneas and the limitations of current tissue adhesives. Here, we developed a biocompatible hydrogel via ultrafast in situ photo-crosslinking between di-o-nitrobenzyl-modified Arg-Gly-Asp (RGD) peptide and carboxymethyl chitosan. This hydrogel exhibits shape adaptability, high transparency, and robust bioadhesion, making it suitable for suture-free corneal repair. In vitro experiments confirm that the hydrogel promotes corneal epithelial cell migration. In a rabbit model of penetrating corneal injury, the hydrogel achieves rapid sealing within 60 s while maintaining anterior chamber integrity. In a deep corneal defect model, it effectively seals the stromal wound and supports corneal regeneration, enhancing epithelial barrier restoration with upregulated expression of zonula occludens-1 (ZO-1) and cytokeratin 3 (CK3). Moreover, incorporation of the neuropeptide CGRP into the hydrogel reduces stromal fibrosis, as indicated by decreased expression of α-smooth muscle actin (α-SMA) and vimentin. This bioactive peptides-integrated photo-crosslinking hydrogel represents a promising alternative for suture-free repair of severe corneal injuries and offers a new, effective strategy for clinical corneal wound management.
Ambrisentan for Early-Stage Low-Risk Pulmonary Arterial Hypertension: Design of the Randomized, Double-Blind, Placebo-Controlled ALEPH Trial.
JACC Asia
Jun-Yan Kan, Xiao-Juan Zhang, Wan-de Yu +9 more
Early-stage pulmonary arterial hypertension (PAH) with mild hemodynamic abnormalities is increasingly being concerned because of the revised PAH definition. However, there is a lack of randomized controlled trials evaluating the efficacy of currently available medications in this population.
Advances in the pathogenesis of rosacea.
Front Immunol
Hui Wang, Cheng Zhou
Rosacea is a chronic inflammatory cutaneous disorder predominantly affecting the centrofacial region, whose pathogenesis is complex and not yet fully understood. In this review we summarized the latest significant advances in the pathogenesis of rosacea in recent years. In genomic studies, the application of bioinformatics techniques such as whole-genome sequencing has identified novel susceptibility genes and linked multiple pathogenic mechanisms. Neurovascular dysfunction resulting from abnormal neuropeptides expression and dysregulated amino acid metabolism constitutes an important pathogenic factor in rosacea. The TLR2/LL-37/mTORC1 signaling axis, as a core regulatory pathway in innate immunity has been elucidated in detail. In addition, the dysbiosis of skin and gut microbiota, together with the impairment of skin barrier function, is also closely associated with the onset and progression of this disease. The deeper understanding of the pathogenesis of rosacea will benefit the development of new drugs and promote individualized diagnosis and treatment.
Design of Experiments (DoE)-Optimized Polymeric Oxytocin Nanoparticles for Enhanced Nose-to-Brain Delivery.
Small
Naveed Ahmad, Shunping Han, Rifka Utami +9 more
Oxytocin (OT) is a promising candidate for regulating social behavior in autism spectrum disorder (ASD). However, its inconsistent efficacy can be attributed to the lack of an efficient delivery system that selectively target the brain without inducing peripheral side effects following intranasal (IN) administration. In this study, OT is encapsulated within an FDA-approved poly (lactic-co-glycolic acid) (PLGA) nanoparticles (OT-NP) to improve nose-to-brain (NTB) delivery. A PEGylated version (OT-NP-PEG) is developed to improve nasal mucosal diffusion. Optimization using a design of experiments (DoE) approach produced nanoparticles with hydrodynamic diameters of ≈93-116 nm, polydispersity index ≈0.20, zeta potential -21 to -33 mV, and drug loading ≈2.8-3.5% (w/w). The stable OT-NP-PEG showed sustained release (>42% and 58% at 24 and 72 h) and greater diffusion through simulated nasal mucus. [14C] OT is synthesized with chemical and radiochemical yields of 74% and 53%, respectively. Following IN administration in mice, [14C] OT-NP-PEG demonstrated rapid brain uptake, particularly in the olfactory bulb and frontal cortex, with reduced blood and liver exposure compared with free [14C] OT. Finally, IN OT-NP-PEG significantly increased self-grooming frequency in mice, indicating maintained bioactivity and behavioral effects. Overall, OT-NP-PEG offers a rationally designed nanoplatform for brain-targeted OT delivery in ASD and other neuropsychiatric disorders.
The joint-local renin-angiotensin system in rheumatoid arthritis and osteoarthritis: mechanistic evidence, disease-specific patterns, and translational perspectives.
Rheumatol Int
Emre Bilgin, İbrahim C Haznedaroğlu
The renin-angiotensin system (RAS), traditionally regarded as a hormonal cascade regulating cardiovascular and renal homeostasis, is increasingly recognized as a locally active, tissue-specific network within joint structures. Accumulating evidence indicates that synovial tissue, synovial fluid, and articular cartilage harbor a functionally active joint-local renin-angiotensin system that operates partially autonomously from the systemic RAS circulation and is implicated in the pathogenesis of both arthritis (RA) and osteoarthritis (OA). This narrative review integrates human, animal, and in vitro evidence to examine the dual-axis organization of the joint RAS, comprising a pathogenic angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II)/ Angiotensin II type 1 receptor (AT1R) axis and a counter-regulatory ACE2/Angiotensin-(1-7) (Ang-(1-7))/Mas receptor-Mas related G protein-coupled receptor D (Mas-MrgD) axis, and to explore how imbalance between these pathways may differentially influence inflammatory and degenerative joint diseases. In RA, experimental and translational studies suggest that enhanced activity of the classical axis within synovial tissue is associated with synovial inflammation, fibroblast-like synoviocyte survival, angiogenesis, and bone erosion through pathways involving nuclear factor kappa B (NF-kB), mitogen-activated protein kinase (MAPK), and receptor activator of nuclear factor kB ligand (RANKL)/Wingless-related integration site (Wnt) signaling pathway. In OA, available data indicate that chondrocyte expression of AT1R/Angiotensin II type 2 receptor (AT2R), together with cytokine-induced receptor upregulation, may sensitize cartilage to Ang II-mediated effects, contributing to matrix metalloproteinase-13 (MMP-13)-mediated matrix degradation and activation of interleukin-6 (IL-6)/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling. Genetic studies support disease-specific patterns, with the ACE insertion/deletion polymorphism showing a more consistent association with RA susceptibility than with knee OA, although findings vary across populations and do not consistently correlate with disease severity. From a therapeutic perspective, modulation of the joint-local RAS is currently supported mainly by preclinical evidence. Experimental models suggest that classical RAS inhibitors and emerging strategies targeting the protective axis-such as putative ACE2 activators, AT2R agonists, and bone-targeted peptide delivery can influence inflammatory and structural pathways within the joint, while direct clinical evidence remains limited. Overall, current data support the biological relevance of a local joint RAS in arthritis pathophysiology and highlight key gaps between experimental findings and clinical translation.