Search Results (2,456)

Our understanding of Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor 1a (GHSR1a), has expanded from considering it to be a “hunger hormone” to a pleiotropic regulator of whole-body physiology. This review synthesizes the current advances spanning ghrelin biogenesis, signaling, and systems biology. Physiologically, preproghrelin processing and O-acylation by ghrelin O-acyltransferase (GOAT) generate acyl-ghrelin, a high-potency GHSR1a agonist; des-acyl ghrelin predominates in circulation and exerts context-dependent, GHSR1a-independent, or low-potency effects, while truncated “mini-ghrelins” can act as competitive antagonists. The emergence of synthetic ligands, agonists, antagonists, and reverse-agonists has provided the necessary tools to decipher GHSR1a activity. Recent cryo-EM structures of GHSR1a with peptide and small-molecule ligands reveal a bipartite binding pocket and provide a framework for biased signaling, constitutive activity, and receptor partner selectivity. Beyond the regulation of feeding and growth-hormone release, ghrelin modulates glucose homeostasis, gastric secretion and motility, cardiovascular tone, bone remodeling, renal hemodynamics, and innate immunity. Ghrelin broadly dampens pro-inflammatory responses and promotes reparative macrophage phenotypes. In the emerging scholarship on ghrelin’s activity in the central nervous system, ghrelin has been found to influence neuroprotection, stress reactivity, and sleep architecture, and has also been implicated in depression, Alzheimer’s disease, and substance-abuse disorders. Practical and transitional aspects are also highlighted in the literature: approaches for ghrelin stabilization; recent GHSR1a agonists/antagonists and inverse agonists findings; LEAP-2-based strategies; and emerging GOAT inhibitors. Together, structural insights and pathway selectivity position the ghrelin system as a druggable axis for the management of inflammatory diseases, neuropsychiatric and addiction conditions, and for obesity treatment in the post-GLP-1 receptor agonist era. Full article

The hypothalamus orchestrates systemic homeostasis by integrating neuroendocrine, autonomic, and immune–metabolic functions. In this review, we synthesize evidence that hypothalamic microglia act as dual hubs along a periphery–central–periphery axis across three domains: Peripheral effects: Microglia decode circulating cues and relay them to hypothalamic circuits, thereby modulating autonomic tone and endocrine pathways that impact immune–metabolic balance. Central mechanisms: Microglia sense and shape hypothalamic neural circuits via cytokine–neurotransmitter crosstalk, synaptic remodeling, and glial–neuronal signaling that tune neuroendocrine output. Translational links: Microglial states associate with biomarkers and clinical phenotypes in metabolic and inflammatory disorders, suggesting therapeutic entry points. Drawing on the literature from the last 20 years, we highlight convergent mechanisms, unresolved heterogeneity across models, and priorities for causal dissection and target validation. This framework clarifies how hypothalamic microglia coordinate local CNS processes with systemic physiology in health and disease. Full article

Glycosaminoglycans (GAGs), also named ‘mucopolysaccharides’, are nodal constituents of the connective tissue matrix which go through synthesis, demolition, and reconstruction within several cellular structures: an abnormal GAG catabolism is the basis of progressive intra-lysosomal accumulation of non-metabolized GAGs, defining all mucopolysaccharidoses (MPS), protean disorders characterized by physical abnormalities and multi-organ failure depending on the specific site of non-renewable GAGs stored. A severe cognitive decline is typically observed in the Sanfilippo syndrome, which corresponds to MPS type III, a group of four inherited neurodegenerative diseases resulting from the lack of specific enzymes involved in heparan sulfate (HS) metabolism. As a consequence, the storage of partially degraded HS fragments within lysosomes of the central nervous system elicits chain inflammatory reactions involving the NLRP3-inflammasome in microglia and astrocytes, which cease their homeostatic and immune functions and finally compromise neuron survival. This article provides an overview of the neuroinflammatory picture observed in children with MPS type III, postulating a role of HS accumulation to prime innate immunity responses which culminate with pro-inflammatory cytokine release in the brain and highlighting the relevance of interleukin-1 as a main contributor to neuroinflammation. Full article

Type I interferons (IFN-I) are pivotal effectors of innate immunity and constitute a central axis of host defense against pathogens. Sensing of exogenous or endogenous nucleic acids by pattern-recognition receptors—exemplified by Toll-like receptors—triggers transcriptional induction of IFN-I. Engagement of the heterodimeric IFN-I receptor on nucleated cells reprograms cellular states via canonical Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling as well as STAT-independent, noncanonical pathways. This axis is tempered by multilayered regulatory mechanisms, including epigenetic remodeling, and important aspects remain incompletely defined. Dysregulation of IFN-I activity underlies diverse autoimmune disorders, notably systemic lupus erythematosus, wherein IFN-responsive gene signatures stratify disease endotypes, reflect disease activity trajectories, and predict therapeutic responsiveness. In recent years, therapeutic strategies targeting this pathway are now available: anti-IFN-I receptor therapy for systemic lupus erythematosus (SLE) and JAK inhibition for rheumatoid arthritis (RA) and giant cell arteritis (GCA). Altogether, a refined understanding of the IFN-I axis furnishes a pragmatic framework for patient stratification, response prediction, and mechanism-informed therapy design across immune-mediated diseases. Full article

Sleep disorders represent a growing global health concern with significant socio-economic impacts. GABA, a natural bioactive compound abundant in various fermented foods, especially probiotic-fermented foods, has garnered increasing attention for its potential to improve sleep quality. This review systematically elucidates the multi-pathway mechanisms by which GABA regulates sleep, focusing on (1) indirect modulation of central sleep–wake circuits via the gut–brain axis through vagal nerve, neuroendocrine, and immune pathways; (2) potential entry into the brain by leveraging the dynamic permeability of the blood–brain barrier (BBB) and transporter-mediated active transport; and (3) metabolic conversion into active substances like γ-hydroxybutyrate (GHB), which synergistically optimizes sleep architecture via multiple receptor systems and energy metabolism. Furthermore, we summarize the sleep-promoting effects of GABA-enriched foods observed in animal and clinical studies and discuss emerging applications, including high-GABA-yielding probiotics and personalized nutrition strategies for sleep intervention. This review provides a theoretical basis and innovative directions for the development of GABA-based functional foods and sleep health management. Full article

Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic immune-mediated disorders characterized by mucosal injury, cycles of inflammation and repair, and tissue damage. Persistent inflammation accelerates epithelial turnover, generates oxidative and replication stress, and remodels the stromal niche, contributing to the risk of colorectal cancer (CRC). Systematic dysplasia surveillance remains essential. Cellular senescence has emerged as a unifying mechanism linking inflammation, impaired epithelial repair, fibrosis, and neoplasia. In UC, p16/p21 upregulation, telomere erosion, and loss of lamin B1 accumulate and adopt a senescence-associated secretory phenotype (SASP) that perpetuates barrier dysfunction. In CD, senescence within stem and stromal compartments limits regeneration, promotes pro-fibrotic remodeling, and sustains cycles of injury and repair via chronic SASP signaling. IBD prevalence continues to rise from environmental factors, dietary changes, antibiotic exposures, and gut microbiota alterations. Pathogenesis integrates genetic factors (e.g., NOD2, IL23R, HLA, and ATG16L1 mutations), environmental modifiers, dysbiosis characterized by loss of short-chain fatty-acid-producing Gram-positive bacteria and expansion of Proteobacteria, and a dysregulated immune system. Therapeutic strategies have shifted toward targeted biologics and small molecules to promote mucosal healing. In this review, we recapitulate the mechanistic axes of inflammation, oxidative stress, and senescence in IBD and then critically evaluate emerging targeted therapies. Topics include anti-TNFα, integrin blockade, IL-12/23 and IL-23 inhibition, JAK inhibitors, S1P receptor modulators, microRNA modulation, senomorphics, mesenchymal cell therapy, and microbiome interventions. We endorse biomarker-guided therapy and propose future directions to break the SASP-driven inflammatory loop and mitigate long-term carcinogenic risk. Full article

Background: Children with special health care needs (CSHCN) are at heightened risk of delayed or missed vaccinations because of clinical complexity and provider uncertainty. Although China has issued expert consensus guidelines and established immunization advisory services, little is known about vaccination decision-making within routine district-level immunization services. This study examined vaccination recommendation patterns and factors associated with deferral or non-recommendation among CSHCN in these settings. Methods: This cross-sectional study was conducted between 1 April 2023, and 31 March 2024, in Changshou District, Chongqing, China, encompassing 18 primary health centers, five general hospitals and one special hospital. Children aged 0–18 years identified by physicians as having conditions potentially affecting vaccination decisions and with at least one documented vaccination-related consultation were included. Clinical characteristics and physician recommendations (“recommended,” “temporarily deferred,” “not recommended”) were recorded via the national Epidemiological Dynamic Data Collection (EDDC) system; subsequent vaccination uptake was verified using the Chongqing Immunization Information Management System. Logistic regression identified factors associated with deferral or non-recommendation. Results: A total of 761 participants were included in the analysis, with a median age of 12 months (IQR: 1–47). Among all vaccine-specific recommendations, 55.2% were classified as “recommended,” 43.4% as “temporarily deferred,” and 1.5% as “not recommended”. Deferral proportions varied markedly, highest in respiratory (73.6%) and immunologic (42.1%) conditions and lowest in neonatal disorders (4.0%). Compared with 0–6-month-olds, children aged 7–12 months (adjusted odds ratio [aOR] = 5.26, 95% CI 2.30–12.33) and >13 months (aOR = 13.48, 95% CI 6.69–28.34) were more likely to receive deferral or non-recommendation; multimorbidity also increased odds (aOR = 20.68, 95% CI 11.26–40.10). Consultations at primary health centers were associated with a lower likelihood of deferral or non-recommendation (aOR = 0.26, 95% CI 0.15–0.45). Conclusion: Vaccination recommendations for CSHCN vary considerably across clinical profiles and facility types in routine immunization settings. Despite national initiatives, many vaccine doses remain deferred or not recommended. Disease-specific guidelines, enhanced provider training, and context-adapted decision-support tools are needed to promote timely and equitable immunization for this medically vulnerable population. Full article

Thalidomide, once withdrawn due to teratogenicity, has re-emerged as a repurposed agent to treat a broad spectrum of diseases because of its anti-inflammatory, immunomodulatory, and anti-angiogenic properties. Over the past two decades, thalidomide has also been increasingly used in digestive diseases, including gastrointestinal and hepatobiliary–pancreatic disorders. Despite these expanding indications, its broader clinical use remains restricted by safety concerns and the absence of standardized, evidence-based guidance. In particular, practical strategies for optimizing efficacy while minimizing toxicity have not been systematically summarized. This review aims to provide an updated, integrated, and clinically oriented overview of thalidomide in digestive diseases, summarizing the expanded applications from immune-mediated to non-immune-related conditions, highlighting real-world applications, therapeutic strategies, and approaches to risk mitigation. Furthermore, we discuss structural analogs and novel delivery systems that may enhance safety and efficacy, paving the way for thalidomide’s rational and safe use as a modern “phoenix drug”. Full article

Chromodomain helicase DNA-binding protein 8 (CHD8), a frequently mutated gene in autism spectrum disorder (ASD), is an ATP-dependent chromatin remodeler with emerging roles in hematopoiesis. While CHD8 is known to maintain hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, its function during developmental hematopoiesis remains undefined. Here, using a zebrafish model, we demonstrate that chd8 loss severely depletes the HSPC pool in the caudal hematopoietic tissue through a p53-dependent apoptotic mechanism. Furthermore, chd8^−/− embryos exhibit a p53-independent expansion of myelopoiesis. chd8 deficiency upregulates brd4, which promotes systemic inflammatory cytokine expression. Inhibiting brd4 alleviates cytokine expression, suppresses excessive myelopoiesis, and restores HSPC development. Our findings reveal a dual regulatory mechanism in which chd8 governs HSPC development by repressing p53-mediated apoptosis and constraining brd4-driven immune cell differentiation. Full article

Background: Lichen planus (LP) is a chronic immune-mediated inflammatory disorder affecting skin, mucosae, nails, and appendages, often with significant impact on quality of life. While associations between oral LP (OLP) and other localizations have been described, comprehensive analyses of patients presenting with multiple LP localizations remain limited. The aim of the study was describing the association of multisite LP among our patients in order to contribute to knowledge about this rare, but possible, clinical situation and its clinical implications in terms of follow-up. Methods: We conducted a retrospective observational study including 44 adult patients with histologically confirmed OLP and at least two additional LP subtypes. Data were collected at the joint dermatology–oral pathology clinic of Policlinico Sant’Orsola Malpighi, Bologna, between January 2022 and December 2024. Demographic characteristics, clinical manifestations, comorbidities, and therapeutic approaches were analyzed. Results: The cohort comprised 31 women and 13 men (mean age at first LP diagnosis: 56 years). All patients presented OLP, predominantly erosive (73%). During a follow-up, 39 patients developed three LP subtypes, and 5 patients developed four LP subtypes. Cutaneous LP was universal, while mucosal involvement included genital LP (n = 23), esophageal/pharyngeal/laryngeal LP (n = 8), and vulvar lichen sclerosus (n = 6). Nail LP was diagnosed in seven cases and frontal fibrosing alopecia in ten cases. Autoimmune comorbidities were frequent, including thyroiditis, psoriasis, systemic sclerosis, lupus, and Sjögren’s syndrome. First-line therapy consisted of topical and systemic corticosteroids, with adjuvant retinoids, cyclosporine, or immunosuppressants in refractory cases. No malignant transformation or dysplasia was detected during the observation period, and the mean follow-up period was 24 months (range: 12–36 months). Conclusions: Multisite LP is a complex, underrecognized condition requiring multidisciplinary management. OLP frequently represents the initial manifestation, followed by progressive involvement of cutaneous and mucosal sites. Regular full-body, oral, and genital examinations, together with tailored systemic treatments, are essential to prevent scarring sequelae and improve quality of life. Our findings highlight the need for heightened clinical vigilance and integrated care pathways for patients with multi-site LP. Full article

Anorexia nervosa (AN) is a severe psychiatric disorder with the highest mortality rate among mental illnesses, characterized by an intense fear of weight gain, persistent restriction of energy intake, and a distorted perception of body image. Despite decades of investigation, the pathogenesis of AN is only partially understood and is recognized as multifactorial, involving genetic, sociocultural, and neurobiological determinants. Beyond its core psychopathological features, AN leads to a wide spectrum of systemic complications, including cardiovascular, renal, skeletal, and endocrine dysfunctions. Increasing evidence implicates autophagy and oxidative stress as key molecular mechanisms underpinning its pathophysiology, while growing attention has been directed toward immune dysregulation and alterations in the gut–brain axis as potential mediators of disease onset and progression. Therapeutic advances, however, remain limited. Current management relies primarily on nutritional rehabilitation and psychotherapeutic interventions, while treatment outcomes are constrained by high relapse rates and the lack of pharmacological agents with proven efficacy. In this context, a more comprehensive understanding of the clinical spectrum and molecular substrates of AN is essential to improving prognosis and guiding the development of novel therapeutic strategies. This narrative review synthesizes current evidence on the non-psychopathological dimensions of AN, encompassing its clinical manifestations, systemic complications, and implicated molecular pathways. It also appraises existing treatment modalities and examines emerging interventions with translational potential. Overall, this review aims to provide clinicians and researchers with an updated and integrative overview of AN, shedding light on novel directions in ongoing research. Full article

Major depressive disorder (MDD) is a multifaceted psychiatric disorder that has been a longstanding focus of research. However, its underlying mechanisms remain underexplored. Recently, the inflammatory hypothesis has gained attention, highlighting inflammation’s role in MDD progression. Potential contributors to increased systemic inflammation in MDD include hyperactivation of the hypothalamic–pituitary–adrenal axis, dysregulation of the sympathetic nervous system, gut microbiota imbalances, the “pathogen host defense” hypothesis, and damage-associated molecular patterns. Traditional pathways explaining how systemic inflammation affects the central nervous system (CNS) do not fully account for the observed desynchrony between systemic and neuroinflammation in most depressed individuals. Alternative models suggest mechanisms such as reduced blood–brain barrier permeability and the involvement of immune cells from the skull. This review examines the link between inflammation and MDD, focusing on systemic and neuroinflammation interactions, with special emphasis on the heterogeneity of MDD symptoms and the potential impact of dysfunction in the brain’s lymphatic system. Gaining insight into the origins of inflammation in both the central nervous system and the peripheral body, along with their interactions, offers an important understanding of the inflammatory mechanisms associated with MDD for future treatment. Full article

Mature erythrocytes are traditionally regarded as anucleate cells lacking nuclear DNA. However, evidence shows they retain residual genetic material, including mitochondrial DNA (mtDNA) and RNA fragments. This review explores the role of such genetic material in cellular function, diagnostics, and erythropoiesis. A comprehensive literature review was conducted, focusing on (i) erythropoiesis, (ii) enucleation of erythroid precursors, (iii) the presence of DNA in red blood cells (RBCs), and (iv) RNA fragments such as messenger RNA (mRNA), microRNA (miRNA), and other non-coding RNAs. Mature RBCs harbor small amounts of DNA and diverse RNA species. Residual DNA can act as damage-associated molecular patterns (DAMPs), triggering immune responses when released under stress or injury. RNA fragments reflect the transcriptional activity of precursor cells and have been linked to potential diagnostic applications. Studies suggest that RBC-derived RNA signatures may serve as non-invasive biomarkers for diseases such as diabetes, cardiovascular conditions, and hematological disorders. These profiles mirror changes in erythropoiesis and provide insights into systemic pathophysiology. Residual genetic material in RBCs extends their role beyond oxygen transport. It contributes to immune modulation and may provide novel diagnostic and therapeutic opportunities, enhancing disease detection and understanding of erythropoiesis. Full article

Subarachnoid hemorrhage (SAH), often resulting from aneurysmal rupture, remains a life-threatening cerebrovascular disorder with high morbidity and mortality. While previous research has focused primarily on cerebral damage and neurological outcomes, growing evidence suggests that SAH also causes systemic complications, including pulmonary dysfunction. The underlying mechanisms linking SAH to lung injury, however, are not fully understood. The glymphatic system, a perivascular network that facilitates the clearance of cerebrospinal fluid (CSF) and interstitial waste from the brain, plays a critical role in maintaining central nervous system (CNS) homeostasis. Aquaporin-4 (AQP4) water channels, predominantly expressed in astrocytic end feet, are essential for efficient glymphatic flow. Emerging studies have shown that SAH impairs glymphatic function by disrupting AQP4 polarity and CSF circulation, resulting in the accumulation of neurotoxic substances and neuroinflammation. Recent findings further suggest that glymphatic dysfunction may exert systemic effects beyond the CNS, contributing to a breakdown of the brain–lung axis. The release of pro-inflammatory cytokines, blood degradation products, and damage-associated molecular patterns (DAMPs) into systemic circulation can promote pulmonary endothelial injury and trigger immune responses in the lungs. This phenomenon is exacerbated by impaired clearance via the glymphatic system, amplifying systemic inflammation and increasing the risk of acute lung injury (ALI) or neurogenic pulmonary edema (NPE). This review proposes a novel perspective linking glymphatic impairment with pulmonary complications after SAH. Understanding this connection could open new therapeutic avenues—such as targeting AQP4 function, enhancing CSF circulation, or modulating the inflammatory response—to mitigate both neurological and respiratory sequelae in SAH patients. Full article

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder characterized by complex interactions between the innate and adaptive immune systems, being potentially associated with an enhanced intestinal permeability. Zonulin represents a key protein in the modulation of intestinal permeability, being a gut leakage marker. The purpose of the present work was to evaluate the intestinal permeability, through serum zonulin levels, and to explore the relationships between zonulin, disease activity, and organ involvement in Caucasian SLE patients. The study had a cross-sectional design and included two groups of subjects: the SLE group (n = 41) and the control group (n = 29). Plasma zonulin level was measured using indirect ELISA. Despite the fact that Caucasian SLE patients exhibited higher plasma zonulin levels compared to the control group (7.566 ± 1.368 ng/mL vs. 2.306 ± 0.286 ng/mL, p < 0.01, Mann–Whitney-U-test), plasma zonulin levels did not correlate with disease activity measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). SLE patients with clinical articular involvement had paradoxically lower plasma zonulin levels than those without this manifestation. The results support the hypothesis of a mutually exclusive inflammatory “signature” between intestinal mucosa and synovium. Full article