Search Results (1,146)

The menstrual cycle represents a dynamic infradian rhythm characterized by coordinated fluctuations in ovarian steroids that extend beyond reproductive function and influence systemic metabolism. This narrative review synthesizes current evidence on how menstrual cycle phase modulates energy balance, macronutrient metabolism, micronutrient handling, and responses to dietary bioactive compounds. Across phases, small-to-moderate but consistent differences emerge in energy intake, resting energy expenditure, substrate utilization, and protein turnover, with a tendency toward increased energy intake and lipid oxidation during the mid-luteal phase compared with the early follicular and peri-ovulatory phases. Emerging metabolomics data further reveal coordinated cyclical variation in amino acids, B vitamins, and lipid species, suggesting temporally sensitive windows in which low energy availability or micronutrient insufficiency may more readily impair performance, recovery, or symptom burden. Importantly, menstrual cycle-related metabolic variability reflects not only estradiol and progesterone oscillations but also integrated adaptations across the hypothalamic–pituitary–adrenal axis, autonomic nervous system, immune signaling, and gut microbiota. These interconnected systems contribute to inter- and intra-individual heterogeneity in metabolic phenotype. From a clinical and applied perspective, the evidence supports “cycle-aware” but non-dogmatic nutritional strategies, particularly in contexts of metabolic dysfunction, high training loads, or reproductive disorders. Future research should systematically verify cycle phase, incorporate multi-system biomarkers, and adopt sex-specific analytical frameworks to improve translational relevance. Recognizing the menstrual cycle as a biologically meaningful metabolic variable may enhance precision nutrition, exercise prescription, and metabolic risk assessment in women. Full article

Chronic inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, are systemic immune-mediated disorders driven by dysregulated immune responses. The gut–skin axis is a bidirectional network linking intestinal microorganisms, their metabolites, and host immunity. It connects microbiome composition and function with systemic inflammation and cutaneous pathology, shaping disease-specific mechanisms such as Th2/IL-4/IL-13-mediated barrier dysfunction in AD and Th17/IL-23/IL-17-driven hyperproliferation in psoriasis. Microbiota-derived metabolites, including short-chain fatty acids, tryptophan-derived aryl hydrocarbon receptor ligands, and bile acid-dependent FXR/TGR5 signaling, modulate immune homeostasis and epithelial integrity. Gut dysbiosis, impaired metabolite production, and barrier dysfunction disrupt regulatory networks, amplifying inflammation. Microbiota-targeted interventions, including probiotics, synbiotics, postbiotics, and precision nutrition, may serve as adjunctive therapies, although further well-controlled clinical studies are needed. Integrating multi-omics, metabolomics, and functional microbial profiling, alongside investigations of the gut mycobiome and virome, will be critical to identify predictive biomarkers and optimize therapeutic strategies. These concepts remain mechanistically compelling but largely theoretical, requiring validation in longitudinal and interventional studies. Full article

Introduction/Objective: Common hop (Humulus lupulus L.) is a multi-component plant material that has been extensively studied for its antioxidant, anti-inflammatory, cardioprotective, metabolic, neuroprotective, immunomodulatory and anti-cancer properties. This review summarises current data on the molecular mechanisms of action of hop compounds, their therapeutic potential, metabolic interactions and biological significance, with particular emphasis on bioavailability, signalling pathways and organ-specific effects. Methods: A comprehensive literature review was conducted, covering in vitro and in vivo studies and available clinical trials analysing the biochemical activity, molecular targets and physiological effects of bioactive compounds in hops. Particular attention was paid to the regulation of oxidative stress, inflammatory signalling, mitochondrial function, metabolic pathways, interactions with the gut microbiota and their impact on the development of chronic diseases. Results: Bioactive compounds in hops modulate numerous key signalling pathways, including NF-κB, Nrf2, AMPK, MAPK, PPAR and PI3K/AKT/mTOR. They have been shown to reduce oxidative stress, inhibit the production of pro-inflammatory cytokines, regulate apoptosis, improve mitochondrial function, and activate endogenous antioxidant systems. Hops have a protective effect in cardiovascular diseases, metabolic disorders, neurodegenerative diseases and selected cancers through anti-inflammatory, anti-proliferative and metabolic mechanisms. In addition, hop compounds modulate the composition and activity of the gut microbiota, which promotes improved metabolic homeostasis. Despite relatively good intestinal absorption, systemic bioavailability remains limited; however, modern delivery systems significantly increase the stability and plasma concentrations of these compounds. Conclusions: Common hops have broad therapeutic potential due to their ability to regulate oxidative, inflammatory, metabolic and apoptotic processes at multiple levels. Their pleiotropic activity makes them a promising candidate for the prevention and treatment of chronic diseases. The development of delivery systems and consideration of the role of the gut microbiota may further increase its clinical application. Full article

Type 2 Diabetes Mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance, chronic low-grade inflammation, and progressive metabolic dysfunction affecting multiple organs. This review explores the molecular and physiological mechanisms underlying T2DM, emphasizing the role of intracellular metabolic signaling pathways, mitochondrial function, and inter-organ communication in the development and progression of metabolic dysregulation. Particular attention is given to key regulatory pathways such as AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin (mTOR), which play central roles in cellular energy sensing, glucose metabolism, and lipid homeostasis. Dysregulation of these pathways contributes to impaired insulin signaling, mitochondrial dysfunction, oxidative stress, and altered adipogenesis, all of which are critical factors in the pathophysiology of T2DM. In addition, growing evidence highlights the importance of metabolic crosstalk between skeletal muscle, adipose tissue, liver, pancreas, and the gut microbiota through signaling molecules including adipokines, myokines, hepatokines, and gut-derived metabolites. These inter-organ networks influence systemic inflammation, metabolic flexibility, and glucose homeostasis. Lifestyle factors such as physical activity, nutritional patterns, and micronutrient status have also been shown to modulate these molecular pathways, improving mitochondrial function and insulin sensitivity while reducing inflammatory signaling. Despite significant advances in understanding the molecular basis of T2DM, important challenges remain, including heterogeneity in disease progression and variability in individual metabolic responses. In conclusion, T2DM should be understood as a multisystem metabolic disorder driven by complex interactions between molecular signaling pathways and systemic metabolic regulation. Future research integrating molecular mechanisms with clinical and lifestyle interventions may help develop more effective strategies for prevention and treatment. Full article

Background/Objectives: The medical mushroom Ophiocordyceps sinensis (Caterpillar Fungus), known for its ability to enhance “vitality,” is one of the most popular medicines in Asian traditional medical systems. According to the Chinese Pharmacopeia, O. sinensis is standardized for its adenosine content, the precursor of ATP, which mediates numerous physiological and pathological processes in many diseases. The related fungus of order Hypocreales, Cordyceps militaris, and its major bioactive constituents, 3′-deoxyadenosine (cordycepin), also exhibit pleiotropic biological activities. This review aims to provide a rationale for the adaptogenic and resilience-supporting effects of these medicinal fungi and to align food and drug regulation in Western countries. Methods: In this narrative review, we integrated results from chemical, pharmacokinetic, network pharmacology, preclinical, and clinical studies of O. sinensis, C. militaris, and cordycepin using network pharmacology and bioinformatics tools. Results: Across studies, recurrent mechanistic hubs included PI3K–Akt, AMPK–mTOR, MAPK, NF-κB, apoptosis, and adaptive stress-response signaling pathways, linking immune regulation and metabolic homeostasis. Experimental studies confirmed modulation of cytokine production, kinase signaling, and mitochondrial regulators. Clinical meta-analyses demonstrate consistent adjunctive benefits in renal and pulmonary disorders, although heterogeneity in preparation and methodological limitations remains significant. The review reveals controversy regarding the bioavailability of cordycepin in vivo and its concentration in vitro studies, raising the hypothesis that cordycepin may act as a driver, triggering the organism’s adaptive stress response in stress-induced and aging-related diseases. Pharmacokinetic data indicate that systemic cordycepin concentrations after oral administration remain in the nanomolar range, suggesting that some predicted molecular interactions may occur indirectly or through systems-level mechanisms. The review, for the first time, suggests establishing a regulatory category for resilience-supporting physiological modulators to align food and drug regulation in the EU with contemporary systems biology, thereby complementing the work of EFSA, EMA, FDA, and Asian authorities. Conclusions:O. sinensis, C. militaris, and 3-deoxyadenosine share a common adaptogenic mechanism for maintaining homeostasis of cellular and integrated biological system functions. The systems-level network analysis and reductionistic molecular ligand preceptor pharmacology provide complementary approaches for understanding the multi-target bioactivity of these fungi. This review clarifies conceptual and regulatory barriers to recognizing resilience-supporting interventions and informs future regulatory innovation. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which amyloid-beta (Aβ) accumulation, oxidative stress (OS), and chronic inflammation drive synaptic dysfunction and cognitive decline. Molecular hydrogen (H₂) has emerged as a candidate neuroprotective gas with selective antioxidant and anti-inflammatory properties, although its efficacy in amyloid-driven pathology remains incompletely defined. In this study, 5xFAD transgenic mice harboring human amyloid precursor protein (APP) and presenilin-1 (PSEN1) mutations and age-matched C57BL/6 wild-type mice were exposed to 2% H₂ by inhalation for 1 h/day over 4 weeks. H₂ inhalation reduced hippocampal reactive oxygen species (ROS), increased systemic catalase activity, and enhanced hippocampal ATP levels. In serum, H₂ decreased tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, restored IL-10, and partially normalized IL-13, shifting the peripheral environment toward a less pro-inflammatory profile. In the hippocampus, H₂ upregulated nuclear factor erythroid 2-related factor 2 (NRF2), attenuated nuclear factor kappa B (NF-κB) activation, reduced the BAX/BCL-2 ratio, preserved neuronal nuclei (NEUN) expression, and decreased hippocampal Aβ42 burden. Collectively, these findings indicate that H₂ inhalation confers multi-faceted neuroprotection in 5xFAD mice by restoring redox homeostasis, suppressing inflammation, improving mitochondrial function, and limiting Aβ accumulation. Full article

Multicentric reticulohistiocytosis (MRH) is a rare systemic histiocytic disorder of uncertain etiology characterized by papulonodular cutaneous lesions and potentially destructive polyarthritis, with variable multisystem involvement. Owing to its low prevalence, evidence for optimal management remains limited, and treatment responses are heterogeneous. Emerging reports suggest that Janus kinase (JAK) inhibition may provide benefit in refractory disease. We report a 60-year-old woman with MRH presenting with papulonodular skin lesions, symmetric polyarthritis, constitutional symptoms, and interstitial lung disease (nonspecific interstitial pneumonia pattern) in the context of co-existing primary biliary cholangitis and no evidence of malignancy. Prior therapies (glucocorticoids, methotrexate, leflunomide) achieved suboptimal control. Upadacitinib, a selective JAK1 inhibitor, induced rapid and complete remission of cutaneous and articular disease with improvement of pulmonary involvement. Secondary weight gain and incident diabetes were managed with tirzepatide. This case adds to the limited literature supporting JAK inhibition as a targeted option for refractory MRH, including multisystem disease with pulmonary involvement. Systematic evaluation of efficacy, durability, and safety is warranted. Full article

Mitochondria play a fundamental role in human reproduction by supplying the energy required for key early reproductive processes. As mitochondrial Deoxyribonucleic acid (mtDNA) is maternally inherited, pathogenic mutations can lead to multisystem disorders that are transmitted to offspring. Mitochondrial replacement therapy (MRT) has emerged as a promising assisted reproductive approach to prevent the transmission of pathogenic mtDNA by replacing defective mitochondria with healthy donor mitochondria. There have been recent reports of successful MRT in humans. However, MRT remains a relatively new procedure and needs further experiments to establish its long-term safety and effectiveness. Overall, mitochondrial replacement therapy holds significant promise in helping families build healthier futures. This review explores the evolution of mitochondrial DNA modification in reproductive cells and addresses the associated ethical considerations, including acceptable clinical indications, reproductive choices, and long-term considerations for affected children. Full article

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), characterized by immune system disorders and multiple organ damage. Current clinical treatment of LN requires a complex multi-drug combination, which is often associated with severe side effects and low patient compliance. The aim of this study was to design a self-nanoemulsifying drug delivery system (SNEDDS) co-loading total glucosides of Paeonia (TGP) and dihydroartemisinin (DHA) to increase the solubility of the drug as well as achieve synergistic anti-inflammatory and immunomodulatory effects for LN therapy. Network pharmacology, molecular docking and molecular dynamics simulations were employed to predict the core therapeutic targets and related signaling pathways. The SNEDDS co-loaded with TGP and DHA was optimized via central composite design response surface methodology (CCD-RSM). Its physicochemical properties, particle size and the polydispersity index (PDI) of the optimized formulation were characterized. In vivo therapeutic efficacy was evaluated in MRL/lpr mice by measuring disease-related indicators (urinary protein, serum ANA, and anti-ds-DNA) and inflammatory cytokines (TNF-α, IL-6, and IL-1β). Renal tissue pathology was also examined. All data were analyzed by one-way analysis of variance (ANOVA) with p < 0.05 considered statistically significant. The core therapeutic targets predicted with high relevance were AKT1, MAPK1, MAPK3, and RELA. The optimized SNEDDS achieved a high loading capacity of 16.11 ± 0.43 mg/g for TGP and 12.79 ± 1.33 mg/g for DHA, with a particle size of (25.84 ± 0.30) nm and PDI of (0.07 ± 0.02). In MRL/lpr mice, SNEDDS treatment significantly reduced urinary protein levels (p < 0.01), serum ANA (p < 0.01) and anti-ds-DNA titers (p < 0.01) compared with the model group. Additionally, the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) were markedly decreased (p < 0.05), and renal tissue damage was alleviated. Conclusions: The SNEDDS co-loaded TGP and DHA is a promising oral nanotherapeutic strategy for LN, offering synergistic anti-inflammatory and immunomodulatory effects. Full article

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder that presents as neuronal cell death caused by the pyroptosis pathway. Currently, curcumin is widely reported in the treatment of AD due to its dual inhibitory effects on NLRP3-associated inflammasome activation, but it suffers from poor bioavailability. Therefore, in this study, a highly stable curcumin-based Zn–organic framework (medi-MOF-1) loaded with taxifolin (TAX@medi-MOF-1) was presented to overcome the defect with a specific surface area of 2530.652 m² g⁻¹. The loaded TAX could further enhance the anti-inflammatory and antioxidant properties. In 5×FAD transgenic mice, TAX@medi-MOF-1 significantly improved cognitive and motor functions, reduced Aβ plaque deposition, and downregulated key pyroptosis proteins (NLRP3, caspase-1, and GSDMD-N). The dual-drug system exhibited synergistic effects, offering a promising multi-target therapeutic strategy for AD. Full article

Chronic non-communicable diseases rarely occur in isolation; cardiovascular, metabolic, neurodegenerative, malignant, and age-associated disorders share upstream drivers including oxidative stress, chronic inflammation, mitochondrial dysfunction, and metabolic imbalance. This narrative review synthesizes epidemiological, interventional, and mechanistic studies identified through targeted literature searches to examine redox biology as a shared mechanistic hub linking these conditions. We evaluate antioxidant-rich dietary patterns, selected nutraceuticals, myocardial ischemia–reperfusion injury as a clinical exemplar, rare redox-imbalance disorders as mechanistic stress models, and emerging gene-based reinforcement of endogenous antioxidant systems. Rather than proposing clinical targets, we present an integrative, hypothesis-generating framework illustrating how coordinated lifestyle-driven modulation of redox balance may simultaneously influence multiple disease trajectories. Collectively, the evidence supports a unified redox framework for multi-disease prevention for multi-disease prevention and future intervention design. Full article

Background/Objectives: Paediatric cataract is among the most common treatable causes of childhood blindness, caused by a genetically diverse disorder with variable clinical features. Although genetic factors significantly contribute to the development of paediatric cataracts, recent data on their genetic makeup and genotype–phenotype relationships in Saudi Arabia is limited. This study aims to investigate the genetic spectrum, inheritance patterns, and genotype–phenotype correlations of paediatric cataract in a Saudi population over twenty years. Methods: We conducted a retrospective cohort study of children diagnosed with congenital or juvenile cataracts between 2000 and 2019 at two major referral centres in Riyadh. Clinical, ocular, and systemic data were collected through multidisciplinary evaluations. Genetic analysis involved whole-exome and whole-genome sequencing performed at College of American Pathologists (CAP)-accredited laboratories. Variant interpretation was supported by bioinformatic and Artificial Intelligence (AI) prediction tools. Genotype–phenotype relationships were systematically analysed. Results: The study included 28 cases of genetically confirmed paediatric cataracts. Variants classified as pathogenic or likely pathogenic were identified in 13 genes. Autosomal recessive inheritance was predominant, with many patients exhibiting homozygous variants, often due to consanguinity. Two novel variants were identified in the Collagen Type XVIII Alpha 1 Chain (COL18A1) and the RAB3 GTPase-activating protein catalytic subunit 2 (RAB3GAP2) genes. Considerable phenotypic variability was observed, even among patients with the same mutation, particularly those with the recurrent CRYBB1 c.171del (p.Asn58fs) mutation. Syndromic cataracts were more frequently associated with loss-of-function variants and multisystem features. Conclusions: This study offers updated insights into the genetics and clinical presentation of paediatric cataract in Saudi Arabia. It highlights high genetic diversity, unique inheritance patterns, and notable genotype–phenotype variability, emphasising the importance of early genetic testing and multidisciplinary assessment for improved diagnosis, management, and counselling. Full article

Early diagnosis of glaucoma remains challenging due to its asymptomatic onset and multifactorial pathological mechanisms. Growing evidence indicates that metabolic disorders and systemic molecular alterations play significant roles in glaucoma pathogenesis. However, reliable biomarkers and corresponding specific mechanisms remain unclear. In this study, we employed a multi-omics approach that encompassed metabolomics, transcriptomics, and Mendelian randomization to investigate the association between glaucoma and 35 types of blood and urine biomarkers. Metabolic pathway analysis was conducted using pathway enrichment analysis of differentially expressed genes based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Our study indicated that glaucoma contributed to elevated calcium concentration (OR = 1.044, 95% CI: 1.002–1.088, p = 0.039) in blood and urine, mediated by cell membrane calcium channels and calcium release from intracellular storage. Conversely, glucose was found to contribute to high glaucoma risk (OR = 1.324, 95% CI: 1.143–1.533, p = 0.0002), mediated by increased aqueous humor production, elevated intraocular pressure, endoplasmic reticulum stress, and oxidative stress. Validation experiments showed that calcium levels in blood, urine, and retina were elevated in the glaucoma group, and elevated glucose levels significantly reduced the 661W cell viability and induced apoptosis. This study offers new insights into the specific mechanisms linking blood and urine biomarkers to glaucoma, contributing to its prevention and screening. Full article

NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) are rare autoinflammatory disorders caused by uncontrolled inflammasome activation. While IL-1β blockade is first-line therapy, many patients respond inadequately, highlighting a need for alternative strategies. Transcriptomic analysis was performed on immune cells from a patient with an NLRP3 L573W mutation. Functional validation of CD177 as a downstream effector of NLRP3 activation was conducted. A novel NLRP3 L573W knock-in mouse model was established. Correlation between CD177 expression, disease severity, neutrophilia, and tissue damage was assessed. Therapeutic efficacy of siRNA-mediated CD177 silencing was evaluated and compared with IL-1β blockade. CD177, a neutrophil-specific protein, was significantly upregulated in NLRP3-mutant cells and confirmed as a direct downstream effector of NLRP3 activation. The NLRP3 L573W knock-in mouse recapitulated human disease heterogeneity, from mild self-limited inflammation to severe multi-organ pathology. CD177 expression correlated with disease severity, neutrophilia, and tissue damage. siRNA-mediated CD177 silencing attenuated systemic inflammation, reduced neutrophil infiltration and cytokine levels (IL-1β, IL-6, TNFα), and ameliorated multi-organ damage, with effects comparable to or exceeding those of IL-1β blockade. CD177 is a non-canonical amplifier of NLRP3-driven inflammation. Targeting CD177 represents a superior therapeutic strategy for NLRP3-AIDs, including IL-1β-refractory cases. Full article

Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder with a multifactorial pathogenesis involving immune dysregulation, oxidative stress, neuroendocrine signaling, and alterations of the epidermal barrier–lipid axis. Increasing molecular evidence indicates that SD is associated with both systemic and cutaneous abnormalities, including elevated β-endorphin levels, disturbed redox homeostasis, enhanced lipid peroxidation, dysregulated cytokine signaling, and genetic and epigenetic susceptibility factors. This systematic review was conducted in accordance with PRISMA guidelines. Comprehensive literature searches of PubMed, Scopus, and Web of Science identified eight studies that met the inclusion criteria. The included investigations comprised clinical case–control studies, genetic and epigenetic analyses, and multi-omics profiling of human blood and skin samples. Collectively, the findings demonstrate consistent systemic oxidative and neuroendocrine alterations alongside pronounced local immune activation characterized by Th1- and Th17-skewed responses, cytokine and stress-ligand upregulation, and activation of inflammatory signaling pathways. Genetic association signals and disease-specific microRNA profiles further implicate post-transcriptional regulation of immune and keratinocyte-related pathways in SD pathogenesis. Moreover, multi-omics studies revealed coordinated immune activation accompanied by impaired epidermal barrier function and altered lipid metabolism, supporting a dysregulated immune–barrier–lipid axis. Overall, SD emerges as a disorder driven by interconnected systemic and cutaneous molecular mechanisms. The identified pathways may represent promising directions for future biomarker research and targeted therapeutic development rather than established diagnostic or treatment strategies. Full article