Search Results (1,822)

Dental infections continue to pose a major health concern worldwide, driven by persistent microbial biofilms, dysregulated host responses, and suboptimal efficacy of conventional antimicrobial therapies. The emergence of nanotechnology has facilitated the development of therapeutic approaches that offer spatiotemporal, minimally invasive, and resistance-preventing alternatives for treating complex dental infections. This review critically assesses novel nanomaterial-based therapies designed to directly eradicate pathogenic microorganisms involved in periodontal disease, dental caries, oral candidiasis and endodontic infections. We first explore the roles of microbial dysbiosis and biofilm-associated pathogenicity as key factors in disease progression, thereby providing a biological rationale for targeted therapies. Particular emphasis is placed on pathogen-directed modalities such as photodynamic, photothermal, sonodynamic, chemodynamic, and nanozyme-based therapies, which allow localized microbial eradication while reducing antibiotic resistance. The design and effectiveness of multifunctional nanomaterials, ranging from bioactive nanoparticles and polymeric hydrogels to microsphere-based delivery systems and implant surface modifications, are analysed in the context of antimicrobial efficacy, biofilm disruption, and compatibility with regenerative processes. Meanwhile, recent advances in integration with tissue regeneration and the potential of artificial intelligence in diagnosis, treatment strategies and materials design are explored as complementary strategies that could improve therapeutic outcomes. By consolidating mechanistic and translational insights, this review highlights how pathogen-targeted nanotherapeutics are revolutionizing the treatment of dental infections with more effective and clinically viable solutions. Full article

Background/Objectives: Schizophrenia is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms, as well as disturbances of the self and metacognitive dysfunction. Increasing evidence suggests that these dimensions contribute substantially to psychosocial functioning and recovery, yet they are often investigated separately. This narrative review aims to integrate current knowledge on self-disturbances and metacognition in schizophrenia and discuss their relevance for contemporary therapeutic approaches. This review proposes an integrative conceptual framework positioning disturbances of the minimal self and metacognitive dysfunction as complementary dimensions that may contribute to schizophrenia psychopathology and may have relevance for recovery-oriented interventions. Methods: A narrative review of the peer-reviewed literature was conducted. Classical theoretical papers, recent empirical studies, systematic reviews, and meta-analyses addressing self-disturbances, metacognition, and therapeutic interventions in schizophrenia spectrum disorders were analyzed. Results: Current evidence indicates that disturbances of the minimal self and metacognitive dysfunction may represent complementary and interacting dimensions of schizophrenia psychopathology. Self-disturbances affect the subjective sense of identity, agency, and self-presence, whereas metacognitive deficits impair the integration of information about oneself and others into coherent mental representations. These impairments are associated with poorer psychosocial functioning, reduced quality of life, and limited recovery. Interventions targeting metacognitive functioning, including Metacognitive Reflection and Insight Therapy, Metacognitive Training, and cognitive remediation, have shown promising effects on functional outcomes and recovery. Conclusions: Integrating phenomenological concepts of self-disturbance with contemporary metacognitive models may provide a broader understanding of schizophrenia than symptom-based approaches alone. In clinical practice, instruments such as the Examination of Anomalous Self-Experience (EASE) and Metacognition Assessment Scale–Abbreviated (MAS-A) may complement standard assessment by providing information about anomalous self-experiences, insight, and psychosocial functioning. However, the additional diagnostic value of combining these assessments with established clinical procedures has not yet been clearly demonstrated. They should therefore be regarded as supplementary tools that may inform clinical formulation and individualized, recovery-oriented treatment planning rather than as standalone diagnostic measures. Full article

The hepatocyte growth factor (HGF)/c-Met signaling pathway plays a central role in cellular proliferation, survival, migration, invasion, angiogenesis, and therapeutic resistance. Aberrant c-Met activation, driven by gene amplification, overexpression, activating mutations, exon 14-skipping alterations, or ligand-dependent stimulation, drives the development and progression of many solid tumors, positioning c-Met as a key target for anticancer drug development. The clinical effectiveness of c-Met-targeted treatments such as crizotinib, capmatinib, tepotinib, savolitinib, and cabozantinib has confirmed c-Met as a viable oncogenic driver for therapy, leading to the development of various next-generation inhibitors with different structures. This review provides a comprehensive perspective on small-molecule c-Met inhibitors from the perspectives of medicinal chemistry and structure-based drug design, encompassing approved drugs, investigational agents, natural-product-inspired leads, and emerging multitarget anticancer therapeutics. Particular emphasis is given to the principles of molecular recognition that govern c-Met inhibition. This includes the structure of the kinase domain, interactions at the ATP-binding site, recognition of the hinge region, and the different binding modes of Type I, Type II, and allosteric inhibitors. The design, synthesis, biological evaluation, and structure–activity relationships of diverse heterocyclic scaffolds that have shaped c-Met inhibitor discovery are critically analyzed. Key medicinal chemistry strategies, including scaffold hopping, bioisosteric replacement, conformational optimization, molecular hybridization, and multitarget pharmacophore integration, are discussed in the context of potency, selectivity, resistance management, and drug-like properties. Particular attention is given to the integration of structural biology, molecular docking, binding-mode analysis, and structure-guided optimization approaches that have enabled the development of potent c-Met-directed inhibitors. In addition, recent advances in dual- and multitarget agents that simultaneously modulate c-Met and complementary therapeutic targets, including VEGFR-2, EGFR, AXL, MER, PARP1, CDK2, and tubulin, are highlighted as promising strategies for overcoming pathway redundancy and acquired resistance. This review summarizes contemporary structure-based and medicinal chemistry principles underlying c-Met inhibitor discovery, critically evaluates the relationship between biochemical potency and therapeutic efficacy, and provides a framework for the rational design of next-generation c-Met-targeted and multitarget anticancer agents. Full article

Chronic kidney disease–mineral and bone disorder (CKD-MBD) confers a substantial fracture burden that is only partly addressed by therapies targeting phosphate, parathyroid hormone, and vitamin D. Redox dysregulation may represent a complementary mechanism: reactive oxygen species (ROS) are required for receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclastogenesis, whereas excessive ROS impair Wnt/β-catenin signalling in osteoblast precursors and promote osteocyte dysfunction. Uremic toxins, inflammation, and dialysis further increase oxidative stress. Molecular hydrogen (H₂) is a highly diffusible redox modulator that has been proposed to limit damaging radical-chain reactions while preserving physiological oxidant signalling. In non-uremic skeletal models, H₂ consistently suppresses osteoclast differentiation and bone loss, but evidence for osteoblast rescue is heterogeneous. In CKD and dialysis, H₂-based interventions have shown signals of reduced oxidative stress and symptomatic benefit; however, human evidence is predominantly observational, and no study identified in this review assessed a bone-specific endpoint. We therefore integrate uremic bone redox biology with H₂ pharmacology and propose a turnover-state-dependent model in which H₂ may restrain excessive resorption in high-turnover disease, while its net effect in low-turnover adynamic bone remains uncertain because potential osteoblast rescue competes with anti-osteoclastic activity established only in non-uremic models. H₂ should therefore be considered an experimental, mechanistically differentiated strategy requiring direct evaluation in uremic models and turnover-stratified clinical trials with parallel skeletal and vascular safety endpoints. Full article

Sensitive detection of treatment-associated Raman spectral alterations in tumor tissues remains challenging, particularly when such changes are not readily apparent from conventional morphological evaluation. Here, we developed a label-free Raman biosensing strategy combined with explainable machine learning to characterise treatment-associated spectral signatures in melanoma tumours. A B16-F10 melanoma-bearing mouse model was used to compare untreated and PBS-treated controls with cohorts receiving immune checkpoint blockade, anti-angiogenic intervention, or combination therapy. Raman spectra were acquired from multiple spatial regions of melanoma tissues and analyzed using nonlinear dimensionality reduction, supervised classification, and SHAP-based feature interpretation. Although cohort-averaged spectra showed substantial overlap, multivariate analysis revealed treatment-dependent spectral organization, with the combination-treatment cohort showing the most compact and distinguishable spectral profile. Supervised models, including convolutional neural networks, support vector machines, and k-nearest neighbors, further supported the reproducibility of treatment-associated Raman signatures when evaluated using mouse-level validation strategies. SHAP analysis identified discriminative Raman features mainly located within lipid, phospholipid, ester, protein, and collagen-associated vibrational domains, suggesting potential contributions from metabolic- and extracellular-matrix-related biochemical components to treatment-associated spectral discrimination. These findings indicate that Raman spectroscopy integrated with explainable machine learning provides a sensitive, label-free method for distinguishing treatment-associated spectral differences among melanoma tissues. The proposed approach may serve as a complementary spectroscopic tool alongside conventional histological and molecular analyses for investigating treatment-associated tissue-state alterations. Full article

Background: The Lung Immune Prognostic Index (LIPI), based on the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase, may reflect systemic inflammation and tumor-related metabolic burden. This study evaluated the prognostic value of pretreatment LIPI and its relationship with programmed death-ligand 1 (PD-L1) expression in patients with advanced non-small cell lung cancer (NSCLC) receiving nivolumab after first-line therapy. Methods: A total of 158 patients were included in this retrospective, single-center study. Patients were classified into LIPI 0, LIPI 1, or LIPI 2 groups according to their pretreatment LIPI scores. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan–Meier analysis and multivariable Cox regression. The prognostic value of LIPI was also evaluated within PD-L1-negative and PD-L1-positive subgroups, and LIPI × PD-L1 interactions were explored. Harrell’s concordance index was used to examine whether adding LIPI improved model discrimination beyond clinical variables and PD-L1 expression. PD-L1 data were available for 145 patients. Results: Median PFS was 566, 340, and 109 days for the LIPI 0, LIPI 1, and LIPI 2 groups, respectively, while median OS was 841, 760, and 201 days, respectively; the differences were statistically significant for both outcomes (both p < 0.001). The objective response rate (ORR) was 55.6%, 36.5%, and 4.9%, whereas the disease control rate (DCR) was 75.9%, 65.1%, and 14.6% in the LIPI 0, LIPI 1, and LIPI 2 groups, respectively (both p < 0.001). In multivariable analyses, higher LIPI remained independently associated with shorter PFS and OS, with the strongest association observed in the LIPI 2 group. LIPI also differentiated survival outcomes within both PD-L1-negative and PD-L1-positive subgroups, although no significant LIPI × PD-L1 interaction was identified for PFS or OS. The addition of LIPI increased the C-index from 0.583 to 0.698 for PFS (ΔC-index, 0.115; p < 0.001) and from 0.588 to 0.697 for OS (ΔC-index, 0.109; p = 0.003). Conclusions: Pretreatment LIPI was independently associated with PFS and OS in patients with advanced NSCLC receiving nivolumab after first-line therapy. Its association remained after adjustment for available PD-L1 expression data, and its addition improved model discrimination. These findings suggest that LIPI may provide prognostic information complementary to PD-L1 expression and routinely available clinical factors. Full article

Oxidative stress is strongly associated with neuronal damage in neurodegenerative diseases, such as Parkinson’s disease (PD). Fungal melanins are remarkable free radical scavengers; however, their capacity to protect neurons from reactive oxygen species (ROS)-induced damage remains understudied. This research evaluated the neuroprotective effects of fungal melanins and their arginine-modified counterparts on SH-SY5Y cells against neurotoxins, as well as their impact on ROS levels. Exposure to 0.6 mM H₂O₂ or 1 mM MPP⁺ markedly elevated ROS levels and reduced cell viability to approximately 56% and 60%, respectively. At 10 μg/mL, melanins from Apioperdon pyriforme, Russula nigricans, and Xylaria nigripes significantly protected cells against H₂O₂ cytotoxicity, whereas arginine-modified melanin from the skin of Scleroderma sinnamariense significantly attenuated MPP⁺ cytotoxicity. Further dose-dependent evaluation revealed that melanin from A. pyriforme (10–12 μg/mL) displayed activity comparable to the positive control (164 μg/mL N-Acetylcysteine (NAC)) against H₂O₂ by increasing cell viability up to 90%. Similarly, arginine-modified melanin from S. sinnamariense (6–10 μg/mL) and NAC showed a comparable protective effect against MPP⁺, boosting cell viability up to 80%. Both samples suppressed ROS to levels comparable to, or lower than, the untreated control. Melanin from A. pyriforme is a promising candidate for further research into complementary therapies for PD. Full article

Standard pharmacotherapy for mental disorders, including depression and anxiety, is supported by extensive clinical validation and international treatment guidelines. However, it is frequently associated with limitations such as adverse side effects, low patient adherence, and the risk of relapse. Conventional approaches rely primarily on antidepressants, anxiolytics, mood stabilizers, neuroleptics, and stimulants, which modulate monoaminergic, GABAergic, and dopaminergic neurotransmission. Recently, preclinical and emerging clinical studies have suggested that selected natural substances—specifically mushroom-derived compounds and well-established medicinal plants—may offer complementary therapeutic pathways. This narrative review critically evaluates the pharmacological efficacy, mechanisms of action, and safety profiles of selected natural compounds, including psilocybin-related tryptamines, Hericium erinaceus, ibotenic acid/muscimol from Amanita muscaria, ergothioneine, as well as notable botanical agents (e.g., Hypericum perforatum, Valeriana officinalis). We systematically distinguish between robust human clinical data (e.g., psilocybin-assisted therapy) and preliminary in vitro/in vivo findings. Particular attention is paid to their neurotrophic, anti-inflammatory, and neuromodulatory properties, while emphasizing substantial safety concerns, including intoxication risks associated with isoxazole derivatives, and potentially severe cytochrome P450-mediated drug–drug interactions. Ultimately, while certain natural compounds show promise as adjunctive interventions, most remain strictly investigational and cannot replace evidence-based conventional pharmacotherapy without further long-term, large-scale randomized controlled trials. Full article

Background and Objectives: The main neurodegenerative diseases (NDs)—Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)—represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing to its pleiotropic antioxidant, anti-inflammatory, and neuroprotective profile observed mainly in preclinical models, but the poor oral bioavailability (<1%) and negligible BBB penetration (<0.1%) have substantially limited curcumin’s clinical translation. The objective of this work was to critically examine the therapeutic potential of curcumin in NDs, focusing on advanced drug delivery systems (DDSs) designed to overcome its pharmacokinetic barriers. Methods: This is a narrative, non-systematic review of PubMed/MEDLINE, Scopus, and Web of Science. The review is organized around five complementary thematic areas selected to span the full translational pipeline of curcumin in neurodegeneration, from mechanistic rationale to clinical applicability: (1) molecular mechanisms, addressing the pleiotropic activities that justify therapeutic interest; (2) pharmacokinetic barriers, the principal obstacle to clinical translation; (3) the evolution of drug delivery systems (DDSs), documenting the technological strategies developed to overcome these barriers; (4) disease-specific applications, evaluating the available evidence across the four main NDs; and (5) translational limitations, identifying the methodological and regulatory gaps that must be closed to enable clinical implementation. Results: Curcumin exhibits neuroprotective activity in preclinical models of the four NDs analysed, acting on six interconnected mechanisms and the gut–brain axis. Four generations of DDSs have been developed, from phytosomes and clinically used lipid dispersions (Meriva^®, BCM-95^®, Longvida^®, and Theracurmin^®) to fourth-generation systems (biomimetic nanoparticles, MOFs, microneedles, 3D scaffolds, hydrogels, and carbon dots) that substantially increase the bioavailability in preclinical studies. Combination strategies, such as curcumin with resveratrol and dutasteride, show preliminary clinical signals in ALS. However, clinical translation remains limited: over 80% of positive animal findings have not been replicated in humans, formulation characterization is frequently incomplete, and most trials lack CNS-exposure biomarkers. Importantly, most of the reported bioavailability claims are based on total curcumin measurements (parent aglycone plus its inactive Phase II conjugates) rather than the active aglycone alone, a methodological limitation that should be considered when interpreting the magnitude of the bioavailability improvements reported for novel formulations. Conclusions: Curcumin exhibits pleiotropic neuroprotective activity in preclinical models of AD, PD, MS, and ALS, mediated by interconnected antioxidant, anti-inflammatory, anti-amyloidogenic, mitochondrial, and gut–brain axis mechanisms. However, its poor systemic bioavailability (<1%), minimal blood–brain barrier penetration, and extensive first-pass metabolism have limited clinical translation. Advanced drug delivery systems (including lipid-based carriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles (PLGA and chitosan), and bioinspired vesicles (exosomes)) are essential in order to overcome these barriers. Nevertheless, the formulation heterogeneity, limited long-term safety data, and reliance on preclinical models remain major obstacles; a definitive clinical translation will therefore require well-characterized formulations validated in phase II/III trials with cerebrospinal fluid exposure biomarkers, the pharmacokinetic monitoring of active aglycone (rather than total curcumin including inactive conjugates), and adaptive trial designs in neurological populations. Full article

Background: Rare diseases collectively affect millions of children worldwide and are a major cause of pediatric morbidity, mortality, and lifelong disability. Although most have a genetic basis, obtaining a timely molecular diagnosis remains challenging because of substantial clinical and genetic heterogeneity. Advances in genomic medicine are transforming rare disease diagnosis and establishing genomics as the center of precision medicine. Methods: This review summarizes current evidence on genomic approaches for pediatric rare diseases, including established and emerging sequencing technologies, their clinical applications, implementation challenges, and future directions. Results: Whole-genome sequencing is increasingly being adopted as a first-line genomic test for suspected rare genetic disorders, particularly when the phenotype is heterogeneous or does not point to a specific diagnosis. Conventional cytogenetic and targeted molecular techniques remain important complementary approaches for selected phenotypes, variant classes, and orthogonal confirmation. Gene panels are effective for well-defined phenotypes, whereas whole-exome sequencing remains a high-yield approach for genetically heterogeneous disorders, particularly when whole-genome sequencing is not available or is not clinically indicated. Long-read whole-genome sequencing expands diagnostic capacity by detecting structural variants, repeat expansions, complex rearrangements, and non-coding pathogenic variants that frequently escape short-read technologies. Emerging multi-omics approaches further improve variant interpretation and help resolve previously unsolved cases. Beyond diagnosis, molecular findings guide personalized clinical management, genetic counselling, reproductive planning, and access to targeted therapies and genotype-driven clinical trials. However, broad implementation is constrained by challenges in variant interpretation, ethical and legal considerations, data governance, workforce capacity, cost, and inequitable access to genomic services. Artificial intelligence, international data-sharing initiatives, and coordinated healthcare networks are helping overcome these barriers and improve diagnostic equity. Conclusions: Whole-genome sequencing is increasingly emerging as a first-line genomic strategy for pediatric rare diseases, while complementary technologies, expert phenotyping, and iterative data interpretation remain essential for comprehensive and accurate diagnosis and equitable access to genomic medicine. Full article

Lower-limb rehabilitation exoskeletons have emerged as a promising complementary technology to conventional therapy, enabling repetitive, intensive, and personalized gait training. However, achieving accurate trajectory tracking while maintaining robustness against parametric uncertainties, external disturbances, and unpredictable human–robot interaction remains a significant control challenge due to the highly nonlinear dynamics of coupled human–exoskeleton systems. This paper presents an experimental performance comparison of five control strategies for gait rehabilitation exoskeletons, including a classical proportional–integral–derivative (PID) controller, a model-based proportional–derivative controller with gravity compensation (PD+G), a computed torque sliding mode controller (CT-SMC), a computed torque–super-twisting sliding mode controller (CT–ST-SMC) and a hybrid backstepping–super-twisting sliding mode controller (BS–ST-SMC). All the controllers were implemented on the same lower-limb rehabilitation exoskeleton under identical operating conditions. The experimental results demonstrate that the proposed BS–ST-SMC architecture outperforms classical and traditional robust approaches, particularly in mitigating chattering and managing human–robot interaction uncertainties. Specifically, the BS–ST-SMC achieved the highest tracking precision with a mean squared position error (MSEp) of $1.32\times {10}^{-3}{\mathrm{rad}}^2$ and effectively synchronized with the user by reducing the phase lag to just 4.22° at the knee joint. Their overall performance was evaluated using the following metrics: mean squared position error (MSEP), mean squared velocity error (MSEv), peak error, phase lag, jerk index, peak torque, and peak power. Full article

Background: In the wake of the COVID-19 pandemic, nursing students and educators are navigating an increasingly complex academic environment. The rigorous demands of nursing education, combined with diminished academic preparedness and growing mental health concerns, have heightened the need for effective wellness interventions. The SKY Happiness Retreat©, an evidence-based program incorporating breathwork, meditation, and mindfulness practices, offers a potential strategy to enhance student resilience and reduce stress. Purpose: This pilot study examined the impact of integrating the SKY Happiness Retreat© into a Bachelor of Science in Nursing (BSN) program. This study evaluated whether participation reduced perceived stress and improved students’ ability to manage stressful situations. Methods: A quasi-experimental pretest–post-test design was used with junior-level BSN students recruited through convenience sampling at a rural university. Participants completed a structured three-day retreat focused on breathwork, meditation, and mindfulness. Outcomes were measured using the Mood and Anxiety Symptom Questionnaire (Mini-MASQ), the Perceived Stress Scale (PSS), and the Brief Resilience Scale (BRS). Results: Perceived stress significantly decreased following the intervention (PSS: pre M = 18.50, SD = 4.583; post M = 17.30, SD = 5.841; t(43) = 2.072, p = 0.022). General distress also significantly improved (Mini-MASQ: pre M = 15.51, SD = 6.535; post M = 12.82, SD = 5.118; t(44) = 3.941, p < 0.001). No significant changes were observed in anxious arousal or anhedonic depression. BRS scores demonstrated a modest increase in resilience. Conclusions: The SKY Happiness Retreat© shows promise as an experiential learning strategy within undergraduate nursing education. Findings suggest participation was associated with reductions in perceived stress and general distress while promoting resilience. Integrating evidence-based wellness programs into prelicensure nursing curricula may better prepare students to manage academic and professional stress. Larger, longitudinal studies are needed to evaluate long-term effectiveness. Full article

The C-C chemokine receptor type 5 (CCR5) is the principal co-receptor for R5-tropic HIV-1 and remains one of the most promising therapeutic targets in the pursuit of an HIV cure. The discovery that individuals carrying the naturally occurring CCR5Δ32 mutation exhibit marked resistance to HIV infection established the foundation for both genetic and pharmacological approaches to CCR5 inhibition. This review summarizes recent advances in CCR5-targeted therapies with a focus on CRISPR/Cas9-mediated gene editing and maraviroc-mediated receptor blockade. We discuss the molecular mechanisms, preclinical evidence and emerging clinical data supporting CRISPR-based CCR5 disruption, including multiplex editing strategies designed to overcome viral tropism switching. We also examine the evolving role of maraviroc beyond viral entry inhibition, highlighting its immunomodulatory effects, potential latency-reversing activity and applications in graft-versus-host disease and cancer. Together, these complementary strategies underscore the potential of CCR5-targeted interventions as integral components of future combination therapies aimed at achieving durable HIV remission or functional cure. Full article

In vivo models have been central to understanding hyperoxaluria pathogenesis and to the development of emerging therapeutic strategies, but no single model fully reproduces the complexity of human disease. This narrative review critically evaluates currently available in vivo models of hyperoxaluria and provides a framework for their selection, interpretation, and integration according to the specific phenotype and biological or therapeutic question under investigation. A structured, non-systematic literature search was conducted in PubMed, Web of Science, Scopus, and Google Scholar, with emphasis on peer-reviewed primary studies and relevant reviews addressing experimental models, disease mechanisms, and therapeutic interventions. Chemically and dietary induced, genetic, enteric and microbial, and large-animal models were evaluated with respect to model validity, experimental endpoints, pathophysiological relevance, and translational potential. A central feature of this review is the distinction between related but non-interchangeable phenotypes, including hyperoxaluria, crystalluria, nephrocalcinosis, oxalate nephropathy, and nephrolithiasis. This distinction provides the conceptual basis for comparing models that reproduce different stages or consequences of oxalate exposure rather than treating all calcium oxalate-associated phenotypes as equivalent. Chemically induced models are particularly useful for studying hyperoxaluria, calcium oxalate crystallization, and acute or subacute renal injury, whereas genetic models reproduce specific molecular defects underlying primary hyperoxaluria and support the development of mechanism-based therapies. Enteric and microbial models address intestinal oxalate handling and the gut–kidney axis and are particularly relevant for investigating gut-directed therapeutic strategies. Naturally occurring models may provide complementary insight into chronic clinical phenotypes, whereas large-animal models can facilitate selected translational and experimentally intensive investigations. The reviewed evidence demonstrates that no model can be considered superior. Instead, model selection should be guided by the specific mechanism, phenotype, or therapeutic intervention under investigation. This review therefore proposes a phenotype-oriented and question-driven framework for model selection and interpretation, taking into consideration validity, reproducibility, ethical aspects, and the limits of translational extrapolation. Full article

Endometriosis is a chronic estrogen-dependent systemic inflammatory disorder characterized by ectopic implantation of endometrial-like tissue, primarily on the ovaries, pelvic peritoneum, and bowel. According to the World Health Organization (WHO) estimate updated in 2025, endometriosis affects approximately 10% (about 190 million) of reproductive-age women worldwide and is a major contributor to chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility. Standard medical therapies focus on ovarian suppression, which alleviates symptoms but precludes conception and carries significant metabolic and skeletal adverse effects. Recent multi-omics research has raised interest in the gut microbiome and the estrobolome, defined as the microbial gene repertoire involved in estrogen metabolism, as potential modulators of systemic estrogen exposure and immune homeostasis. Altered microbiota composition and microbial β-glucuronidase activity may influence enterohepatic estrogen recirculation; however, endometriosis-specific evidence is predominantly associative or preclinical and does not establish a causal pathway. Dysbiosis and increased bacterial β-glucuronidase activity promote enterohepatic recirculation of estrogens, contributing to hyperestrogenism and ectopic lesion proliferation. Concurrently, oxidative stress, peritoneal inflammation, aberrant macrophage polarization, and neoangiogenesis sustain lesion survival and contribute to chronic pelvic pain. This comprehensive review synthesizes mechanistic, preclinical, and clinical evidence regarding microbiome-targeted interventions and nutritional compounds, including probiotics, prebiotics, N-acetyl cysteine (NAC), curcumin, resveratrol, epigallocatechin gallate (EGCG), omega-3 polyunsaturated fatty acids (PUFAs), and vitamin D, in modulating the estrobolome, immune responses, and oxidative microenvironment in endometriosis. We further discuss dietary patterns, bioavailability challenges, and the potential of precision nutrition to optimize reproductive outcomes. These approaches may be considered complementary or investigational adjuncts; current evidence is insufficient to demonstrate disease modification or improvements in spontaneous pregnancy, assisted reproductive technology (ART) outcomes, or live birth. Here, “fertility-sparing” denotes the absence of intentional ovulation suppression rather than proven fertility enhancement. Full article