Search Results (629)

This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders—including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis—evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management. Full article

Background: Growing evidence indicates that oral microbiome dysbiosis contributes to systemic inflammation, immune activation, and neural dysfunction. These processes may influence the onset and progression of major neuropsychiatric and neurodegenerative disorders. This review integrates clinical, epidemiological, and mechanistic findings linking periodontal pathogens and oral microbial imbalance to Alzheimer’s disease (AD), Parkinson’s disease (PD), depression, and anxiety. Methods: A narrative review was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar to identify recent studies examining alterations in the oral microbiota, microbial translocation, systemic inflammatory responses, blood–brain barrier disruption, cytokine signaling, and neural pathways implicated in brain disorders. Results: Evidence from human and experimental models demonstrates that oral pathogens, particularly Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola, can disseminate systemically, alter immune tone, and affect neural tissues. Their virulence factors promote microglial activation, cytokine release (IL-1β, IL-6, TNF-α), amyloid-β aggregation, and α-synuclein misfolding. Epidemiological studies show associations between oral dysbiosis and cognitive impairment, motor symptoms in PD, and alterations in mood-related taxa linked to stress hormone profiles. Immunometabolic pathways, HPA-axis activation, and the oral–gut–brain axis further integrate these findings into a shared neuroinflammatory framework. Conclusions: Oral dysbiosis emerges as a modifiable contributor to neuroinflammation and brain health. Periodontal therapy, probiotics, prebiotics, synbiotics, and targeted inhibitors of bacterial virulence factors represent promising strategies to reduce systemic and neural inflammation. Longitudinal human studies and standardized microbiome methodologies are still needed to clarify causality and evaluate whether restoring oral microbial balance can modify the course of neuropsychiatric and neurodegenerative disorders. Full article

Background and Objectives: The integrated stress response (ISR) is a convergent node in neurodegeneration. We systematically mapped open-access mammalian in vivo evidence for synthetic ISR modulators, comparing efficacy signals, biomarker engagement, and safety across mechanisms and disease classes. Methods: Following PRISMA 2020, we searched PubMed (MEDLINE), Embase, and Scopus from inception to 22 September 2025. Inclusion required mammalian neurodegeneration models; synthetic ISR modulators (eIF2B activators, PERK inhibitors or activators, GADD34–PP1 ISR prolongers); prespecified outcomes; and full open access. Extracted data included model, dose and route, outcomes, translational biomarkers (ATF4, phosphorylated eIF2α), and safety. Results: Twelve studies met the criteria across tauopathies and Alzheimer’s disease (n = 5), prion disease (n = 1), amyotrophic lateral sclerosis and Huntington’s disease (n = 3), hereditary neuropathies (n = 2), demyelination (n = 1), and aging (n = 1). Among interpretable in vivo entries, 10 of 11 reported benefit in at least one domain. By class, eIF2B activation with ISRIB was positive in three of four studies, with one null Alzheimer’s hAPP-J20 study; PERK inhibition was positive in all three studies; ISR prolongation with Sephin1 or IFB-088 was positive in both studies; and PERK activation was positive in both studies. Typical regimens included ISRIB 0.1–2.5 mg per kg given intraperitoneally (often two to three doses) with reduced ATF4 and phosphorylated eIF2α; oral GSK2606414 50 mg per kg twice daily for six to seven weeks, achieving brain-level exposures; continuous MK-28 delivery at approximately 1 mg per kg; and oral IFB-088 or Sephin1 given over several weeks. Safety was mechanism-linked: systemic PERK inhibition produced pancreatic and other exocrine toxicities at higher exposures, whereas ISRIB and ISR-prolonging agents were generally well-tolerated in the included reports. Conclusions: Directional ISR control yields consistent, context-dependent improvements in behavior, structure, or survival, with biomarker evidence of target engagement. Mechanism matching (down-tuning versus prolonging the ISR) and exposure-driven safety management are central for translation. Full article

Background/Objectives: Oral hygiene is crucial for maintaining overall health, as poor oral care can lead to various systemic diseases. Although xylitol is widely used to inhibit plaque formation, more effective agents are needed to control oral biofilms. Herein, we evaluated the inhibitory effects of sialyllactose (SL), a type of human milk oligosaccharide (HMO), and its partial structure N-acetylneuraminic acid (Neu5Ac) against Streptococcus biofilm. Methods: Under a CO₂ atmosphere, Streptococcus mutans and mixed Streptococcus species were each cultivated in vitro, and the inhibitory effects of HMOs [2′-fucosyllactose, 3′-sialyllactose (3′-SL) and 6′-sialyllactose (6′-SL)] and Neu5Ac on biofilm formation were evaluated. Bacterial biofilm formation was quantified using the crystal violet assay. Biofilm architecture and viability were visualized using confocal laser-scanning microscopy (CLSM) with SYTO9/propidium iodide staining. Transcriptomic responses of S. mutans biofilms to the test compounds were analyzed by RNA-Seq. Statistical analysis was performed using one-way analysis of variance followed by Tukey’s test. Results: SLs and Neu5Ac at 100 mM significantly inhibited S. mutans biofilm formation, with stronger effects than those of xylitol. The inhibitory effects varied among HMOs, with 6′-SL being more effective than 3′-SL and Neu5Ac being most effective. These effects were consistent in assays targeting biofilms formed by other S. mutans strains and in a mixed biofilm comprising Streptococcus species. Gene expression analysis suggested that the inhibitory mechanism involves the physical inhibition of surface adhesion and stress-induced regulation of gene expression. Conclusions: This study provides insights into the physiological significance of HMOs in the oral cavities of humans. HMOs exhibited potential as functional foods to control oral biofilm formation and reduce the risk of oral and systemic diseases. Full article

During the last ten years, the scientific community has increasingly acquired greater knowledge of the importance of oral microbiota, in general, for the physical condition of humans. Not only oral diseases, related to oral dysbiosis, are examined, but also several systemic inflammatory degenerative diseases induced by this condition. This narrative review aims to shed light on the communication mechanisms between the oral cavity and different mucosal compartments, and to explain how the changes in microorganisms may alter their balance, leading to disease. Many potential pathogenic bacteria can induce oral dysbiosis, among them Porphyromonas gingivalis and Fusobacterium nucleatum are the most explored; however, other bacterial species such as Tannerella forsythia, Treponema denticola, Aggregatibacter actinomycetemcomitans and Filifactor alocis are able to give rise to local and systemic diseases through the release of toxins. The two-way communication system between the gastrointestinal tract and the central nervous system, known as the gut–brain axis, is strongly influenced by the gut microbiota and can ultimately be studied even more broadly and in depth if we consider the influence of the oral microbiota on this axis. Taste receptors’ activity also has a significant role, being able to affect a subject’s food choice by interacting with the microbiota. Qualitative and quantitative alterations in microorganisms existing in the main mucosal compartments may easily lead the host to develop systemic degenerative inflammatory diseases. Full article

Background/Objectives: Chagas disease remains a major unmet medical need due to the limited efficacy and safety of current therapies. Here, we investigated sixteen thiosemicarbazone (TSC) derivatives as cruzain inhibitors using an integrated in silico/in vitro workflow. Methods: Docking against cruzain (PDB 3KKU) guided hit prioritization and correlated with enzyme inhibition; validation by redocking supported the protocol’s reliability. Results: The top compounds—H7, H10 and H11—showed potent cruzain inhibition (IC₅₀ = 0.306, 0.512 and 0.412 µM, respectively) and low-micromolar trypanocidal activity, with negligible cytotoxicity in human fibroblasts (CC₅₀ > 64 µM) and favorable selectivity. Structure–activity insights highlighted the role of expanded aromatic systems and electron-donating groups in enhancing binding within S2/S1′ subsites, while nitro substituents were associated with higher cytotoxicity. In silico ADMET parameters supported oral drug-likeness and acceptable metabolic liabilities. Conclusions: Overall, these data position TSCs as promising anti-T. cruzi leads and underscore the value of rational design against cruzain. Full article

Multiple sclerosis (MS) is a heterogeneous autoimmune disease driven by peripheral immune dysregulation and compartmentalized central nervous system (CNS) inflammation. Despite more than 20 approved disease-modifying therapies, disability accrual remains common, particularly in patients with highly active relapsing disease and progressive phenotypes characterized by silent progression and smoldering neuroinflammation. Two emerging therapeutic strategies address these unmet needs: Bruton’s tyrosine kinase (BTK) inhibitors and autologous haematopoietic stem cell transplantation (HSCT). Although mechanistically distinct, both aim to overcome limitations of conventional immunosuppression by intervening more deeply in the autoimmune cascade. This narrative review synthesized mechanistic, clinical, and translational evidence identified through a comprehensive search of PubMed, Scopus, Web of Science, and ClinicalTrials.gov from January 2010 to August 2025. BTK inhibitors are oral, CNS-penetrant therapies that selectively modulate B-cell signaling and CNS-resident myeloid cells without broad lymphocyte depletion, enabling continuous immunomodulation. Phase II–III trials of evobrutinib, tolebrutinib, and fenebrutinib show consistent MRI activity suppression but variable effects on relapses and disability, suggesting relevance in microglial-driven, relapse-independent disease. HSCT is a one-time immune reconstitution therapy that eradicates autoreactive immune clones and restores immune tolerance. Randomized and real-world studies demonstrate profound suppression of inflammatory activity, stabilization or improvement of disability, and durable treatment-free remission in selected patients with highly active relapsing–remitting MS, although procedure-related risks require strict eligibility criteria and experienced centers. Together with BTK inhibitors, HSCT represents a complementary strategy within an increasingly personalized MS treatment paradigm, emphasizing biomarker-guided patient selection and optimized therapeutic sequencing. Full article

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease characterized by the main clinical manifestation of oral and ocular dryness, predominantly affecting middle-aged and elderly women. As the most commonly affected target organs in SS, pathological changes in the salivary glands (SGs) and their underlying mechanisms are of great significance for understanding the disease progression. Recent studies have revealed that a dynamic imbalance of the extracellular matrix (ECM) in the SGs plays a crucial role in the pathogenesis of SS. Dysregulation of matrix metalloproteinases (MMPs) and the fibrotic processes they mediate constitute the core pathological changes. These alterations intertwine with local chronic inflammatory responses, cellular senescence, and hyperosmolarity, collectively leading to the destruction of the SG parenchymal structure and progressive loss of secretory function, significantly impairing the patients’ quality of life. However, research on the pathological mechanisms of the SG ECM remains insufficient, and there are currently no specific therapeutic interventions targeting ECM alterations in clinical practice. This review systematically elucidates the characteristics of pathological and physiological changes in the SG ECM in SS and thoroughly explores novel therapeutic strategies based on ECM regulation, as well as their clinical application prospects. Full article

Metabolic syndrome (MetS) and its associated conditions, namely, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), obesity, and polycystic ovary syndrome (PCOS) are characterized by insulin resistance, dyslipidemia, and low-grade inflammation. Curcumin, a polyphenolic compound derived from Curcuma longa Linn., exhibits pleiotropic metabolic and anti-inflammatory properties and has thus been evaluated as a nutraceutical intervention for these conditions, but findings remain inconsistent. This systematic review and meta-analysis evaluated the clinical efficacy of Curcuma longa supplementation on anthropometric, glycemic, lipid, inflammatory, and oxidative stress parameters in adults with MetS or related disorders. A comprehensive search of databases (PubMed, Scopus, AMED, LILACS, and Google Scholar) identified 104 eligible randomized controlled trials (RCTs). The included trials primarily assessed standardized oral turmeric/curcumin supplements and bioavailability-enhanced formulations rather than whole culinary turmeric. Pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were computed using random-effects models. Subgroup analyses were conducted by disease category, dose, and formulation. Risk of bias was assessed using the Cochrane RoB 2 tool. Curcumin supplementation significantly reduced fasting blood sugar (SMD = −0.54, 95% CI −0.72 to −0.36) and HbA1c (SMD = −0.41, 95% CI −0.60 to −0.23) in T2DM; decreased triglycerides (SMD = −0.48; 95% CI: −0.70 to −0.25), and LDL cholesterol (SMD = −0.39; 95% CI: −0.59 to −0.18) while elevating HDL cholesterol (SMD = 0.45; 95% CI: 0.25 to 0.65) and total antioxidant capacity (SMD = 0.73; 95% CI: 0.51 to 0.94). Curcuma longa also attenuated systemic inflammation, lowering C-reactive protein (SMD = −0.62; 95% CI: −0.81 to −0.43), TNF-α (SMD = −0.57; 95% CI: −0.80 to −0.34), and IL-6 (SMD = −0.50; 95% CI: −0.70 to −0.29). Heterogeneity was moderate-to-high, reflecting some differences in the formulation, dosage, and duration. Collectively, these findings affirm that Curcuma longa exerts measurable, clinically relevant improvements on glycemic regulation, lipid metabolism, and inflammatory−oxidative balance, supporting its role as a nutraceutical adjunct in metabolic health management, while its bioavailability-enhanced formulations show superior efficacy. Larger, long-term, multicenter RCTs are warranted to confirm durability, optimal dosing, and safety. Full article

The relationship between the oral microbiome and autoimmune diseases (ADs) has attracted considerable research interest. This study employed two-sample Mendelian randomization (MR) to investigate causal relationships between oral microbiota and six ADs, including rheumatoid arthritis (RA), type 1 diabetes (T1D), inflammatory bowel disease (IBD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS). Using genome-wide association study data from oral microbiome features and ADs, we applied inverse-variance weighted estimation complemented by sensitivity analyses and reverse MR to assess robustness and reverse causation. Analysis of 309 tongue dorsum and 285 salivary microbial features identified four tongue dorsum and five salivary taxa with genome-wide significant causal effects. Specific microbial taxa from both oral niches demonstrated protective or risk-enhancing effects for RA, T1D, IBD, and MS, while no causal associations were found for SLE or SS. These findings establish the causal role of specific oral microbiota in autoimmune pathogenesis and highlight priority candidates for further investigation as potential microbial biomarkers. Full article

Contagious ecthyma (CE) is a widespread, highly contagious zoonotic skin disease of small ruminants caused by the Orf virus (ORFV), leading to substantial economic losses and welfare concerns. There is no specific treatment, with topical antiseptics and oral or parenteral antibiotics often administered for preventing secondary infections, risking antimicrobial resistance. This study assessed the effect of treating CE in lambs with an antibiotic-free topical anaesthetic/antiseptic formulation (Tri-Solfen^®; T-S; Medical Ethics, Australia/MultiSolfen^®; M-S; Dechra, UK). Serum amyloid A (SAA), a marker of systemic inflammation, was measured in both experimentally and naturally infected lambs allocated to treated and untreated groups. Samples were collected prior to (T0) and at 2 (T2), 7 (T7) and 14 (T14) days post-treatment in experimentally infected lambs and at T0, 10 (T10) and 20 (T20) days post-treatment in naturally affected lambs. In the experimental infection, SAA concentrations were lower in the treated group than in controls at T7 and significantly lower at T14. In the natural outbreak, SAA concentrations significantly decreased over time in the treated group, with a consistent trend toward lower values than in controls. These findings indicate that this therapeutic formulation reduces systemic inflammatory responses in lambs affected by CE, supporting its use as an alternative to antibiotics. Full article

Background: Systemic lupus erythematosus is a multi-faceted auto-immune disease. Growing evidence points to gut permeability and microbiota as key players in the development of the disease. Cinnamomum cassia is gaining attention as a potential modifier of the gut and liver health. We aim in this study to explore the effect of cinnamon on key elements of the gut–liver axis in imiquimod-induced lupus. Methods: Female C57BL/6J mice were stratified into five experimental groups: sham, sham plus cinnamon, lupus, lupus with cinnamon treatment, and lupus with pre- and post-induction cinnamon treatment. Lupus was induced through application of 1.25 mg of 5% imiquimod cream to the right ear, three times per week over six weeks. Cinnamomum cassia was given orally at 200 mg/kg, five days weekly. High-Throughput Sequencing of Bacterial 16S rRNA Gene was used on fecal samples with subsequent bioinformatic analysis of microbiota. Western blot and antibody array were used to measure E. coli translocation, and hepatic inflammatory, oxidative, and apoptotic markers. Results: Cinnamon treatment mitigated the trend toward a lower Firmicutes/Bacteroidota ratio in the lupus mice. While not statistically significant, cinnamon also led to a decrease in Lachnospiraceae abundance. Interestingly, sham mice given cinnamon had more Lactobacillus and Limosilactobacillus. Furthermore, cinnamon effectively reversed the increase in E. coli protein in the liver and normalized the enhanced expression of TLR-7, p-NFκB/NFκB, SOD1 and SOD2 induced by lupus. Conclusions: Cinnamomum cassia modulates oxidative, inflammatory, and microbial elements of the gut–liver axis in lupus, offering a new perspective on lupus pathogenesis and potential nutritional interventions. Full article

Alzheimer’s disease (AD), the leading cause of dementia worldwide, is characterized by progressive neuronal loss, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, cholinergic dysfunction, and gut–brain axis dysregulation. Despite advances in anti-amyloid therapeutics, current interventions provide only modest symptomatic relief and face limitations in accessibility, cost, and long-term efficacy. Plant-derived bioactive compounds, rooted in traditional medicine systems such as Ayurveda and Traditional Chinese Medicine, have gained increasing attention as multi-target therapeutic agents due to their pleiotropic actions, relative safety, and ability to cross the blood–brain barrier. This review synthesizes mechanistic and translational evidence on major phytochemicals, including withanolides (Withania somnifera), curcumin (Curcuma longa), ginkgolides and bilobalide (Ginkgo biloba), bacosides (Bacopa monnieri), ginsenosides (Panax ginseng), crocin/safranal (Crocus sativus), epigallocatechin-3-gallate (Camellia sinensis), rosmarinic acid (Salvia officinalis, Melissa officinalis), and asiaticosides (Centella asiatica). These compounds exert neuroprotective effects by inhibiting Aβ aggregation, reducing tau phosphorylation, scavenging reactive oxygen species, attenuating NF-κB-mediated inflammation, modulating cholinergic signaling, enhancing synaptic plasticity via brain-derived neurotrophic factor/cAMP response element-binding protein (BDNF/CREB) activation, and regulating gut microbiota. Multi-target approach analyses underscore their synergistic potential in targeting interconnected AD pathways. However, translation remains hindered by poor oral bioavailability, rapid metabolism, and variability in clinical outcomes. Advances in delivery platforms, including liposomes, bilosomes, solid lipid nanoparticles, and nanostructured lipid carriers, are improving stability, blood–brain penetration, and therapeutic efficacy in preclinical models. Collectively, plant-derived phytochemicals serve as promising, affordable, and multi-modal candidates for reshaping AD management, bridging traditional knowledge with modern therapeutic innovation. Full article

This article explores a rare and diagnostically challenging form of Crohn’s disease, known as Oral Crohn’s Disease (OCD), in which the condition is confined to the oral cavity without gastrointestinal involvement. Additionally, Crohn’s disease is typically associated with digestive manifestations, and oral lesions may occasionally represent the first- or even the sole- signs of the disease, making diagnosis difficult due to their non-specific presentation. We report the case of a 22-year-old presenting woman suffering from chronic painful gingivitis and macrocheilitis, in the absence of gastrointestinal symptoms. Despite multiple topical treatments and an initial non-specific histopathological report, a multidisciplinary case discussion and re-evaluation of biopsies led to the diagnosis of OCD. Comprehensive gastrointestinal assessments revealed no intestinal involvement. Owing to the persistence of symptoms and resistance to topical therapies, the patient was subsequently treated with an anti–TNFα (Tumor Necrosis Factor alpha) biologic agent. To contextualize this case, we conducted a literature review and identified six similar cases published between 2000 and 2025. Reported patients presenting with symptoms such as lip swelling, cheilitis, mucosal ulcerations, and gingivitis. Histopathological findings consistently demonstrate non-caseating granulomas and inflammatory cell infiltration. Most cases responded favorably to corticosteroids, while some required systemic or biologic therapy. The article highlights that OCD remains underrecognized due to its variable clinical presentation and absence of gastrointestinal manifestations. It emphasizes the importance of integrating clinical, histological, and exclusion-based diagnostic criteria and advocates for a multidisciplinary approach involving dental surgeons, dermatologists, pathologists, and gastroenterologists. Early recognition and long-term monitoring are essential, as gastrointestinal involvement may develop years after the onset of oral symptoms. Full article

Background and Objectives: Oral Squamous Cell Carcinoma (OSCC) requires early diagnosis for favorable outcomes, but global healthcare disruptions caused by the COVID-19 pandemic severely affected cancer care delivery. This study aimed to investigate the pandemic’s influence on OSCC pathological staging and disease-related characteristics at a single medical center. Materials and Methods: A retrospective study was conducted on 148 patients who underwent curative-intent surgery for newly diagnosed OSCC between March 2018 and October 2024. Patients were stratified into a Pre-COVID-19 group (March 2018–January 2020, N = 52) and a Post-COVID-19 group (February 2020–October 2024, N = 96). Patient demographics and risk factors were compared using Chi-squared and Wilcoxon rank-sum tests, while pathological stage, Depth of Invasion (DOI), and surgical outcomes were analyzed. Results: Patient demographics, risk factors, and comorbidities were comparable between the two groups. The Post-COVID-19 cohort presented with significantly more advanced pathological disease, evidenced by an increase in overall TNM stage, including a dramatically higher rate of Stage 4 diagnosis (35% vs. 3.2% in the Pre-COVID-19 group). This group also showed a significantly higher Depth of Invasion (median DOI: 5.0 mm vs. 3.0 mm). Consequently, the Post-COVID-19 group required more aggressive treatment (e.g., higher rates of adjuvant radiotherapy) and experienced worse short-term outcomes, including significantly longer hospitalization (median 15 days vs. 6 days) and higher rates of postoperative pulmonary infection and tracheostomy. Conclusions: The COVID-19 pandemic was associated with a dramatic shift toward the diagnosis of OSCC at advanced pathological stages. This diagnostic delay necessitated more complex surgical management and resulted in significantly worse short-term outcomes. These findings underscore the urgent need for resilient strategies to prevent systemic diagnostic delays during public health crises. Full article