Search Results (11,434)

Cannabinoids (CBs) derived from Cannabis sativa have attracted growing interest for dermatological applications due to their anti-inflammatory, antiproliferative, antimicrobial, antifibrotic, and antipruritic properties. However, their clinical translation is significantly limited by physicochemical and pharmacokinetic challenges, including poor aqueous solubility, lipophilicity, instability, variable skin penetration, and inconsistent bioavailability. At the molecular level, CBs modulate keratinocyte proliferation, sebocyte activity, fibroblast function, melanocyte balance, and immune signalling through CB1/CB2 receptors, TRP channels, and PPARγ pathways. Evidence supports their potential in the treatment of psoriasis, atopic dermatitis, acne, allergic contact dermatitis, pruritus, scleroderma, and skin cancers. Clinical evidence remains preliminary: topical and oral formulations have demonstrated anti-inflammatory, antiproliferative, antibacterial, and antifibrotic effects, with improvements in pruritus, lesion severity, and quality of life in early-phase studies. However, most trials are small, uncontrolled, and lack placebo comparators, limiting generalisability. To overcome formulation barriers and enhance dermal delivery, advanced pharmaceutical strategies such as liposomes, nanoemulsions, polymeric nanoparticles, micelles, and transdermal systems have been investigated to improve stability, controlled release, and targeted skin deposition while minimising systemic exposure. This review integrates mechanistic insights, clinical evidence, and emerging nanotechnology-enabled delivery approaches, emphasising rational formulation design and translational considerations necessary for advancing CBs toward standardised and clinically reliable dermatological therapeutics. Full article

Multiple sclerosis (MS) reflects a dynamic interplay between peripheral immune activation and compartmentalized inflammation within the central nervous system (CNS). While current disease-modifying therapies effectively reduce relapse activity driven by transient peripheral immune infiltration, their impact on progressive disability remains limited, prompting interest in strategies targeting CNS-resident immune mechanisms. Bruton’s tyrosine kinase (BTK), expressed in B cells and myeloid-derived cells, including microglia, serves as a shared intracellular signaling node linking adaptive and innate immune pathways. Second-generation BTK inhibitors, including evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, and orelabrutinib, have advanced through Phase II-III development in MS. These agents differ in binding mode, selectivity, pharmacokinetics, CNS penetration, and safety profiles, distinctions that may influence stage-specific therapeutic performance. Recent trials across relapsing and progressive phenotypes have yielded heterogeneous outcomes. Divergent signals in primary and secondary progressive MS reflect underlying biological heterogeneity and suggest that therapeutic responsiveness may depend on residual inflammatory activity, lesion biology, and pharmacologic characteristics. Emerging biomarker frameworks further emphasize the importance of stratifying inflammatory activity and degenerative progression when interpreting trial data. This review integrates molecular pharmacology and the most recent clinical evidence available through 2026 to examine how pharmacologic properties translate into stage-dependent therapeutic positioning. We also consider safety constraints within a disease-stage-specific benefit-risk framework, aiming to clarify the evolving role of BTK inhibition in MS. Full article

Nitrate-rich vegetables are increasingly recognised as a key subgroup of phytochemical-dense foods that have significant potential for preventing and managing chronic diseases. Although dietary nitrates were historically approached with caution due to concerns about nitrosamine formation, contemporary evidence highlights their beneficial effects on vascular, metabolic and cognitive functions. Ageing is characterised by endothelial dysfunction, impaired nitric oxide (NO) synthesis and increased oxidative stress, which elevates cardiovascular risk. In this context, nitrate-rich vegetables offer a natural way to restore NO bioavailability and support cardiometabolic health. This narrative review provides an integrative overview of nitrate-rich vegetables as sources of bioactive phytochemicals with therapeutic relevance. We summarise the biochemical pathways of nitrate and nitrite metabolism, including the enterosalivary nitrate–nitrite–NO cycle, the role of oral microbiota, and red blood cell-mediated nitrite reduction. Particular emphasis is placed on NOS-independent NO production, which becomes increasingly important with age, and on the synergistic interactions between dietary nitrates and other phytochemicals such as polyphenols, vitamin C, flavonoids and betalains. These compounds enhance NO stability, reduce oxidative stress, modulate inflammatory signalling and support mitochondrial function, thereby amplifying the health benefits of nitrate-rich vegetables. Beetroot, with its high nitrate content and distinctive antioxidant profile, is highlighted as a prime example. Clinical and mechanistic studies suggest that nitrate-rich vegetables may lower blood pressure, improve endothelial function and cerebral perfusion, enhance cognitive performance and muscle oxygenation, and increase exercise efficiency, particularly in older adults. Additional benefits include anti-inflammatory effects, modulation of platelet function and improvements in metabolic parameters, all of which are relevant to the prevention of chronic diseases such as hypertension, type 2 diabetes and atherosclerosis. While dietary nitrate is generally considered low-risk for healthy adults, caution is warranted in susceptible populations, such as infants and individuals with impaired renal function. Finally, significant research gaps remain, including the need for long-term, well-controlled trials and personalised strategies that account for variability in microbiota composition and nitrate metabolism between individuals. Full article

This study aims to evaluate the therapeutic efficacy of emodin (EMO) in rheumatoid arthritis (RA) and to verify whether its underlying mechanism involves the blockade of pathological angiogenesis via the inhibition of the nuclear factor-kappa B (NF-κB)/hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling axis. Bovine type II collagen-induced arthritis (CIA) mouse models and lipopolysaccharide (LPS)-stimulated EA.hy926 endothelial cells were utilized in this study. The effects of EMO on joint pathological alterations, the expression of NF-κB/HIF-1α/VEGF axis proteins, inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β)), and angiogenic capacity were assessed using histopathological analysis, Western blotting, immunohistochemistry (IHC), immunofluorescence, and tube formation assays. Furthermore, small interfering RNA (siRNA) interference targeting key molecules was employed to validate the molecular mechanisms underlying the therapeutic effects of EMO. In the CIA model group, the ankle joints of mice exhibited pronounced inflammatory infiltration, synovial hyperplasia, and bone destruction. Compared with the model group, both the EMO and methotrexate (MTX) treatment groups demonstrated attenuated synovial hyperplasia and cartilage destruction, along with significantly downregulated expression levels of key NF-κB pathway proteins, HIF-1α, and VEGF in joint tissues (p < 0.001). In vitro experiments revealed that EMO treatment significantly reduced the LPS-induced secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) (p < 0.001), and decreased both the number and total length of tubular structures formed by endothelial cells compared to the control (p < 0.001). Notably, siRNA-mediated knockdown of p65 resulted in decreased intracellular protein levels of HIF-1α and VEGF, accompanied by a significant reduction in tube formation (p < 0.001). This study demonstrates that EMO alleviates pathological damage in RA by inhibiting the activation of the NF-κB signaling pathway, which subsequently downregulates pathological angiogenesis and inflammatory responses mediated by the HIF-1α/VEGF axis. These findings provide a robust experimental basis for the potential application of EMO as a therapeutic agent for RA. Full article

Background: Prostate cancer (PCa) arises from complex interactions among host genetics, androgen signaling, and microbial communities. Emerging genomic evidence supports the presence of microbial consortia within prostate tissue, suggesting that microbial genes, metabolites, and host–microbe interactions may contribute to chronic inflammation, oncogenic signaling, and therapeutic resistance. Methods: We conducted a narrative review using targeted searches of PubMed and Google Scholar for studies published between 2020 and 2025, complemented by selected mechanistic reports published in March 2026. Human studies and experimental research providing mechanistic insights into prostate models were prioritized. Due to the heterogeneous methodologies, evidence was synthesized qualitatively, with an emphasis on genomic and signaling perspectives. Results: Low-biomass microbial DNA is consistently detected in prostate tissue. Proteomic analyses of Corpora amylacea suggest a “fossil record” of past infections through sequestered microbial DNA and antimicrobial proteins, potentially priming tissue for long-term carcinogenic processes, although contamination remains a key limitation. Recurrent bacterial and viral signals, including Cutibacterium acnes, Escherichia coli, Pseudomonas, Acinetobacter, human papillomavirus, Epstein–Barr virus, and cytomegalovirus, appear to converge on a restricted set of tumor-relevant pathways, including TLR–NF-κB, MAPK, PI3K/AKT/mTOR, cGAS–STING, and p53/pRb disruption. These interactions may promote cytokine production, oxidative stress, DNA damage, epithelial–mesenchymal transition, extracellular matrix remodeling, immune evasion, and resistance to therapy. The gut–prostate axis further links intestinal dysbiosis and microbial metabolites with systemic IGF-1 signaling and castration resistance. Conclusions: Microbial genomic consortia in the prostate and gut may shape inflammatory, metabolic, and immune networks that influence PCa initiation and progression. However, most available data remain correlative and are limited by low-biomass sampling, contamination risk, and heterogeneous study designs. Future research should prioritize rigorous contamination control, longitudinal and prostate-specific mechanistic studies, and integrated multi-omic approaches to clarify causality and identify actionable microbial targets for prevention, diagnosis, and therapy. Full article

Myocardial fibrosis is a key pathological process driving the progression of cardiovascular diseases toward heart failure, closely linked to persistent inflammation and immune dysregulation. Among CC chemokines, CCL17 has emerged as an important mediator connecting immune cell dynamics with fibrotic remodeling. This review outlines current understanding of the cellular sources, regulatory mechanisms, and functional roles of CCL17, with particular attention to its impact on regulatory T cell (Treg) recruitment through ligand-biased signaling. Beyond this mechanism, CCL17 likely operates within a broader inflammatory network, with potential interactions involving CCR2⁺ macrophages and IL-17-related pathways. Experimental studies show that disruption of CCL17 signaling attenuates fibrosis and improves cardiac function, while clinical data link elevated circulating CCL17 to cardiac dysfunction and adverse outcomes. However, the absence of clinical trials and the redundancy of chemokine networks remain key challenges for translation. Overall, CCL17 may serve as a biomarker and therapeutic target, although its clinical application will require a more integrated, network-based understanding. Full article

Cellular senescence represents a critical biological paradox in oncology. Although it evolved as a safety mechanism to halt tumorigenesis through stable cell cycle arrest, its persistence in tissues can alter the microenvironment, promoting tumor recurrence. In the context of glioblastoma (GBM), this phenomenon is critically important, as current standard therapies, such as radiotherapy and chemotherapy, inadvertently induce a state of senescence known as “therapy-induced senescence” (TIS). Senescent cells remain metabolically active and acquire a unique Senescence-Associated Secretory Phenotype (SASP), characterized by the release of pro-inflammatory cytokines, proteases, and growth factors. SASP reshapes the tumor microenvironment (TME) through paracrine signals, promoting immunosuppression, invasiveness, drug resistance and tumor recurrence. Different glial populations, including astrocytes, microglia, and oligodendrocyte precursor cells (OPCs), respond differently to senescence, specifically contributing to the creation of a permissive niche for tumor recurrence. To contrast the effects of this phenomenon, a promising therapeutic strategy has emerged, the “one-two punch,” which induces initial DNA damage followed by selective elimination of senescent cells with senolytic drugs. In this review, we analyze in detail the efficacy of targeted synthetic agents, such as the Bcl-2 family inhibitor Navitoclax, and natural bioactive compounds such as Quercetin and Fisetin. The analysis focuses on the molecular mechanisms through which these agents disrupt anti-apoptotic pathways (SCAPs) and inhibit the PI3K/AKT/mTOR axis, restoring sensitivity to apoptosis. We propose that the integration of senolytic adjuvants into standard clinical protocols may represent a crucial frontier for eliminating residual disease reservoirs and we also suggest the possibility of combining them with molecules with neuroprotective action to significantly improve the prognosis in GBM. Full article

Chronic low-grade inflammation, altered microvascular support, and progressive stress-related cellular dysfunction are major contributors to tissue aging and impaired repair. Dermal fibroblasts are central regulators of these processes because they integrate cytokine-related signaling, redox balance, and extracellular matrix homeostasis. Increasing evidence indicates that endogenous bioelectrical activity may influence these cellular functions by shaping upstream regulatory conditions linked to downstream molecular responses. In the present study, we investigated the molecular effects of the Radio Electric Asymmetric Conveyer Anti-Inflammatory Cellular Treatment delivered under Inside Blue Zone conditions (REAC ACT-IBZ) in human dermal fibroblasts (HFF1). Cells were exposed to nine standardized treatment sessions, and molecular changes were assessed by RT-qPCR, ELISA, and immunofluorescence analysis complemented by supportive semi-quantitative fluorescence intensity assessment. REAC ACT-IBZ exposure was associated with increased SIRT1 and VEGF expression and with transcriptional modulation of selected cytokine-related genes, including IL-1α, IL-1β, IL-2, and IL-8. Immunofluorescence analysis, complemented by supportive semi-quantitative fluorescence intensity assessment, showed a pattern consistent with increased FOXO1 and SIRT1 staining and reduced mTOR staining in treated cells. Overall, these findings identify a molecular profile associated with REAC ACT-IBZ exposure in human dermal fibroblasts, involving stress-response regulators, angiogenesis-related signaling, and selective cytokine-related transcriptional changes. Within the limits of the present in vitro model, the data support the view that endogenous bioelectrical modulation may interact with molecular networks relevant to tissue homeostasis and inflammaging. Full article

Oral lichen planus (OLP) is a chronic, T cell-mediated inflammatory disorder classified by the World Health Organization as an oral potentially malignant disorder (OPMD). Despite decades of research, its precise etiology remains incompletely understood and involves a complex interplay between genetic predisposition, environmental triggers, and autoimmune-like responses. This review provides a comprehensive update on OLP pathogenesis, emphasizing the role of CD8 positive cytotoxic T lymphocyte-driven basal keratinocyte apoptosis and the skewing of the T-cell receptor (TCR) repertoire. We highlight the significance of the epidermal growth factor receptor (EGFR) signaling pathway as a molecular bridge between chronic inflammation and epithelial proliferation. Furthermore, we discuss a stepwise therapeutic approach that prioritizes the management of the oral microenvironment—specifically Candida colonization and periodontal health—before escalating to immunosuppressive agents. Finally, we explore emerging precision medicine frontiers, including IL-17/IL-23 inhibitors and JAK inhibitors, alongside traditional Japanese Kampo medicine (Hange-shashin-to) and systemic adjuncts like Cepharanthine, offering a contemporary perspective on modern OLP management. This integrative framework redefines OLP not merely as a chronic inflammatory disorder, but as an immunologically sustained, microenvironment-driven, potentially malignant condition. Full article

Lyme disease (LD) is classically defined as a tick-borne infection caused by Borrelia burgdorferi sensu lato (Bbsl). However, accumulating evidence indicates that, beyond microbial persistence, Bbsl infection can initiate sustained immune dysregulation and post-infectious inflammatory phenotypes in a subset of patients. This narrative review integrates open-access experimental, translational, and clinical data and discusses LD within the spectrum of infection-triggered, immune-mediated processes. We review key immunopathogenic mechanisms, including dysregulated innate immune activation, type I interferon (IFN-I) signaling, T helper 1 and T helper 17 (Th1/Th17) polarization with regulatory T-cell (Treg) insufficiency, antigen persistence (notably borrelial peptidoglycan), and pathways linking infection to autoimmunity such as molecular mimicry, epitope spreading, and human leukocyte antigen (HLA)-restricted susceptibility. These mechanisms are integrated with immune-mediated clinical manifestations affecting the central nervous system (CNS), peripheral nervous system (PNS), musculoskeletal system, heart, skin, and hematologic compartment. Finally, we discuss translational implications for diagnosis, biomarker-guided stratification, and emerging therapeutic strategies that extend beyond antimicrobial therapy, while addressing current controversies and limitations. This framework supports a mechanistic model in which Lyme disease-associated morbidity in selected patients reflects persistent immune activation and dysregulated host responses triggered by infection. Full article

The present review discusses vitamin A/retinoid metabolism as a cross-organ axis in which hepatic clock-dependent retinoid handling may affect immune clock gene expression through the stimulation of retinoic acid 6–Janus kinase 2–signal transducer and activator of transcription 5 signaling, potentially promoting pro-inflammatory monocyte states. We further highlight mechanosensory signaling as a second convergent layer that integrates hemodynamic forces with tissue microenvironmental cues. Among these pathways, G protein-coupled receptor 68, a proton- and flow-sensitive G protein-coupled receptor, is discussed as a representative druggable node linking mechanical and inflammatory signaling in chronic kidney disease-associated cardiac injury. Finally, we outline potential therapeutic directions, including (i) circadian alignment/chronopharmacology, (ii) modulation of retinoid metabolism and signaling, and (iii) targeted inhibition of primary immune and mechanosensory effectors. Full article

Pseudomonas plecoglossicida causes bacterial hemorrhagic ascites in ayu (Plecoglossus altivelis), a lethal disease characterized by abdominal distension with hemorrhagic ascites, multifocal organ hemorrhages, and histopathologically evident hepatocellular necrosis and inflammatory infiltration. The lack of effective treatments exacerbates mass mortalities, posing a significant threat to aquaculture. Given the severe pathogenesis of P. plecoglossicida infection—which involves bacterial colonization, tissue necrosis, and host immune dysregulation—effective therapeutic strategies are urgently needed. Through a screen of traditional Chinese medicine monomers, we identified harmine, an indole alkaloid derived from Peganum harmala seeds, as a potent agent against this pathogen. In vivo, harmine exhibited direct bactericidal activity by disrupting membrane integrity, as evidenced by increasing membrane permeability, and inhibiting biofilm formation. In an ayu infection model, harmine significantly increased host survival, reduced tissue bacterial load, and enhanced innate immunity by augmenting monocyte/macrophage phagocytosis and bactericidal capacity while suppressing pro-inflammatory cytokine release and apoptosis. Mechanistically, the Drug Affinity Responsive Target Stability assay was used to identify the molecular target of harmine, followed by functional validation through PRDX6−knockdown experiments. Harmine exhibited direct bactericidal activity by disrupting membrane integrity and inhibiting biofilm formation. In the ayu infection model, harmine significantly increased host survival, reduced tissue bacteria1 load, and enhanced innate immunity by augmenting monocyte/macrophage system and bactericidal capacity while suppressing pro-inflammatory cytokine release and apoptosis, the latter likely through modulation of PRDX6−mediated oxidative stress and downstream caspase signaling. Mechanistically, DARTS revealed that harmine binds to peroxiredoxin 6 (PRDX6), a multifunctional enzyme possessing peroxidase, phospholipase A₂, and lysophosphatidylcholine acyltransferase activities. This binding liberates TNF receptor-associated factor 6 (TRAF6), facilitating its mitochondrial translocation and association with the ECSIT signaling integrator complex, thereby amplifying mitochondrial reactive oxygen species (mROS) production and potentiating macrophage-mediated bacterial killing. These findings establish harmine as a promising therapeutic candidate for controlling P. plecoglossicida infections and underscore the value of host-directed immunomodulation derived from natural products in aquaculture medicine. Full article

Shoseiryuto (SST) is a Kampo medicine widely used to treat respiratory diseases. We previously showed that SST attenuates lipopolysaccharide (LPS)-induced tight junction (TJ) barrier disruption in human bronchial epithelial (16HBE) cells. However, the underlying mechanisms remain unclear. This study aimed to clarify the mechanisms underlying the protective effects of SST. SST attenuated inflammatory responses (increased IL-6 protein and mRNA levels) and TJ disruption (decreased transepithelial electrical resistance, increased sodium fluorescein permeability, and decreased occludin mRNA and protein expression) induced by LPS, hydrogen peroxide (H₂O₂), tumor necrosis factor-α (TNF-α), and polyinosinic–polycytidylic acid (Poly I:C). Further analyses using the Poly I:C model confirmed that the effects of SST were comparable to those of the nuclear factor κB (NF-κB) inhibitors SC-514 and BAY11-7085. SST reduced the activation of NF-κB signaling (increased phosphorylation of NF-κB and IκB), similar to BAY11-7085. SST components, isoliquiritigenin (ILQG) and glycyrrhizin (GL), also attenuated inflammation, barrier dysfunction, and NF-κB signaling activity. These findings suggest that (1) activation of the NF-κB signaling pathway might be associated with both inflammatory responses and TJ barrier disruption; (2) SST could reduce these effects, potentially through modulation of NF-κB signaling; and (3) ILQG and GL may contribute, in part, to these activities. Overall, this study provides the first evidence suggesting that SST may exert anti-inflammatory and epithelial barrier-protective effects, possibly via the suppression of the NF-κB signaling pathway. Full article

Chemotherapy- and/or radiotherapy-induced oral mucositis (CRIOM) is a common complication in patients with head and neck cancer, driven largely by excessive proinflammatory cytokine signalling and treatment-associated bacterial dysbiosis. This narrative review synthesizes current mechanistic evidence and summarizes emerging therapeutic strategies targeting these pathways. Research indicates that elevated levels of IL-1β, IL-6, TNF, iNOS, and nitric oxide amplify tissue injury and ulceration, while disruption of oral and gut microbial communities, characterized by loss of beneficial commensals and enrichment of pathogenic taxa, further exacerbates mucosal inflammation. Anti-inflammatory agents, including pentoxifylline, atorvastatin, trans-caryophyllene, azilsartan, recombinant human IL-11, and low-level laser therapy have been shown in preclinical models to reduce cytokine levels and promote mucosal healing. Similarly, microbiome-targeted approaches, such as oral microbiota transplantation and multi-strain probiotic formulations, have demonstrated potential in restoring microbial balance and attenuating CRIOM severity, with current evidence including both preclinical and clinical studies. Overall, current findings highlight cytokine toxicity and dysbiosis as synergistic drivers of CRIOM and support anti-inflammatory and microbiome-modulating strategies as promising adjunctive approaches; however, further well-designed clinical studies are required to validate their efficacy and guide clinical translation. Full article

Cardiac fibrosis is a hallmark of cardiac aging and a major contributor to development of heart failure. However, therapeutic strategies that specifically target cardiac fibrosis remain limited. In this study, we demonstrate that small-molecule compound ML216 exerts protective effects against aging-associated or β-adrenoceptor agonist isoproterenol-induced cardiac fibrosis in vitro or in vivo. Mechanistically, ML216 inhibits transforming growth factor-β1 (TGF-β1) signaling by reducing TGF-β1 protein levels, thereby attenuating Mothers against decapentaplegic homolog (SMAD) phosphorylation and downstream induction of connective tissue growth factor (CTGF). This leads to a marked suppression of fibrotic genes Col1a1, Cnn2, and Acta2, ultimately resulting in reduced fibrosis. Additionally, the inhibition of the TGF-β1 pathway alleviates cardiomyocytes apoptosis, which may further limit inflammatory responses and contributes to the overall attenuation of cardiac fibrosis. Collectively, these findings demonstrate that ML216 mitigates cardiac fibrosis through the inhibition of TGF-β1 pathway-mediated fibrotic signaling and apoptosis, highlighting its potential as a therapeutic candidate for the treatment of cardiac fibrosis. Full article