Search Results (29,486)

Lycopus lucidus Turcz. var. hirtus Regel (L. lucidus var. hirtus) is a medicinal herb traditionally used in Chinese folk medicine for the treatment of inflammatory disorders, joint pain, and rheumatoid arthritis (RA)-like symptoms. However, systematic research on the bioactive flavonoids of this herb in RA-related cellular models is limited. The aim of this study was to isolate the main flavonoid from this herb and evaluate its in vitro anti-inhibitory effects in TNF-α-induced human RA fibroblast-like synoviocytes (HFLS-RA). Flavonoids were extracted, purified, and isolated using chromatographic techniques. The structure was elucidated by spectroscopic analysis. The effects of the isolated compound were assessed in a TNF-α-induced HFLS-RA cell model by evaluating pro-inflammatory cytokine secretion and cell proliferation/metabolic activity. A main flavonoid was identified as formononetin. Formononetin exhibited antioxidant activity and inhibited TNF-α-provoked inflammatory responses in HFLS-RA cells under cell-safe concentrations, as evidenced by reduced secretion of IL-6, IL-8, and IL-1β and suppression of TNF-α-induced hyperproliferation. In conclusion, formononetin is a major flavonoid constituent of L. lucidus var. hirtus, and these findings provide preliminary in vitro cellular evidence that formononetin exerts in vitro anti-inflammatory inhibitory activity on TNF-α-activated human RA fibroblast-like synoviocytes. Further in vivo and mechanistic studies are required to explore its potential for anti-RA-related pharmacological application. Full article

Leprosy is characterized by complex biological and cellular interactions, driven primarily by the interplay between Th${}_1$ and Th${}_2$ cells. In this study, we develop a deterministic mathematical model to investigate the interactions among healthy and infected Schwann cells, M. leprae bacteria, and Th${}_1$–Th${}_2$ immune responses. The positivity and boundedness of the proposed five-dimensional system are established, and the disease persistence condition is characterized in terms of the basic reproduction number (${\mathcal{R}}_0$). The existence conditions for the endemic equilibrium are derived, while the global asymptotic stability of the endemic state is established through the construction of an appropriate Lyapunov function. To evaluate the robustness of the proposed model, parameter sensitivity with respect to ${\mathcal{R}}_0$ is investigated using Latin Hypercube Sampling (LHS) and Partial Rank Correlation Coefficient sensitivity analysis. Furthermore, Monte Carlo uncertainty analysis (UA) is incorporated to account for the inherent uncertainty in the system, whereas a Sobol-based global sensitivity analysis quantifies the contribution of individual model parameters to the overall uncertainty. To further validate the dynamical behavior of the proposed system numerically, Lyapunov exponents are computed using the Benettin (renormalization) algorithm. The impact of combined multidrug therapy (MDT) and IL-10 inhibitor therapy is subsequently investigated within an optimal control framework, and the corresponding optimal treatment strategies are derived using Pontryagin’s maximum principle. Numerical simulations demonstrate that suppressing the Th${}_2$-mediated weakening of the host immune response through IL-10 inhibitor therapy provides superior long-term control of leprosy. The proposed treatment strategy therefore identifies IL-10 inhibitor therapy as a promising adjunct immunomodulatory intervention alongside MDT for enhancing protective cellular immunity against M. leprae in a cost-effective manner. Full article

Background: Retroviral vectors remain widely used for CAR T-cell manufacturing, including emerging multi-component engineering strategies that incorporate additional functional modules to enhance therapeutic performance. However, genome-wide profiling of integration patterns in CAR T cells subjected to multiplex retroviral engineering has not previously been reported. Methods: We performed genome-wide profiling of retroviral integration sites in CAR T-cell products derived from two targeting platforms (IL15-GPC3 and HER2). Each platform was evaluated under conditions with or without co-transduction of a retroviral vector encoding ADA1 and CD26. Experiments were conducted using cells obtained from a single donor with three technical replicates. Vector copy number (VCN), chromosomal distribution, genomic feature annotation, and integration hotspot analyses were conducted. Results: VCN levels were comparable across all CAR T-cell products and were not significantly affected by ADA1/CD26 co-expression. Integration events were broadly distributed across the genome with enrichment in gene-dense chromosomal regions. Chromosome 19 showed a prominent integration preference, with a secondary enrichment observed on chromosome 17. The majority of integration sites were located within intronic regions, with no enrichment observed in promoter regions. Recurrent integration hotspots were identified; however, no evidence of dominant clonal expansion was observed across conditions. Comparative analyses between ADA1/CD26 and control groups showed minimal differences in integration patterns. Conclusions: To our knowledge, this study provides the first comprehensive, genome-wide characterization of retroviral integration site profiles in CAR T-cell products manufactured by multi-vector co-transduction with an ADA1/CD26 module. By employing harmonized comparison with external reference datasets, we offer a directly benchmarked integration site characterization of multi-component CAR T-cell manufacturing. These findings establish a reference framework for integration site monitoring in next-generation CAR T-cell engineering systems and inform risk evaluation for emerging combinatorial vector strategies. Full article

Astragalus membranaceus (AM) has been reported to support immune function, but its epigenetic mechanism on immune restoration of cyclophosphamide (CTX)-induced immunosuppression remains unclear. To evaluate the recovery of immune function, we assessed the injury of splenic pathology, cytokines levels in serum, proportional changes in CD4⁺ and CD8⁺ T cells, and the recall response of Hspx-specific T cell. In addition, to define the underlying epigenetic regulatory mechanism, we measured the expression levels of DNA methyltransferases (Dnmt1, Dnmt3a and Dnmt3b) and the methylation status of the Carnitine palmitoyltransferase 1A (Cpt1a) gene. The results showed that the crude extract of AM repaired the immunosuppression induced by CTX. This is reflected in the alleviation of splenic pathological injury, the elevated proportions of CD4⁺ and CD8⁺ T cells, and the increased levels of serum IL-2 and IFN-γ. The crude extract of AM also enhanced the recall response of Hspx-specific CD8⁺ T cells; that is, the frequencies of the resulting IL-2⁺ and IFN-γ⁺ cells were significantly higher than those in the CTX + Vaccine group. All these results indicate that the adaptive immune response induced by the crude extract of AM is significantly enhanced. On the other hand, AM crude extract reversed the CTX-induced downregulation of Dnmt3a mRNA and restored CpG methylation of Cpt1a gene to a level comparable to the vaccine group at molecular level. Consistent with the elevated CpG methylation, CTX-induced upregulation of Cpt1a mRNA was also reduced. These findings reveal that AM extract enhances the antigen-specific functional recall responses of CD8⁺ T cells in immunosuppressed mice were associated with Cpt1a gene methylation, thereby establishing a translational link between traditional herbal medicine and modern epigenetics. Full article

Background/Objectives: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most frequently encountered periodic fever syndrome in pediatric populations. It is characterized by recurrent, stereotyped episodes of fever accompanied by pharyngitis, cervical lymphadenopathy, and aphthous stomatitis, sometimes with other additional nonspecific symptoms. Episodes usually last 3–7 days and recur at regular intervals of approximately 2–8 weeks. The etiopathogenesis of PFAPA remains incompletely understood. Accumulating evidence supports a central role of immune dysregulation with multiple genetic variants that contribute to disease susceptibility. Diagnosis is primarily based on clinical evaluation, although targeted genetic testing may be considered in selected cases particularly when overlapping with other monogenic autoinflammatory disorders. Management of PFAPA aims to decrease the frequency and intensity of febrile episodes. Acute flares are managed with antipyretics, corticosteroids, or, in selected cases, anti-interleukin-1 (IL-1) therapy, while preventive strategies include colchicine, cimetidine, or tonsillectomy. Adjunctive approaches such as vitamin D supplementation, probiotics, and other immunomodulatory interventions have also been investigated. This updated review summarizes current insights into the pathogenesis and therapeutic approaches of PFAPA. Methods: This narrative review was conducted using PubMed, and Scopus to identify English-language publications from 2010 to 2026 addressing PFAPA. Conclusions: Pediatricians should consider PFAPA in children with recurrent fevers and oropharyngeal symptoms, especially when standard treatments fail, to ensure proper management and avoid unnecessary antibiotic use. Full article

Medicinal plants in the Acanthaceae family have long been used in Thai traditional medicine. In this study, ethanolic extracts of four plant species, Andrographis paniculata, Thunbergia laurifolia, Acanthus ebracteatus, and Rhinacanthus nasutus, were prepared and their phytochemical and pharmacological properties were evaluated. Total phenolic and flavonoid content assays were used to investigate phytochemical content and phytochemical profiles were characterized with LC-MS, while antioxidant activities were assessed via colorimetric methods. The extracts were also tested for antibacterial activity against several skin pathogens, such as Pseudomonas aeruginosa, Cutibacterium acnes, Micrococcus luteus, Staphylococcus aureus, and methicillin-resistant S. aureus, using agar well diffusion and broth dilution methods. Cytotoxic effects on the RAW 264.7 macrophage cell were assessed using the MTT assay. The extracts were further evaluated for anti-inflammatory activity in an LPS-stimulated RAW 264.7 cell. Inflammatory gene expression was assessed by quantifying the mRNA levels of iNOS, COX-2, TNF-α, IL-1β, IL-6, and NF-κB genes using RT-qPCR. The results revealed that among the four species, T. laurifolia extract showed the highest phenolic and flavonoid levels, consistent with the greatest antioxidant activity. Moreover, LC-MS profiling annotated a range of secondary metabolites in the extracts. The inhibition zones were observed for all plant extracts when tested against the skin pathogenic bacteria except C. acnes, and A. paniculata did not inhibit P. aeruginosa, indicating the antibacterial activity of the extracts. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values differed across the extracts and bacterial strains. T. laurifolia exhibited the most potent activity against various bacterial pathogens, while A. paniculata was most effective against C. acnes at 0.98 mg/mL. In addition, all plant extracts reduced nitric oxide production and downregulated the expression of inflammatory genes. Among all plant species, A. paniculata showed the most potent activity with the highest NO inhibition of 65.68% at 60 µg/mL. Therefore, these findings support the antioxidant, antibacterial, and anti-inflammatory potential of A. paniculata, T. laurifolia, A. ebracteatus and R. nasutus, which are traditionally used in folk medicine. Full article

Curcumin and natural curcuminoids possess numerous beneficial properties, including antioxidant, antitumor, and anti-inflammatory effects. However, their application is challenging because of instability and rapid metabolism. Cyclic C₅-curcuminoids, a subgroup of curcuminoids, are chemically more stable and less susceptible to hydrolysis or metabolism. In our study, seven synthetic compounds—five cyclic C₅-curcuminoids (compounds 8, 9, 11, 12, and 13) and two cyclic chalcones (compounds 4 and 5)—were examined using an in vitro 6-hydroxydopamine-induced neuronal damage model established with all-trans retinoic acid-differentiated SH-SY5Y and BV-2 microglial cells. The antioxidant, anti-apoptotic (including ferroptosis markers (iron, GSH/GSSG, and malondialdehyde)), apoptotic (PARP, cytochrome c, caspase 9, active caspase-3, and oligonucleosome release), and anti-inflammatory effects of these compounds were also investigated. Compounds 5, 9, 12, and 13 significantly decreased reactive oxygen species production (percentage changes: 5: 28.9%; 9: 32%; 12: 29.8%; 13: 49.2%) and increased antioxidant capacity (percentage changes: 5: 63.4%; 9: 85.8%; 12: 31.2%; 13: 85.9%) and antioxidant enzyme activity (catalase, superoxide dismutase, and glutathione peroxidase) in SH-SY5Y cells. Compounds 5, 9, and 12 decreased microglial activation by downregulating Iba1 expression (fold changes: 5: 0.73; 9: 0.39; 12: 0.33) and decreasing glutamate concentration (percentage changes: 5: 26.5%; 9: 41.2%; 12: 27.3%). Together with compound 13, they reduced pro-inflammatory cytokine (IL-6, TNFα) secretion and induced anti-inflammatory cytokine (IL-10) release in SH-SY5Y and BV-2 cells. Based on these results, the blood–brain barrier penetrations of compounds 5, 9, 12, and 13 were also investigated. The highest blood–brain barrier penetration was observed for compound 12 (P_app value 13.6 × 10⁻⁶ cm/s). Synthetic cyclic C₅-curcuminoids derived from curcumin overcome the limitations of stability and bioavailability and exhibit strong antioxidant, anti-inflammatory, and anti-apoptotic effects, making them promising candidates for treating neurodegenerative diseases. Full article

Background: Influenza A virus (IAV) remains an important respiratory pathogen, and medicinal plants continue to provide chemically diverse sources for antiviral research. Dipsacus asperoides and Phlomis umbrosa have both been used under the traditional name ‘Sokdan’ despite their distinct botanical origins and phytochemical compositions. This study comparatively characterized their chemical profiles and in vitro responses to IAV and used network pharmacology as an exploratory approach to identify candidate pathways for subsequent mechanistic studies. Methods: Ethanolic extracts were evaluated for cytotoxicity in MDCK cells, cytopathic effect (CPE) reduction against IAV A/PR/8/34 (H1N1), and neuraminidase (NA) inhibition. LC-QTOF-MS was used for qualitative chemical profiling, and species-specific compound sets were subjected to target prediction, protein–protein interaction analysis, and pathway enrichment. Results: D. asperoides was non-cytotoxic up to 100 µg/mL and P. umbrosa up to 300 µg/mL under the tested conditions. Both extracts produced modest CPE reduction, reaching maximum inhibition of 21.8 ± 1.4% at 100 µg/mL for D. asperoides and 17.1 ± 6.1% at 200 µg/mL for P. umbrosa, whereas zanamivir (5 µM) produced 76.2 ± 0.8% inhibition. NA inhibition was limited for both extracts. LC-QTOF-MS identified twelve constituents with distinct species-associated detection patterns, including phenylpropanoids, iridoid glycosides, and triterpenoid saponins. Exploratory network analysis identified partially overlapping predicted hubs, including MAPK1/3, RELA, IL-6, TNF, and CASP3, together with additional species-specific nodes. Conclusions: Despite clearly different phytochemical profiles, the two Sokdan species showed a shared pattern of modest in vitro antiviral response. The network pharmacology results should be interpreted as hypothesis-generating rather than mechanistic confirmation and suggest candidate host-response pathways that can guide targeted follow-up experiments. These findings support phytochemical differentiation of the two species while providing a comparative framework for future investigation of their antiviral properties. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by insulin resistance and chronic low-grade inflammation. Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), the systemic immune-inflammation index (SII), and the systemic inflammation response index (SIRI) are important markers used to evaluate inflammatory status in T2DM. This study aimed to compare inflammatory and metabolic parameters between patients receiving metformin monotherapy and those receiving metformin plus sodium-glucose cotransporter-2 (SGLT-2) inhibitor combination therapy in patients with newly diagnosed T2DM. Methods: This prospective observational study included 64 treatment-naïve patients with newly diagnosed T2DM. Patients were divided into two groups according to treatment strategy: metformin monotherapy (n = 32) and metformin plus SGLT-2 inhibitor combination therapy (n = 32). TNF-α, IL-6, SII, systemic inflammation response index (SIRI), neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP), metabolic parameters, and insulin resistance-related indices were evaluated at baseline and after six months. Baseline-adjusted multiple linear regression analyses were performed to assess between-group differences at six months, adjusting for the corresponding baseline biomarker value, baseline HbA1c, age, and sex. Results: After six months of follow-up, significant reductions in TNF-α, IL-6, glycated hemoglobin (HbA1c), and fasting plasma glucose levels were observed in both groups (p < 0.001). In baseline-adjusted analyses, the treatment-group association was not statistically significant for TNF-α (B = −26.80, β = −0.15, p = 0.213), CRP (B = 0.06, β = 0.00, p = 0.977), SII (B = −36.94, β = −0.11, p = 0.441), or NLR (B = −0.20, β = −0.18, p = 0.207). In contrast, the treatment group was associated with a lower six-month IL-6 level (B = −37.87, β = −0.31, p = 0.038; 95% CI, −73.52 to −2.23) after adjustment for baseline IL-6, baseline HbA1c, age, and sex. Serum uric acid levels were lower in the metformin plus SGLT-2 inhibitor group than in the metformin monotherapy group at six months in the unadjusted comparison (p = 0.016). However, the adjusted treatment-group association between treatment group and six-month serum uric acid levels was not statistically significant (B = −0.51, β = −0.20, p = 0.065). Conclusions: In patients with newly diagnosed T2DM, both treatment groups showed significant reductions in TNF-α and IL-6 levels over six months. After adjustment for baseline biomarker levels, baseline HbA1c, age, and sex, no significant incremental association with treatment group was detected for TNF-α, CRP, SII, or NLR, whereas a significant adjusted association was observed for IL-6. Given the observational design and physician-directed treatment allocation, the observed IL-6 association should not be interpreted as evidence of a causal anti-inflammatory effect of SGLT-2 inhibitor therapy. Full article

Background/Objectives: Aerobic exercise is widely recognized as an effective non-pharmacological strategy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effects of different aerobic exercise loads on MASLD-associated hepatic iron dyshomeostasis and ferroptosis, as well as the underlying mechanisms, remain unclear. This study aimed to compare the effects of different aerobic exercise loads on HFD-induced MASLD and to explore whether exercise-induced improvements in hepatic lipid accumulation are associated with changes in iron homeostasis and ferroptosis-related markers. Methods: Forty male Sprague-Dawley rats were randomly assigned to a normal-fat diet group (NFD, n = 8) or a high-fat diet group (HFD, n = 32). After 8 weeks of HFD feeding, HFD-fed rats were further allocated to four groups: HFD control, low-load aerobic exercise (LEH), moderate-load aerobic exercise (MEH), and high-load aerobic exercise (HEH) (n = 8 per group). The exercise intervention lasted for 8 weeks. At the end of the intervention, blood and liver samples were collected to assess metabolic parameters, hepatic steatosis, iron homeostasis, oxidative stress, ferroptosis-related markers, and the IL-6/JAK2/STAT3-hepcidin pathway. Results: All three exercise regimens partially improved hepatic lipid metabolic abnormalities, iron accumulation, and oxidative stress-related liver injury in MASLD rats. These effects were accompanied by suppression of the IL-6/JAK2/STAT3-hepcidin pathway, increased hepatic FPN1 mRNA expression and decreased DMT1 mRNA expression, increased GPX4 expression, reduced PTGS2 expression, and improved antioxidant capacity. MEH and HEH generally produced larger changes than LEH, with HEH showing the most consistent overall response across the measured outcomes. Conclusions: Aerobic exercise attenuated HFD-induced MASLD in association with improved hepatic iron handling and a lower burden of ferroptosis-related molecular alterations. Because ferroptosis-specific rescue experiments and pathway inhibitors were not used, these findings are associative. Within the tested conditions, the 90-min protocol produced the most consistent response, but further dose–response studies are required before translation to humans. Full article

Objectives: This study focuses on exploring the mechanism by which Schisandrin B (Sch B) regulates metabolic dysfunction-associated steatotic liver disease (MASLD) mice induced by a high-fat methionine–choline-deficient (MCD) diet through the activation of peroxisome proliferator-activated receptor γ (PPARγ). Methods: Male C57BL/6 mice were fed a high-fat MCD diet for 8 weeks to establish a mouse MASLD model, and the effects of Sch B on MASLD and the mechanisms were investigated. PPARγ overexpression (OE) was induced by adeno-associated virus (AAV) administration via intrahepatic portal vein injection in mice, and a negative control (NC-OE) was also established. Body weight; wet liver weight; hepatic index; serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β); and hepatic triglyceride (TG) levels were measured in the mice. The histopathology and lipid deposition were observed by hematoxylin and eosin (H&E) staining and Oil Red O staining, while the fibrosis was assessed using Masson staining. Western blot was employed to detect the expression levels of PPARγ, sterol regulatory element-binding protein 1c (SREBP-1c), carnitine palmitoyltransferase 1A (CPT1A), transforming growth factor β1 (TGF-β1), α-smooth muscle actin (α-SMA), collagen type I (collagen I), Smad family members 2/3 (Smad2/3), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase 1/2 (ERK1/2), along with the phosphorylation activation status of these kinases. Results: It was confirmed that Sch B caused effects similar to those induced by PPARγ overexpression, reducing the hepatic index, AST, and ALT levels while alleviating lipid accumulation and fibrosis; and upregulating PPARγ and CPT1A while inhibiting SREBP-1c; and the phosphorylation of the TGF-β/Smad and MAPK pathways were involved in the mechanisms. Conclusions: Sch B can alleviate high-fat MCD-induced MASLD by activating PPARγ in mice. Full article

The aim of this study was to summarize current evidence on dust-related diseases of the bronchopulmonary system, medicinal plants, herbal formulations, and their underlying mechanisms of action. A literature review was conducted based on publications indexed in ScienceDirect, Google Scholar, SciFinder, Scopus, and Medline (PubMed), focusing on the mechanisms underlying dust-related diseases of the bronchopulmonary system, pneumoconiosis, and the potential of phytotherapeutic approaches to modulate these processes. The following keywords were used: bronchopulmonary system, pneumoconiosis, dust-related lung diseases, medicinal plants, herbal preparations, pulmonary rehabilitation, and lymphatic sanitation. The pathogenesis of pneumoconiosis involves the deposition of inhaled dust particles in the lung tissue, followed by chronic inflammation, oxidative stress, and progressive fibrosis. In experimental models, flavonoids, alkaloids, terpenoids, glycosides, tannins, and other phytochemical groups have demonstrated therapeutic potential in bronchopulmonary diseases. Among the compounds investigated, emodin, celastrol, kaempferol, sodium tanshinone IIA sulfonate, astragaloside IV, and dioscin have shown promising effects by modulating key signaling pathways and reducing inflammatory responses. Experimental evidence indicates that these phytochemicals can target major pathways involved in inflammation and fibrogenesis, thereby exerting antioxidant, anti-inflammatory, and antifibrotic effects. The lymphatic system also contributes to the pathogenesis of pneumoconiosis by transporting inhaled dust particles to regional lymph nodes, where their accumulation may promote lymph node sclerosis. Therefore, lymphatic sanitation may represent an important therapeutic mechanism of action of herbal formulations in pneumoconiosis. Our proposed lymphotropic herbal formulation enhances physiological lymphatic drainage and may positively influence the motility and functional activity of the tracheobronchial lymph nodes. The therapeutic potential of medicinal plants and herbal formulations in pneumoconiosis is supported by experimental findings for Tripterygium wilfordii (celastrol, through suppression of the EDNRB/Kng1 – (endothelin receptor type B/kininogen1), Delphinium, Camellia, and Berberis species (kaempferol, through inhibition of TLR4 (Toll-like receptor 4 signaling), Astragalus membranaceus (astragaloside IV, through antifibrotic activity mediated by inhibition of the TGF-β1/Smad3 (transforming growth factor beta1)pathway), and Reynoutria japonica Houtt., Rheum, and Aloe species (emodin, through inhibition of Smad3 (Smad family member 3) and NF-κB (nuclear factor kappa B)phosphorylation and reduction of TGF-β1, α-SMA (alpha-smooth muscle actin), collagen I, TNF-α (tumor necrosis factor alpha), and IL-1β (interleukin-1 beta) levels in lung tissue). For these and several other medicinal plants and their flavonoids, antifibrotic activity has been demonstrated through inhibition of the Akt/NF-κB (protein kinase B/nuclear factor kappa B) signaling pathway. A promising direction for future research is to evaluate the combined use of herbal formulations with established antifibrotic agents to determine whether synergistic therapeutic effects can be achieved. Full article

Healthy nutrition is pivotal for the prevention of atherosclerotic cardiovascular disease (ASCVD). In addition to traditional risk factors, other components, like low-grade chronic inflammation, play a pathogenetic role in ASCVD. Research efforts aim to identify low-grade chronic inflammation in patients with established ASCVD and in subjects with low ASCVD risk, and to validate effective nutritional strategies. Here, current nutritional approaches to counteract low-grade chronic inflammation related to ASCVD and possibly mitigated ASCVD risk are discussed, along with related molecular pathways and clinical biomarkers. Low-grade chronic inflammation results from a pro-inflammatory response promoted by large multiprotein complexes (inflammasomes). Within the ASCVD context, the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome is the most characterized protein complex, whose activation leads to increased release of downstream effectors (interleukin (IL)-1β, IL-18, IL-6). In the current clinical practice, high-sensitivity C-reactive protein (hsCRP) is used as a circulating biomarker for systemic inflammation, although it is not univocally associated with ASCVD. Some nutritional strategies have been shown effective to mitigate low-grade chronic inflammation and to reduce hsCRP, reducing in some cases ASCVD risk. The Mediterranean Diet and related trials showed that their beneficial effects on cardiovascular disorders could also be related to the anti-inflammatory properties of specific active compounds. Contradictory results have also been obtained, due to lack of standardization and to the specific nature of nutritional studies, which often rely on adherence and compliance of participants. Given the relevance of low-grade chronic inflammation for ASCVD risk, future work will need to increase awareness, identify and validate novel biomarkers, and implement novel effective nutrition strategies. Full article

Background: Oxidative stress, neuroinflammation, impaired autophagy, and mitochondrial dysfunction are major contributors to ageing and neurodegenerative diseases. This study investigated whether AgeViva could counteract these processes by modulating redox balance, inflammation, autophagy, and mitochondrial function. Methods: The effects of AgeViva were evaluated using two complementary experimental models: lipopolysaccharide (LPS)-stimulated BV2 microglial cells and Caenorhabditis elegans (C. elegans) nematodes. In BV2 cells, the expression of inflammatory, autophagy-related, and antioxidant response genes, including NRF2, SOD, and GPX, was evaluated by RT-qPCR, while cell viability was assessed by Trypan Blue exclusion assay. In C. elegans, lifespan, healthspan parameters, ROS accumulation, mitochondrial integrity, membrane potential, and the expression of stress-response, longevity, and autophagy-related genes were analyzed following AgeViva supplementation. Results: In LPS-stimulated BV2 cells, AgeViva significantly reduced the expression of mRNA the pro-inflammatory cytokines Interleukin-1 beta (IL-1β) and Tumor Necrosis Factor alpha (TNF-α) while increasing Interleukin-10 (IL-10) levels, AgeViva also induced changes in autophagy-related transcripts, such as modulation of microtubule-associated protein 1a/1b-Light Chain (LC3) and Sequestosome 1 (p62) expression, activated antioxidant-related gene expression, increasing the expression of Superoxide Dismutase 1(SOD1) and Glutathione Peroxidase (GPX). In C. elegans, AgeViva supplementation extended lifespan and improved healthspan parameters, including locomotor activity and pharyngeal pumping. Treated nematodes showed reduced cytosolic and mitochondrial ROS accumulation, preservation of mitochondrial network integrity, and maintenance of mitochondrial-associated fluorescence, reflecting mitochondrial content and/or membrane potential during ageing. Molecular analyses revealed modulation of key pathways involved in stress resistance and longevity, including Insulin-like Growth Factor 1 (Insulin/IGF-1) signaling Dauer Formation-2 and 16 (DAF-2/DAF-16), Skinhead-1 (SKN-1/Nrf2) signaling, and autophagy-related genes, like Ligating (lgg-1), Autophagy-Related-7 (atg-7), Autophagy Related-18 (atg-18), uncoordinated-51 (unc-51), and ectopic p-granules autophagy protein 5 (epg-5). Conclusions: AgeViva promotes healthy ageing by modulating oxidative stress, inflammation, autophagy, and mitochondrial homeostasis. Full article

Background/Objectives: Frozen shoulder (FS) is increasingly recognised as a heterogeneous condition in which clinical presentation, metabolic/endocrine burden, imaging phenotype, psychological factors, lifestyle-related contributors, and inflammatory biology may all contribute to disease expression and outcome. However, these contributors have not previously been integrated within a unified multidomain framework for whole-person phenotyping. To develop an evidence-derived multidomain conceptual framework for FS by integrating clinical, biological, psychological, and lifestyle-related contributors into a clinically interpretable structure. Methods: A systematic review with quantitative evidence synthesis was conducted following methodological principles for systematic reviews and reported in accordance with PRISMA 2020. The protocol was registered in PROSPERO (CRD420251158406). Observational studies relevant to predefined FS domains were identified, classified according to analytic contribution, and synthesised using a structured evidence-weighted approach. Where quantitative pooling was methodologically appropriate, meta-analytic synthesis was undertaken; where heterogeneity precluded conventional pooling, evidence was integrated through structured domain-level quantitative synthesis. Within-sphere and cross-sphere weights were derived from directness, consistency, prognostic or phenotyping relevance, methodological robustness, risk-of-bias profile, and domain specificity, and should be interpreted as exploratory evidence-derived estimates. Results: The final multidomain corpus comprised 63 studies, including 39 allocated to the clinical sphere, 5 to the metabolic/endocrine sphere, 10 to the psychological sphere, 8 to the imaging sphere, and 1 to the inflammatory sphere as direct but lower-confidence support. The final exploratory framework retained five spheres: clinical, metabolic/endocrine, imaging, psychological, and inflammatory. Within-sphere weighting identified baseline stiffness/range-of-motion restriction and symptom duration as dominant clinical components, diabetes-related burden and glycaemic control as dominant metabolic/endocrine components, capsular structural biomarkers as dominant imaging components, distress/mood together with sleep-related burden as dominant psychological components, and IL-1β-related biomarker and susceptibility evidence as the principal retained inflammatory signal. Provisional cross-sphere weighting yielded global contributions of 24.0% for the metabolic/endocrine sphere, 22.9% for the imaging sphere, 21.1% for the clinical sphere, 20.0% for the psychological sphere, and 12.0% for the inflammatory sphere. Conclusions: FS appears to be more appropriately represented as a weighted multidomain condition than purely as a clinical stiffness syndrome. The identified domains should not be interpreted as isolated entities, but rather as interacting and overlapping contributors within a whole-person clinical presentation. The proposed framework should be interpreted as an initial conceptual platform for future validation and personalised treatment-allocation research rather than as a clinically validated decision-support tool. Full article