Search Results (6,684)

Background/Objectives: Senecio scandens Buch.-Ham. is a flavonoid-rich traditional medicinal plant with established immunomodulatory properties. However, the mechanisms underlying the immunoregulatory and intestinal protective effects of its flavonoid extract (Senecio scandens flavonoids—SSF) remain unclear. This study characterized SSF’s bioactive components and evaluated its efficacy against cyclophosphamide (CTX)-induced immunosuppression and intestinal injury. Methods: The constituents of SSF were identified using UHPLC/Q-Orbitrap/HRMS. Mice with CTX-induced immunosuppression were treated with SSF (80, 160, 320 mg/kg) for seven days. Immune parameters (organ indices, lymphocyte proliferation, cytokine, and immunoglobulin levels) and gut barrier integrity markers (ZO-1, Occludin, Claudin-1 protein expression; sIgA secretion; microbiota composition) were assessed. Network pharmacology combined with functional assays elucidated the underlying regulatory mechanisms. Results: Twenty flavonoids were identified in SSF, with six prototype compounds detectable in the blood. The SSF treatment significantly ameliorated CTX-induced weight loss and atrophy of the thymus and spleen. It enhanced splenic T- and B-lymphocyte proliferation by 43.6% and 29.7%, respectively; normalized the CD4⁺/CD8⁺ ratio (1.57-fold increase); and elevated levels of IL-2, IL-6, IL-10, TNF-α, IFN-γ, IgM, and IgG. Moreover, SSF reinforced the intestinal barrier by upregulating tight junction protein expression and sIgA levels while modulating the gut microbiota, enriching beneficial taxa (e.g., the Lachnospiraceae_NK4A136_group, Akkermansia) and suppressing pathogenic Alistipes. Mechanistically, SSF activated the TLR/MyD88/NF-κB pathway, with isoquercitrin identified as a pivotal bioactive constituent. Conclusions: SSF effectively mitigates CTX-induced immunosuppression and intestinal damage. These findings highlight SSF’s potential as a dual-functional natural agent for immunomodulation and intestinal protection. Subsequent research should validate isoquercitrin’s molecular targets and assess SSF’s clinical efficacy. Full article

Background: Ulcerative colitis (UC), characterized by chronic intestinal inflammation, epithelial barrier dysfunction, and immune imbalance demands novel ameliorative strategies beyond conventional approaches. Methods: In this study, the probiotic properties of Lactobacillus paracasei L21 (L. paracasei L21) and its ability to ameliorate colitis were evaluated using an in vitro lipopolysaccharide (LPS)-induced intestinal crypt epithelial cell (IEC-6) model and an in vivo dextran sulfate sodium (DSS)-induced UC mouse model. Results: In vitro, L. paracasei L21 decreased levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-8) while increasing anti-inflammatory IL-10 levels (p < 0.05) in LPS-induced IEC-6 cells, significantly enhancing the expression of tight junction proteins (ZO-1, occludin, claudin-1), thereby restoring the intestinal barrier. In vivo, both viable L. paracasei L21 and its heat-inactivated postbiotic (H-L21) mitigated weight loss, colon shortening, and disease activity indices, concurrently reducing serum LPS and proinflammatory mediators. Interventions inhibited NF-κB signaling while activating HIF1α/AhR pathways, increasing IL-22 and mucin MUC2 to restore goblet cell populations. Gut microbiota analysis showed that both interventions increased the abundance of beneficial gut bacteria (Lactobacillus, Dubococcus, and Akkermansia) and improved faecal propanoic acid and butyric acid levels. H-L21 uniquely exerted an anti-inflammatory effect, marked by the regulation of Dubosiella, while L. paracasei L21 marked by the Akkermansia. Conclusions: These results highlight the potential of L. paracasei L21 as a candidate for the development of both probiotic and postbiotic formulations. It is expected to provide a theoretical basis for the management of UC and to drive the development of the next generation of UC therapies. Full article

Sarcopenia, characterized by progressive skeletal muscle loss and functional decline, represents a major public heath challenge in aging populations. Despite increasing awareness, current management strategies—primarily resistance exercise and nutritional support—remain limited by accessibility, adherence, and inconsistent outcomes. This underscores the urgent need for novel, effective, and scalable therapeutics. Flavonoids, a diverse class of plant-derived polyphenolic compounds, have attracted attention for their muti-targeted biological activities, including anti-inflammatory, antioxidant, metabolic, and myogenic effects. This review aims to evaluate the anti-sarcopenic potential of selected flavonoids—quercetin, rutin, kaempferol glycosides, baicalin, genkwanin, isoschaftoside, naringin, eriocitrin, and puerarin—based on recent preclinical findings and mechanistic insights. These compounds modulate key pathways involved in muscle homeostasis, such as NF-κB and Nrf2 signaling, AMPK and PI3K/Akt activation, mitochondrial biogenesis, proteosomal degradation, and satellite cell function. Importantly, since muscle wasting also features prominently in cancer cachexia—a distinct but overlapping syndrome—understanding flavonoid action may offer broader therapeutic relevance. By targeting shared molecular axes, flavonoids may provide a promising, biologically grounded approach to mitigating sarcopenia and the related muscle-wasting conditions. Further translational studies and clinical trials are warranted to assess their efficacy and safety in human populations. Full article

Activation of macrophages plays a key role in both inflammation and oxidative stress, key features of many chronic diseases. Pro-inflammatory M1-like macrophages, in particular, contribute to pro-oxidative environments and are a frequent focus of immunological research. This research examined the effects of kiwifruit allergen Act d 1, in comparison to LPS, on THP-1 macrophages in vitro differentiated under optimized conditions, both in the presence and in the absence of selected vanilloids. THP-1 monocyte differentiation was optimized by varying PMA exposure and resting time. Act d 1 induced M1-like phenotypic changes comparable to LPS, including upregulation of CD80, IL-1β and IL-6 secretion, gene expression of iNOS and NF-κB activation, in addition to increased reactive oxygen species (ROS) and catalase activity. Treatment with specific vanilloids mitigated these responses, primarily through reduced oxidative stress and NF-κB activation. Notably, vanillin (VN) was the most effective, also reducing CD80 expression and IL-1β levels. These results suggest that vanilloids can affect pro-inflammatory signaling and oxidative stress in THP-1 macrophages and highlight their potential to alter inflammatory conditions characterized by similar immune responses. Full article

Cardiorenal syndrome (CRS) is a multifactorial clinical condition characterized by the bidirectional deterioration of cardiac and renal function, driven by mechanisms such as renin–angiotensin–aldosterone system (RAAS) overactivation, systemic inflammation, oxidative stress, endothelial dysfunction, and fibrosis. The aim of this narrative review is to explore the key molecular pathways involved in CRS and to highlight emerging therapeutic approaches, with a special emphasis on nutritional interventions. We examined recent evidence on the contribution of mitochondrial dysfunction, uremic toxins, and immune activation to CRS progression and assessed the role of dietary and micronutrient factors. Results indicate that a high dietary intake of sodium, phosphorus additives, and processed foods is associated with volume overload, vascular damage, and inflammation, whereas deficiencies in potassium, magnesium, and vitamin D correlate with worse clinical outcomes. Anti-inflammatory and antioxidant bioactives, such as omega-3 PUFAs, curcumin, and anthocyanins from maqui, demonstrate potential to modulate key CRS mechanisms, including the nuclear factor kappa B (NF-κB) pathway and the NLRP3 inflammasome. Gene therapy approaches targeting endothelial nitric oxide synthase (eNOS) and transforming growth factor-beta (TGF-β) signaling are also discussed. An integrative approach combining pharmacological RAAS modulation with personalized medical nutrition therapy and anti-inflammatory nutrients may offer a promising strategy to prevent or delay CRS progression and improve patient outcomes. Full article

Background: Acetaminophen (APAP) is a popular and safe pain reliever. Due to its widespread availability, it is commonly implicated in intentional or unintentional overdoses, which result in severe liver impairment. Pristimerin (Prist) is a natural triterpenoid that has potent antioxidant and anti-inflammatory properties. Our goal was to explore the protective effects of Prist against APAP-induced acute liver damage. Method: Mice were divided into six groups: control, Prist control, N-acetylcysteine (NAC) + APAP, APAP, and two Prist + APAP groups. Prist (0.4 and 0.8 mg/kg) was given for five days and APAP on day 5. Liver and blood samples were taken 24 h after APAP administration and submitted for different biochemical and molecular assessments. Results: Prist counteracted APAP-induced acute liver damage, as it decreased general liver dysfunction biomarkers, and attenuated APAP-induced histopathological lesions. Prist decreased oxidative stress and enforced hepatic antioxidants. Notably, Prist significantly reduced the genetic and protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-II), p-phosphatidylinositol-3-kinase (p-PI3K), p-protein kinase B (p-AKT), and the inflammatory cytokines: nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins-(IL-6 and IL-1β) in hepatic tissues. Additionally, the m-RNA and protein levels of the apoptotic Bcl2-associated X protein (BAX) and caspase-3 were lowered and the anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) was increased upon Prist administration. Conclusion: Prist ameliorated APAP-induced liver injury in mice via its potent anti-inflammatory/antioxidative and anti-apoptotic activities. These effects were mediated through modulation of NF-κB/iNOS/COX-II/cytokines, PI3K/AKT, and BAX/BCL-2/caspase-3 signaling pathways. Full article

Cells are assaulted daily by stresses that jeopardize genome integrity. Primary human cells adapt their response to the intensity of replication stress (RS) in a diphasic manner: below a stress threshold, the canonical DNA damage response (cDDR) is not activated, but a noncanonical cellular response, low-level stress-DDR (LoL-DDR), has recently been described. LoL-DDR prevents the accumulation of premutagenic oxidized bases (8-oxoguanine) through the production of ROS in an adaptive way. The production of RS-induced ROS (RIR) is tightly controlled: RIR are excluded from the nucleus and are produced by the NADPH oxidases DUOX1/DUOX2, which are controlled by NF-κB and PARP1; then, RIR activate the FOXO1-detoxifying pathway. Increasing the intensity of RS suppresses RIR via p53 and ATM. Notably, LoL-DDR is dysregulated in cancer cell lines, in which RIR are not produced by NADPH oxidases, are not detoxified under high-level stress, and favor the accumulation of 8-oxoguanine. LoL-DDR dysregulation occurred at an early stage of cancer progression in an in vitro model. Since, conversely, ROS trigger RS, this establishes a vicious cycle that continuously jeopardizes genome integrity, fueling tumorigenesis. These data reveal a novel type of ROS-controlled DNA damage response and demonstrate the fine-tuning of the cellular response to stress. The effects on genomic stability and carcinogenesis are discussed here. Full article

This study investigated the immunonutritional potential of high-molecular-weight (Mw~85 kDa), non-degraded chitosan (NCS) and gamma-radiation-degraded, low-molecular-weight chitosan (RCS) incorporated into aquafeeds for Nile tilapia (Oreochromis niloticus). RCS was produced by γ-irradiation (10 kGy) in the presence of 0.25% (w/v) H₂O₂, yielding low-viscosity, colloidally stable nanoparticles with Mw ranging from 10 to 13 kDa. Five diets were formulated: a control, NCS at 0.50%, and RCS at 0.025%, 0.050%, and 0.075%. No adverse effects on growth were observed, confirming safety. Immune gene expression (e.g., ifng1, nfκb, tnf), antioxidant markers (e.g., reduced MDA, increased GSH and GR), and nonspecific humoral responses (lysozyme, IgM, and bactericidal activity) were significantly enhanced in the NCS-0.50, RCS-0.050, and RCS-0.075 groups. Notably, these benefits were achieved with RCS at 10-fold lower concentrations than NCS. Following challenge with Edwardsiella tarda, fish fed RCS-0.050 and RCS-0.075 diets exhibited the highest survival rates and relative percent survival, highlighting robust activation of innate and adaptive immunity alongside redox defense. These results support the use of low-Mw RCS as a biologically potent, cost-effective alternative to traditional high-Mw chitosan in functional aquafeeds. RCS-0.050 and RCS-0.075 show strong potential as immunonutritional agents to enhance fish health and disease resistance in aquaculture. Full article

The Chromobox (CBX) family comprises key epigenetic regulators involved in transcriptional repression through chromatin modifications. Dysregulation of polycomb CBX proteins has been linked to epigenetic gene silencing and cancer progression. However, the specific roles and prognostic value of CBX family members in colorectal cancer (CC) remain unclear. In this study, we show that CBX genes are significantly dysregulated in CC tissues and cell models compared to normal colorectal tissue. Among them, CBX4 and CBX8 emerged as the most upregulated isoforms in tumors. Functional analyses revealed that CBX4 overexpression enhances CC cell proliferation, while its silencing reduces tumor growth. Similarly, pharmacological inhibition of CBX4 in patient-derived tumor organoids led to decreased proliferation, supporting its pro-tumorigenic role. Immunofluorescence analysis further revealed alterations in NF-κB signaling upon CBX4 inhibition, along with reduced mRNA levels of pathway components including NF-κB, TNF, IL-1, and c-Myc. These findings point to a potential interplay between CBX4 and inflammation-related pathways in CC. Overall, our study highlights the oncogenic role of CBX4 in colorectal cancer and supports its potential as a novel therapeutic target and early biomarker for disease progression. Full article

Background: Probiotics are live microorganisms known for their health-promoting effects, particularly in modulating immune responses and reducing inflammation within the gastrointestinal tract. Emerging evidence suggests probiotics may also influence respiratory health, prompting investigation into their potential therapeutic application in lung inflammation. Methods: This study examined the anti-inflammatory effects of Ligilactobacillus salivarius (LS01 DSM 22775) and Bifidobacterium breve (B632 DSM 24706) on inflamed pulmonary epithelial cells. Lung carcinoma epithelial cells (A549) and normal bronchial epithelial cells (16HBE) were stimulated with IL-1β and treated with viable and heat-treated probiotics. Results: CCL-2 levels were significantly reduced by up to 40%, in A549 by viable form (10⁵–10⁷ AFU/g), instead of in 16HBE by heat-treated form (10⁷–10⁹ TFU/g). In A549 cells, TNF-α decreased by 20–80% with all formulations; instead, in 16HBE cells, IL-8 was reduced by viable strains (10⁷ AFU/g) by approximately 50%, while heat-treated strains (10⁹ TFU/g) decreased both IL-6 and IL-8 by 50%. All effective treatments completely inhibited IL-4 and eotaxin and suppressed NF-κB activation in both cell lines, with up to 80% reduction in phospho-p65 levels. In A549 cells, heat-treated strains fully blocked PGE2 production; instead, all four probiotics significantly inhibited COX-2 expression by approximately 50%. Conclusions: These findings demonstrate that both viable and heat-treated probiotics can modulate inflammatory responses in pulmonary epithelial cells, suggesting their potential application in inflammatory respiratory diseases. Heat-treated formulations may be particularly suited for local administration via inhalation, offering a promising strategy for targeting airway inflammation directly. Full article

Swertiamarin (SW), a natural iridoid glycoside primarily isolated from the genus Swertia, Gentianaceae family, has been extensively utilized in traditional medicine systems, including Ayurveda, Traditional Chinese Medicine, and Tibetan medicine, for treating fever, diabetes, liver disorders, and inflammatory conditions. Pharmacokinetic studies reveal that SW exhibits rapid absorption but demonstrates low oral bioavailability due to the first-pass effect. Pharmacological studies have demonstrated that SW possesses a wide range of pharmacological activities, including antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and neuroprotective activities. Our analysis demonstrates that SW exerts remarkable therapeutic potential across multiple pathological conditions through coordinated modulation of key signaling cascades, including Nrf2/HO-1, NF-κB, MAPK, PI3K/Akt, and PPAR pathways. This comprehensive review systematically consolidates current knowledge on SW’s pharmacokinetic characteristics, toxicity, diverse biological activities, and underlying molecular mechanisms based on extensive preclinical evidence, establishing a scientific foundation for future drug development strategies and potential clinical applications of the potential natural lead compound. Full article

Oxidative stress, driven by impaired antioxidant defence systems, is a major contributor to cognitive decline and neurodegenerative processes in brain ageing. This study investigates the neuroprotective effects of a natural compound mixture—composed of Hericium erinaceus, Palmitoylethanolamide, Bilberry extract, and Centella asiatica—using a multi-step in vitro strategy. An initial evaluation in a 3D intestinal epithelial model demonstrated that the formulation preserves barrier integrity and may be bioaccessible, as evidenced by transepithelial electrical resistance (TEER) and the expression of tight junctions. Subsequent analysis in an integrated gut–brain axis model under oxidative stress conditions revealed that the formulation significantly reduces inflammatory markers (NF-κB, TNF-α, IL-1β, and IL-6; about 1.5-fold vs. H₂O₂), reactive oxygen species (about 2-fold vs. H₂O₂), and nitric oxide levels (about 1.2-fold vs. H₂O₂). Additionally, it enhances mitochondrial activity while also improving antioxidant responses. In a co-culture of neuronal and astrocytic cells, the combination upregulates neurotrophic factors such as BDNF and NGF (about 2.3-fold and 1.9-fold vs. H₂O₂). Crucially, the formulation also modulates key biomarkers associated with cognitive decline, reducing APP and phosphorylated tau levels (about 98% and 1.6-fold vs. H₂O₂) while increasing Sirtuin 1 and Nrf2 expression (about 3.6-fold and 3-fold vs. H₂O₂). These findings suggest that this nutraceutical combination may support the cellular pathways involved in neuronal resilience and healthy brain ageing, offering potential as a functional food ingredient or dietary supplement. Full article

Chamaecyparis obtusa (Siebold & Zucc.) Endl. (C. obtusa) is an evergreen conifer native to temperate regions such as South Korea and Japan, traditionally used for its anti-inflammatory properties. However, the molecular mechanisms underlying the anti-inflammatory effects of C. obtusa bark extracts remain poorly understood. In this study, I compared the biological activities of C. obtusa bark extracts prepared using boiling water (COWB) and 70% ethanol (COEB), and investigated their anti-inflammatory mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. COEB significantly suppressed both mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), along with decreased production of their respective inflammatory mediators, nitric oxide (NO) and prostaglandin E₂ (PGE₂). Additionally, COEB selectively downregulated interleukin (IL)-1β expression, without affecting tumor necrosis factor-α (TNF-α), and unexpectedly upregulated IL-6. Notably, COEB did not inhibit the LPS-induced activation of major inflammatory signaling pathways, including mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and Janus kinase/signal transducer and activator of transcription (JAK/STAT). These findings suggest that COEB exerts anti-inflammatory effects by modulating key inflammatory mediators independently of canonical signaling pathways and may offer a novel therapeutic strategy for controlling inflammation. Full article

Osteoclastogenesis—the activation and differentiation of osteoclasts—is one of the pivotal processes of bone remodeling and is regulated by RANKL/RANK signaling, the decoy function of osteoprotegerin (OPG), and a cascade of pro- and anti-inflammatory cytokines. The disruption of this balance leads to pathological bone loss in diseases such as osteoporosis and rheumatoid arthritis. FFAR4 (Free Fatty Acid Receptor 4), a G protein-coupled receptor for long-chain omega-3 fatty acids, has been confirmed as a key mediator of metabolic and anti-inflammatory effects. This review focuses on how FFAR4 acts as the selective receptor for the omega-3 fatty acid docosahexaenoic acid (DHA). It activates two divergent signaling pathways. The Gαq-dependent cascade facilitates intracellular calcium mobilization and ERK1/2 activation. Meanwhile, β-arrestin-2 recruitment inhibits NF-κB. These collective actions reshape the cytokine environment. In macrophages, DHA–FFAR4 signaling lowers the levels of TNF-α, interleukin-6 (IL-6), and IL-1β while increasing IL-10 secretion. Consequently, the activation of NFATc1 and NF-κB p65 is profoundly suppressed under TNF-α or RANKL stimulation. Additionally, DHA modulates the RANKL/OPG axis in osteoblastic cells by suppressing RANKL expression, thereby reducing osteoclast differentiation in an inflammatory mouse model. Full article