Search Results (895)

Introduction: Osteoarthritis (OA), a leading cause of disability among the elderly, is characterized by progressive joint tissue destruction. Fucoidan, a sulfated polysaccharide with known anti-inflammatory and antioxidant properties, has been investigated for its potential to protect against interleukin-1 beta (IL-1β)-induced articular tissue damage. Methods: Human primary chondrocytes and synovial fibroblasts were pre-treated with 100 μg/mL fucoidan before stimulation with 1 ng/mL of IL-1β. The protective effects of fucoidan were assessed by measuring oxidative stress markers and catabolic enzyme levels. These in vitro findings were corroborated using a rat anterior cruciate ligament transection-induced OA model. To explore the underlying mechanisms, particularly the interaction between microRNAs (miRs) and heme oxygenase-1 (HO-1), five candidate miRs were identified in silico and experimentally validated. Luciferase reporter assays were used to confirm direct interactions. Results: Fucoidan exhibited protective effects against IL-1β-induced oxidative stress and catabolic processes in both chondrocytes and synovial fibroblasts, consistent with in vivo observations. Fucoidan treatment restored HO-1 expression while reducing inducible nitric oxide synthase and matrix metalloproteinase levels in IL-1β-stimulated cells. Notably, this study revealed that fucoidan modulates the miR-22/HO-1 pathway, a previously uncharacterized mechanism in OA. Specifically, miR-22 was upregulated by IL-1β and subsequently attenuated by fucoidan. Luciferase reporter assays confirmed a direct interaction between miR-22 and HO-1. Conclusion: The results demonstrate that fucoidan mitigates OA-related oxidative stress in chondrocytes and synovial fibroblasts through the novel modulation of the miR-22/HO-1 axis. The miR-22/HO-1 pathway represents a crucial therapeutic target for OA, and fucoidan may offer a promising therapeutic intervention. Full article

Oxidative stress significantly contributes to the exacerbation of brain damage during cerebral ischemia-reperfusion injury (CIR/I). In our previous study, purified cornel iridoid glycoside (PCIG), consisting of morroniside (MOR) and loganin (LOG), showed neuroprotective effects against CIR/I. To further explore the antioxidative effects and underlying molecular mechanisms, we applied PCIG, MOR, and LOG to rats injured by middle cerebral artery occlusion/reperfusion (MCAO/R) as well as H₂O₂-stimulated PC12 cells. Additionally, the molecular docking analysis was performed to assess the interaction between the PCIG constituents and Kelch-like ECH-associated protein 1 (Keap1). The results showed that the treated rats experienced fewer neurological deficits, reduced lesion volumes, and lower cell death accompanied by decreased levels of malondialdehyde (MDA) and protein carbonyl, as well as increased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). In H₂O₂-stimulated PC12 cells, the treatments decreased reactive oxygen species (ROS) production, mitigated mitochondrial dysfunction, and inhibited mitochondrial-dependent apoptosis. Moreover, the treatments facilitated Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) translocation into the nucleus and selectively increased the expression of NAD(P)H quinone oxidoreductase 1 (NQO-1) and heme oxygenase 1 (HO-1) through MOR and LOG, respectively. Both MOR and LOG demonstrated strong binding affinity to Keap1. These findings suggested that PCIG, rather than any individual components, might serve as a valuable treatment for ischemic stroke by activating the Nrf2/NQO-1 and Nrf2/HO-1 signaling pathway. Full article

Cardiovascular disease (CVD) and dementia may share common pathogenic factors such as atherosclerosis and hyperlipoproteinemia. Dyslipidemia-induced oxidative stress contributes to dementia comorbidity in CVD. Abelmoschus esculentus (AE, okra) potentiates in alleviating hyperlipidemia and diabetes-related cognitive impairment. This study evaluated the effects of AE in hyperlipidemic ApoE^−/− mice treated with streptozotocin (50 mg/kg) and fed a high-fat diet (17% lard oil, 1.2% cholesterol). AE fractions F1 or F2 (0.65 mg/kg) were administered for 8 weeks. AE significantly reduced serum LDL-C, HDL-C, triglycerides, and glucose, improved cognitive and memory function, and protected hippocampal neurons. AE also lowered oxidative stress markers (8-hydroxy-2′-deoxyguanosine, 8-OHdG) and modulated neuronal nuclei (NeuN) and doublecortin (DCX) expression. In vitro, AE promoted neurite outgrowth and neuronal differentiation in retinoic acid (RA)-differentiated human SH-SY5Y cells under metabolic stress (glucose and palmitate), alongside the upregulation of heme oxygenase-1 (HO-1), Nuclear factor-erythroid 2-related factor 2 (Nrf2), and brain-derived neurotrophic factor (BDNF). These findings suggest AE may counter cognitive decline via oxidative stress regulation and the enhancement of neuronal differentiation. Full article

Coronavirus disease 2019 (COVID-19) causes cardiovascular complications, which contributes to the high mortality rate of the disease. Emerging evidence indicates that aberrant vascular smooth muscle cell (SMC) function is a key driver of vascular disease in COVID-19. While antivirals alleviate the symptoms of COVID-19, it is not known whether these drugs directly affect SMCs. Accordingly, the present study investigated the ability of three approved COVID-19 antiviral drugs to influence SMC function. Treatment of SMCs with remdesivir (RDV), but not molnupiravir or nirmatrelvir, inhibited cell proliferation, DNA synthesis, and migration without affecting cell viability. RDV also stimulated an increase in heme oxygenase-1 (HO-1) expression that was not observed with molnupiravir or nirmatrelvir. The induction of HO-1 by RDV was abolished by mutating the antioxidant responsive element of the promoter, overexpressing dominant-negative NF-E2-related factor-2 (Nrf2), or treating cells with an antioxidant. Finally, silencing HO-1 partly rescued the proliferative and migratory response of RDV-treated SMCs, and this was reversed by carbon monoxide and bilirubin. In conclusion, the induction of HO-1 via the oxidant-sensitive Nrf2 signaling pathway contributes to the antiproliferative and antimigratory actions of RDV by generating carbon monoxide and bilirubin. These pleiotropic actions of RDV may prevent occlusive vascular disease in COVID-19. Full article

Apples and Korean green chili peppers are rich in phytochemicals and recognized for their diverse bioactive properties. Given the potential to enhance these beneficial compounds, this study investigated the effects of mineral supplementation during cultivation on the antioxidant and antiproliferative activities of extracts from both crops. Mineral-enriched cultivation significantly increased the total phenolic and flavonoid contents in both crops, which was accompanied by enhanced DPPH and ABTS radical scavenging activities. Moreover, the mineral-supplemented extracts of Korean green chili pepper activated the Nrf2 signaling pathway and upregulated downstream antioxidant enzymes, including heme oxygenase-1 (HO-1), γ-glutamylcysteine ligase (GCL), and glutathione peroxidase (GPx). Notably, the mineral-supplemented Korean green chili pepper extract significantly suppressed the proliferation of human colorectal cancer cells. These findings suggest that mineral supplementation during cultivation may improve the functional quality of apples and Korean green chili peppers, supporting their potential application in cancer prevention and complementary therapeutic strategies. Full article

Young leaves of reed (Phragmites communis) have been reported to exhibit antioxidant effects; however, their anti-inflammatory properties have not yet been investigated. In this study, we evaluated the effects of young reed leaf extract (PCE) on LPS-induced inflammation in RAW 264.7 cells and elucidated the underlying molecular mechanisms. Our results demonstrate that PCE significantly inhibited the production of nitric oxide (NO) by approximately 45% at 100 μg/mL (p < 0.01) and pro-inflammatory cytokines such as IL-6, TNF-α, and GM-CSF by 40–60% (p < 0.01) in LPS-stimulated RAW 264.7 macrophages, without cytotoxicity up to 100 μg/mL. PCE also downregulated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and upregulated heme oxygenase-1 (HO-1) expression by approximately 2-fold at 100 μg/mL (p < 0.05). Mechanistically, these effects were associated with the inhibition of IκBα phosphorylation/degradation, IKKα/β phosphorylation, and AP-1 activation via the suppression of JNK and ERK signaling pathways, as well as the inhibition of STAT1/3 phosphorylation. Collectively, our findings suggest that PCE exerts anti-inflammatory effects by modulating the IκB, AP-1, and STAT1/3 signaling pathways, thereby suppressing inflammatory mediator production and enhancing antioxidant defense mechanisms in LPS-treated macrophages. Full article

This study evaluated the inhibitory activity of quercetin at sub-inhibitory concentrations on quorum-sensing (QS) molecules in vitro and the effects of dietary supplementation with quercetin (for 24 consecutive days) on enterotoxigenic Escherichia coli (ETEC)-induced inflammatory and oxidative stress responses in weaned piglets. The piglets were fed one of three diets: the basal diet (Con), ETEC challenge (K88) after the basal diet, or ETEC challenge (quercetin + K88) after the basal diet supplemented with 0.2% quercetin. In vitro experiments revealed that 5 mg/mL quercetin exhibited the strongest QS inhibitory activity and reduced pigment production by Chromobacterium violaceum ATCC12472 by 67.70%. In vivo experiments revealed that quercetin + K88 significantly increased immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG) levels in the serum, ileum mucosa, and colon mucosa; increased glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) levels in the serum, liver, and colon mucosa; and decreased cluster of differentiation 3 (CD3) and cluster of differentiation 8 (CD8)activity in the serum compared with K88 alone. Quercetin + K88 significantly alleviated pathological damage to the liver and spleen and upregulated antioxidant genes (nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1(HO-1), CAT, SOD, and glutathione s-transferase (GST)). Inducible nitric oxide synthase (iNOS) and kelch-like ech-associated protein 1 (Keap1), which cause oxidative damage to the liver and spleen, were significantly downregulated. The acetic acid content in the cecum was significantly increased, and the E. coli count and QS signal molecule autoinducer-2 (AI-2) yield were significantly reduced. In conclusion, 0.2% dietary quercetin can alleviate ETEC-induced inflammation and oxidative stress in weaned piglets. Full article

Liver fibrosis remains a critical health concern with limited therapeutic options. Kaempferol (Kae) is a natural flavonoid widely present in natural plants, yet its role in modulating gut–liver axis interactions during fibrosis is unexplored. This study investigates the hepatoprotective effects of Kae on alleviating carbon tetrachloride (CCl₄)-induced liver fibrosis, and its underlying mechanisms, focusing on oxidative stress, gut microbiota, and short-chain fatty acids (SCFAs), are revealed. A mouse model of hepatic fibrosis was built by the subcutaneous injection of CCl₄. Meanwhile, Kae was administered by gavage at doses of 25, 50, and 100 mg/kg body weight. Serum biomarkers, liver histopathology, oxidative damage markers, and nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase 1 (HO-1) signaling were analyzed. AML12 hepatocytes were pretreated with Kae or SCFAs (acetate, propionate, butyrate) before H₂O₂-induced oxidative injury. The changes in gut microbiota and the levels of SCFAs were assessed via 16S rRNA sequencing and GC-MS, respectively. Kae effectively alleviated the destruction of the liver morphology and tissue structure, reduced the infiltration of inflammatory cells, collagen deposition in the liver, and the expression of fibrotic factors, and downregulated the oxidative stress level in the liver of mice with liver fibrosis by activating the Nrf2/Keap1/HO-1 pathway (p < 0.05 or 0.01). In vitro, Kae significantly mitigated H₂O₂-induced cytotoxicity and oxidative damage (p < 0.05 or 0.01). Furthermore, Kae restored gut microbiota diversity, increased beneficial genera (e.g., Lactobacillus), and elevated both intestinal and hepatic SCFA levels (p < 0.01). The discrepant SCFA pretreatment similarly protected AML12 cells by activating Nrf2 signaling (p < 0.05 or 0.01). Our research suggests that Kae could inhibit CCl₄-induced liver fibrosis by restoring the levels of intestinal metabolite SCFAs to reduce oxidative damage. Full article

BGP-15, a poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor exerts cardioprotective effects; however, the underlying mechanisms remain unclear. Therefore, our study aimed to investigate the effects of BGP-15 on the imatinib (Imtb)-induced cardiac inflammation at the biochemical level. Male rats were divided to control, Imtb-treated (60 mg/kg/day for 14 days), and Imtb + BGP-15-treated animals. In this group Imtb was co-administered with BGP-15 at the dose of 10 mg/kg/day. At the end of the experiment, nuclear factor-kappa B/p65 (NF-κB/p65), nuclear transcription factor erythroid-2 related factor (Nrf2), heme oxygenase-1 (HO-1), high mobility group box 1 (HMGB1), and myeloperoxidase (MPO) were measured by Western blot. Chemokine and interleukins (ILs) were determined by Legendplex. Additionally, cardiac specific changes were visualized by immunohistochemistry. We demonstrated that Imtb increased NF-κB/p65, IL-6, IL-1β, IL-18, MCP-1, HMGB1, as well as the expression and activity of MPO. Conversely, the expressions of antioxidant Nrf2 and HO-1 were decreased. Administration of BGP-15 effectively mitigated these inflammatory alterations by significantly reducing pro-inflammatory cytokines and MPO activity, while simultaneously restoring and enhancing the levels of Nrf2 and HO-1, thereby promoting antioxidant defenses. The immunohistochemical staining further supported these biochemical changes. Our study provides new and comprehensive biochemical insight for managing Imtb-induced inflammatory responses via BGP-15-induced PARP1 inhibition. Full article

Oxidative stress, which contributes to neuronal cell dysfunction, is a critical factor in the pathogenesis of neurodegenerative diseases. Anthocyanins and α-tocopherol have shown potential in mitigating oxidative damage, and their combination may provide synergistic effects. This study investigated the combined effects of a cyanidin-3-glucoside (C3G)-enriched extract derived from Oryza sativa L. cv. RD83 and α-tocopherol (C3GE) on hydrogen peroxide (H₂O₂)-induced oxidative stress in SH-SY5Y cells. Cells were treated with C3GE during exposure to 200 µM H₂O₂. Cell viability, intracellular reactive oxygen species (ROS), and oxidative stress biomarkers, including the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as malondialdehyde (MDA) levels, were evaluated. Protein expression levels of histone deacetylase 1 (HDAC1), nuclear factor erythroid 2 related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and SOD1 were also assessed. The combined treatment markedly improved cell viability, suppressed ROS accumulation, enhanced antioxidant enzyme activities, and significantly reduced MDA levels, suggesting effective protection against oxidative damage. Mechanistically, C3GE downregulated HDAC1 expression while upregulating Nrf2, HO-1, and SOD1, indicating that its antioxidant and neuroprotective effects are mediated, at least in part, through epigenetic modulation of redox-related signaling pathways. These results demonstrate a synergistic interaction between C3G and α-tocopherol that enhances cellular antioxidant defenses and supports redox homeostasis. In conclusion, the C3GE combination offers a promising therapeutic approach for preventing or attenuating oxidative stress-induced neuronal injury, with potential relevance for the treatment of neurodegenerative disorders. Full article

Background/Objectives: 5-Aminolevulinic acid (5-ALA) is a biosynthetic precursor of heme that induces heme oxygenase-1 (HO-1). Therapeutic induction of HO-1 has shown effectiveness in various autoimmune disease models, including type 1 diabetes (T1D). However, the efficacy of 5-ALA as an HO-1 inducer in T1D models remains unexplored. This study aimed to investigate the therapeutic efficacy of oral 5-ALA administration in preventing autoimmune diabetes development in nonobese diabetic (NOD) mice. Methods: We evaluated diabetes incidence, levels of insulin autoantibody, and severity of insulitis in 5-ALA-treated and control NOD mice. HO-1 expression of dendritic cells in the pancreatic islets and spleen of 5-ALA-treated NOD mice was measured. The IFN-γ/IL-17 of islet-infiltrating T cells and IL-10/IL-12 productions of dendritic cells in the spleen of 5-ALA-treated NOD mice were assessed. We stimulated islet antigen-specific CD4⁺ T cells with islet antigen-pulsed dendritic cells in the presence of 5-ALA and examined the proliferation of the T cells. Finally, we adoptively transferred islet antigen-specific CD4⁺ T cells into 5-ALA-treated, immunodeficient NOD-Rag1 knockout mice, and diabetes incidence in recipients was determined. Results: Oral 5-ALA treatment did not significantly impact diabetes incidence, levels of insulin autoantibody, and insulitis. No significant difference was observed in HO-1 expression in dendritic cells and cytokine production of T cells and dendritic cells. Similarly, there was no significant difference in the proliferation of islet antigen-specific CD4⁺ T cells in vitro and diabetes induction in transfer experiments. Conclusions: Oral administration of 5-ALA has a limited effect on suppressing the development of autoimmune diabetes in NOD mice. Full article

Local anesthetics (LAs) are frequently administered via peritendinous ultrasound-guided injections for diagnostic and therapeutic purposes. Since in vitro studies have demonstrated LAs’ tenotoxic effects, raising concerns about their safety in infiltrative treatments, and since lidocaine (LD) emerged as one of the most cytotoxic LAs, we analyzed apoptosis, oxidative stress, and collagen turnover pathways in human tenocytes treated with LD, as well as the possible protection from LD-induced injury elicited by antioxidant ascorbic acid (AA). Tenocytes from gluteal tendons were treated with 0.2 and 1 mg/mL LD, or left untreated (CT), and treated with 50 μg/mL or 250 μg/mL AA. Nuclear morphology, cytochrome c expression, and caspase 3 activation were analyzed to study the effect of LD on apoptosis. Heme Oxygenase 1 (HO-1) mRNA and genes and proteins involved in collagen turnover were investigated using molecular approaches. Our results show that 0.2 and 1 mg/mL LD did not induce apoptosis and did not modify collagen synthesis and maturation. Conversely, increased collagen degradation was observed, and AA was not protective against oxidative stress induction in the presence of LD. Our findings suggest that LD does not affect the cell viability of tenocytes and that peritendinous LD injections are safe in this regard. LD-associated collagen degradation and the AA buffer effect are still debatable. Overall, our study contributes to clarifying the effect of LD on tenocytes’ viability and ECM homeostasis and provides new additional information useful for the safe clinical application of this drug and for further analysis. Full article

The normal development of ovarian follicles, characterized by oocyte growth and granulosa cell proliferation, is essential for maintaining female fertility. Elevated oxidative stress, resulting from various in vivo and in vitro factors, significantly impairs follicular development, ovulation, and overall female fertility. Swertiamarin, a naturally occurring iridoid terpenoid compound, exhibits multiple beneficial properties, including anti-hyperlipidemic, anti-diabetic, and antioxidant effects. This study investigates the impact of Swertiamarin on follicular development impairment induced by oxidative stress, using the commonly applied oxidant 3-nitrophthalic acid (3-NPA) in a murine model. Our findings indicate that Swertiamarin administration mitigates the adverse effects of 3-NPA on follicular development and ovulation. Further analyses reveal that Swertiamarin treatment partially enhances granulosa cell proliferation and inhibits apoptosis under oxidative stress in vivo and in vitro. Moreover, Swertiamarin reduces oxidative stress in ovaries and granulosa cells exposed to 3-NPA. The expression levels of key members of the NRF2/HO-1 signaling pathway, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (Ho-1), and superoxide dismutase 1 (Sod1), were upregulated following Swertiamarin supplementation in 3-NPA-treated ovaries and granulosa cells. In conclusion, the present study demonstrates that Swertiamarin can partially restore defective follicular development induced by oxidative stress via modulating the NRF2/HO-1 pathway in granulosa cells. These findings provide novel insights into the potential application of Swertiamarin in enhancing female reproductive health and offer a promising strategy for addressing reproductive damage caused by oxidative stress. Full article

Dengue virus (DENV) infection is strongly associated with dengue hemorrhagic fever and dengue shock syndrome, both of which carry mortality risks. Addressing the urgent need for effective dengue therapeutics, we identified sofalcone, a gastroprotective agent with antioxidant and anti-inflammatory properties, as a potential inhibitor of DENV replication. Sofalcone demonstrated efficacy against all four DENV serotypes, with the dose inhibiting 50% (IC50) value of 28.1 ± 0.42 μM against viral replication of DENV serotype 2, without significant cytotoxicity. Additionally, sofalcone significantly improved survival rates and reduced viral titers in DENV-infected ICR-suckling mice. Mechanistically, sofalcone induced heme oxygenase-1 (HO-1) expression via the nuclear factor-erythroid 2-reated factor 2 (Nrf2) pathway, which in turn suppressed viral protease activity and restored antiviral interferon (IFN) responses. This included dose-dependent stimulation of IFN downstream antiviral genes such as 2′-5′-oligoadenylate synthetase 1 (OAS1), OAS2, and OAS3. Given its established clinical use as an anti-gastric ulcer drug, sofalcone offers promising potential for rapid application in treating DENV infection. Full article

Elsholtzia blanda (Benth.) Benth. (EBB) is a traditional plant in Nepal with bioactive properties, including antioxidant, cytotoxic, and antitumor activities. In this study, a methanol EBB extract was tested to evaluate the anti-inflammatory effect against lipopolysaccharide (LPS)-induced microglial (BV2) cells. EBB effectively suppressed LPS-induced nitric oxide production and inhibited the secretion of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. In LPS-stimulated BV2 cells, EBB significantly inhibited inducible nitric oxide synthase (iNOS), TNF-α, IL-6, IL-1β, IL-8, IL-18, and IL-10 mRNA expression in a concentration-dependent manner. In particular, EBB significantly reduced the protein expression of iNOS and cyclooxygenase-2, which were upregulated by LPS. Further, EBB could alleviate the inflammatory response in microglia by suppressing the phosphorylation of mitogen-activated protein kinases. EBB also attenuated LPS-induced reactive oxygen species (ROS) in BV2 cells. In addition, EBB enhanced heme oxygenase-1 (HO-1) protein and mRNA expression. The present results show that an EBB extract could effectively suppress the neuroinflammatory response induced by LPS in BV2 cells. Accordingly, an EBB extract is a promising preventive agent against diseases involving neuroinflammatory responses. Full article