Search Results (109)

Neurodegenerative diseases (NDs) pose a significant health burden globally, and this burden is increasing with an ageing population. Despite this challenge, restorative treatments for NDs remain elusive. In these conditions, the brain is vulnerable to oxidative stress and inflammation due to a deficiency or reduction in antioxidative enzymes. Oxidative stress and inflammation damage neuronal cells, leading to neurodegeneration. Various studies have explored the neuroprotective effects of flavonoids in different in vitro and animal models, primarily due to their antioxidative and anti-inflammatory properties. Crude extracts and active metabolites of Semecarpus anacardium L. have shown potential in reversing dysregulated oxidative stress and neuroinflammation. S. anacardium L. extract (SAE) and its phytocomponents, such as butein, anacardic acid, and amentoflavone, have been experimentally demonstrated to modulate oxidative stress and neuroinflammation through coordinated activation of Nrf2-mediated antioxidant pathways and suppression of NF-ĸB-driven inflammatory signaling. At a molecular level, flavonoids from SAE induce the expression of p38 MAPK and Nrf2, as well as antioxidant enzymes. Furthermore, inflammatory genes such as NF-ĸB, MAPK, AP-1, iNOS, and COX-2 are suppressed following treatment with SAE. NF-ĸB inhibition leads to neuroprotection via inhibiting the function of caspase-3 and apoptosis. Overall, this review discusses the protective role of SAE and its phytocomponents in mitigating neuronal oxidative stress, inflammation, and degeneration. Furthermore, this review highlights the translational potential of SAE and its phytocomponents as complementary therapeutic candidates for neurodegenerative disorders. However, variability in extract composition and limited pharmacokinetic characterization remain key barriers to clinical translation. Full article

The abnormal activation of the Nlrp3 (Nod-like receptor pyrin 3) inflammasome, in response to oxidative stress or impaired antioxidant defense, is linked to aging-related diseases. Previously, we have shown that Peroxiredoxin (Prdx)6 deficiency triggers reactive oxygen species (ROS)-dependent activation of Kruppel-like factor (Klf)9/Nlrp3 inflammasome in aging lens epithelial cells (LECs). Herein, we test the therapeutic efficacy of Prdx6 delivery in abating the oxidative stress-induced aberrant activation of the Klf9/NF-ĸB/Nlrp3 pathway and subsequent pyroptotic cell death in LECs and Prdx6-deficient (Prdx6^−/−) LECs. Similar to aged LECs, Prdx6-depleted LECs exhibited activation of Nlrp3 inflammasome components—including ASC, Caspase-1, IL-1β, IL-18, GSDMD—and displayed heightened sensitivity to H₂O₂/UVB-induced oxidative damage. The delivery of TAT-HA-Prdx6 or the overexpression of Prdx6 in Prdx6^−/− mLECs significantly suppressed the aberrant activation of these inflammatory components and restored redox balance by eliminating ROS levels during oxidative stress. Similarly, TAT-HA-Prdx6 effectively internalized into SRA-hLECs and suppressed the H₂O₂- and/or UVB-induced upregulation of Nlrp3 and its components. Furthermore, the oxidative stress or Prdx6 deficiency led to increased Nlrp3 promoter activity and NF-ĸB activation, accompanied by decreased cytosolic IĸBα and increased phosphorylation of IĸBα; these alterations were reversed by Prdx6 overexpression. The elevated Klf9 transcription observed in aging and Prdx6^−/− mLECs or under oxidative stress was also inhibited by Prdx6 delivery. Additionally, Prdx6^−/− mLECs and aging LECs displayed increased TXNIP and reduced TRX levels, which were normalized by Prdx6 restoration. Collectively, this study provides the first evidence that the loss of Prdx6 drives aberrant activation of Klf9/NF-ĸB/Nlrp3 inflammasome axis, leading to pyroptotic cell death. Prdx6 delivery represents a promising therapeutic strategy to rescue cells from pyroptosis (oxidative stress-induced inflammatory cell death). Full article

Background/Objectives: During oral and gut microbiota dysbiosis, lipopolysaccharides (LPSs) of major bacteria, such as Porphyromonas gingivalis and Escherichia coli, translocate into the bloodstream and lead to endotoxemia. Cerebral endothelial cells are targets of LPSs that may aggravate inflammation and cerebrovascular disorders. This study aimed to evaluate the protective role of the characterized polyphenol-rich extract of the Dodonaea viscosa medicinal plant and a predominant component, epicatechin, on murine bEnd.3 cerebral endothelial cells exposed to P. gingivalis or E. coli LPSs. Methods: The effects of LPSs and polyphenols were assessed on cell viability (MTT, trypan blue exclusion assays) and inflammatory, redox, vasoactive and permeability markers (RT-qPCR, Western blot, ELISA, FITC-Dextran test). Results: The data show that LPSs activated the TLR2-4/NFĸB signaling pathway and promoted IL-1β, IL-6, TNF-α, MCP-1, COX-2, iNOS, ICAM-1, VCAM-1 and E-selectin production without affecting cell viability. LPSs induced oxidative stress by elevating intracellular ROS levels and altering the expression of genes encoding NOX2-4, SOD, catalase, GPx, HO-1 and Nrf2. LPSs imbalanced NO vasodilator and ET-1 vasoconstrictor levels and reduced the production of occludin and ZO-1 tight junction proteins. Meanwhile, LPSs raised the permeability to FITC-Dextran, suggesting cell integrity loss. The extent of endothelial dysfunction caused by LPSs depended on their bacterial origin. Importantly, plant polyphenols and epicatechin exerted anti-inflammatory and antioxidant effects, and attenuated LPSs’ deleterious action on vasoactive and permeability markers. Conclusions: This study shows that polyphenols limit cerebral endothelial cell dysfunction under inflammatory conditions mediated by LPSs, highlighting their therapeutic potential in protecting brain homeostasis during oral and gut microbiota dysbiosis. Full article

Disuse-induced muscle atrophy (DMA), commonly resulting from immobilization, is driven by chronic inflammation and oxidative stress, which disrupts the balance between protein synthesis and degradation. Quinic acid (QA), a natural compound with known antioxidant and anti-inflammatory properties, was investigated for its potential to counteract muscle atrophy. Using a DMA-induced immobilization model in male C57BL/6N (8 weeks) mice, we found that oral QA administration significantly restored the weight and cross-sectional area of atrophic muscles and improved muscle function, as measured by grip strength and treadmill performance. QA also reduced the expression of pro-inflammatory cytokines (Tnf, Il6, and Myostatin) and E3 ubiquitin ligases (Trim63 and Fbxo32), while increasing antioxidant enzyme levels and serum IL-15 in DMA. In tumor necrosis factor-α-stimulated L6 myotubes, QA reversed inflammation- and oxidative stress-induced gene changes, suppressed NF-ĸB activation, and downregulated protein degradation pathways mediated by FoxO3α. Furthermore, QA restored the expression of myogenesis-related genes and reactivated PI3K/Akt and mTOR/p70S6K/4EBP1 signaling pathways, enhancing protein synthesis. Collectively, our findings demonstrate that QA mitigates immobilization-induced muscle atrophy by modulating inflammation, oxidative stress, and key anabolic and catabolic signaling pathways. These results suggest that QA is a promising functional compound for preserving skeletal muscle health under conditions of disuse. Full article

Inflammation, oxidative stress, and androgen activity are key features in benign prostate hyperplasia (BPH). Risks associated with the long-term use of 5α-reductase inhibitors have led to the search for alternative therapies, including food supplements. This study investigates the effectiveness of the combination of pollen extracts, namely Graminex^®G96^® (G) and Teupol 25P (T), towards oxidative stress and inflammation on human macrophages and benign prostate hyperplasia cells (BPH-1), both of which are LPS stimulated. The Nrf2-dependent antioxidant intracellular cascade as well as the NF-ĸB-driven inflammatory cascades were analyzed. The anti-proliferative effect of G and T, alone and in association, were evaluated on prostatic adenocarcinoma cells (PC-3) and BPH-1 cells. Finally, the inhibitory activity of GT on 5α-reductase was investigated in PC-3 cells by measuring epiandrosterone amounts, with the 5α-reductase inhibitor finasteride administered for comparison. All experiments were conducted in triplicate; data are presented as mean values ± standard deviations. Statistical analysis was performed using one-way analysis of variance. Our work demonstrates that GT promotes Nrf2-dependent antioxidant responses and counteracts the NF-ĸB-driven pathway in macrophages. GT is effective in counteracting the expression of pro-inflammatory cytokines and the generation of reactive oxygen species by promoting HO-1-dependent antioxidant responses in BPH-1 cells. GT reduces PC-3 and BPH-1 proliferation when associated with finasteride through a statistically significant inhibition of 5α-reductase activity. Data obtained in vitro and in silico demonstrate the potential efficacy of a multitargeted approach in the treatment of BPH. Full article

Increasing evidence reveals that the deregulation of cellular antioxidant response with advancing age, resulting in the continuing amplification of oxidative stress-induced inflammatory response, is a pre-eminent cause for the onset of aging-related disease states, including blinding diseases. However, several safeguards, like an antioxidant defense system, are genetically in place to maintain redox homeostasis. Nonetheless, if the homeostatic capacity of such systems fails (like in aging), an inflammatory pathway elicited by excessive oxidative stress-evoked aberrant NLRP3 (NOD, LRR- and pyrin domain-containing protein 3) inflammasome activation can become pathogenic and lead to disease states. Among all known inflammasomes, NLRP3 is the most studied and acts as an intracellular sensor to detect danger(s). Upon activation, NLRP3 recruits apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and facilitates the recruitment of activated Caspase-1 (Cas-1), which results in the release of inflammatory cytokines, IL-1β and IL-18 and the activation of GasderminD, an executor of pyroptosis. NLRP3 inflammasome is tightly regulated in favor of cell health. However, when and how the activation of NLRP3 and its inflammatory components goes awry, leading to cellular derangement, and what regulatory factors are involved in the normal physiological and aging/oxidative conditions will be included in this review. Also, we address the latest findings to highlight the connection between oxidative stress, antioxidants, and NLRP3 activation as this begets aging diseases and explore the cellular pathways that are in place to regulate oxidative-induced inflammations and the pathobiological consequences of dysregulated inflammatory responses and vice versa. Full article

Infections and chronic inflammation play a crucial role in the development of cancer. During inflammatory processes, reactive oxygen and nitrogen species are generated by both inflammatory and epithelial cells, leading to the induction of oxidative and nitrative DNA damage, such as the formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-nitroguanine (8-nitroG). These DNA alterations can trigger mutations, which are believed to contribute to cancer formation driven by inflammation. The authors observed the generation of 8-nitroG through iNOS expression in human and animal tissues under inflammatory conditions, where cancer is likely to develop. 8-NitroG serves as a predictive and prognostic indicator for cancers linked to inflammation. Inflammation causes DNA damage, and the subsequent DNA damage response can create an inflammatory environment marked by hypoxia, with HMGB1 being a key factor. The interplay between HIF-1α, NF-ĸB, and HMGB1 sustains DNA damage and the accumulation of mutations, driving cancer progression and worsening prognosis. 8-NitroG is involved not only in the onset and advancement of cancer but also in its progression and conversion. Herein, the authors propose a vicious cycle of DNA damage and inflammation in cancer development (initiation and promotion) and progression, including conversion, via HMGB1. Full article

Diabetes-related osteoporosis has been known to be a consequence of oxidative stress caused by excessive reactive oxygen species (ROS) production in the tissues. Despite the increase in the number of individuals with diabetes-related osteoporosis year on year, there is still no effective drug that does not induce adverse side effects. Glabridin, which exerts hypoglycemic effects and possesses antioxidant properties, may have beneficial effects in the treatment of diabetes-related osteoporosis. In this study, we aimed to investigate the preventive effects of glabridin in counteracting oxidative stress-induced bone loss and its underlying mechanisms. A diabetic rat model was established by a single intraperitoneal injection of streptozotocin into male Wistar rats. The diabetic rats were orally gavaged daily with glabridin or glyburide for 8 weeks. The presence of diabetes significantly decreased the rats’ tibia length, bone thickness, epiphyseal plate length, and collagen deposition compared to the control rats; in comparison, treatment with glabridin for 8 weeks significantly reversed these effects. In our in vitro study, the treatment of MC3T3-E1 preosteoblasts with glabridin up to 7.5 µM for 48 h showed no cytotoxic effect. However, pretreatment with glabridin significantly prevented oxidative stress-induced inhibition of cell proliferation. In addition, glabridin significantly diminished ROS production, restored antioxidant enzyme activity, and mitigated cellular apoptosis. These effects occurred by stimulating the phosphorylation of Akt, GSK-3β, and P65 NF-ĸB proteins. The above results show that glabridin alleviated oxidative stress-induced bone loss and osteoblast cell apoptosis by modulating the expression of the Akt/NF-ĸB and Akt/GSK-3β pathways. Full article

Background: Middle-aged and elderly individuals may experience detrimental health effects due to ischemic stroke (IS). The inflammatory response triggered during IS exacerbates neuronal damage, becoming a barrier to effective IS treatment and leading to poor patient prognosis. Nevertheless, the specific role of microglia in the inflammatory response triggered by IS remains mostly unclear. The primary target of this investigation is to study the neuroinflammatory impact of lycorine (LYC) during the IS process. Our objective is to evaluate whether LYC deploys its anti-inflammatory effect with modulation of the NF-κB signaling pathway, thereby reducing IS symptoms. Methods: In this research, BV-2 cells were pre-treated with LYC for 24 h before LPS was added to induce inflammation. Results: It has been discovered that LYC suppresses BV-2 cell polarization and reduces the levels of inflammatory cytokines (IL-1β, IL-6, TNF-α), showing its potential anti-inflammatory effects in vitro. Furthermore, IκBα and p65 play crucial roles in regulating the inflammatory response within the NF-κB signaling pathway. Mechanistic exploration indicates that LYC can activate the expression of IκBα in LPS-induced BV-2 cells. IκBα inhibits NF-κB by binding to its p65 subunit, sequestering it in the cytoplasm and preventing its translocation to the nucleus, thereby inhibiting inflammation. Additionally, p65 is a key transcription factor for pro-inflammatory genes, and its downregulation leads to decreased transcriptional activity of these genes. The combined effect of increased IκBα and decreased p65 results in significantly reduced NF-κB activity, thereby alleviating the inflammatory response. Meanwhile, in vivo studies indicate that LYC pre-treatment significantly reduces the infarct size caused by middle cerebral artery occlusion (MCAO) in rats. The assessment of cerebral infarction volume, neurological scores, brain edema rate and inflammation levels in MCAO rats pre-treated with LYC indicates positive therapeutic effects. Conclusions: In summary, our research indicates that LYC pre-treatment has significant anti-inflammatory effects by attenuating inflammation levels through NF-κB inhibition, which contributes to potential therapeutic benefits in ischemic stroke (IS) and may improve disease prognosis. LYC may serve as an adjunctive clinical pre-treatment for IS, which has to be confirmed by clinical trials in the future. Full article

Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs’ expression, termed miRNA sponging. CircRNAs promote tumorigenesis/lymphomagenesis by competitively binding to miRNAs at miRNA binding sites. In diffuse large B-cell lymphoma (DLBCL), several circRNAs have been identified and their expression is related to both progression and response to therapy. DLBCL is the most prevalent and aggressive subtype of B-cell lymphomas and accounts for about 25% to 30% of all non-Hodgkin lymphomas. DLBCL displays great heterogeneity concerning histopathology, biology, and genetics. Patients who have relapsed or have refractory disease after first-line therapy have a very poor prognosis, demonstrating an important unmet need for new treatment options. As more circRNAs are identified in the future, we will better understand their biological roles and potential use in treating cancer, including DLBCL. For example, circAmotl1 promotes nuclear translocation of MYC and upregulation of translational targets of MYC, thus enhancing lymphomagenesis. Another example is circAPC, which is significantly downregulated in DLBCL and correlates with disease aggressiveness and poor prognosis. CircAPC increases expression of the host gene adenomatous polyposis coli (APC), and in doing so inactivates the canonical Wnt/β-catenin signaling and restrains DLBCL growth. MiRNAs belong to the non-coding regulatory molecules that significantly contribute to lymphomagenesis through their target mRNAs. In DLBCL, among the highly expressed miRNAs, are miR-155-5p and miR-21-5p, which regulate NF-ĸB and PI3K/AKT signaling pathways. The aim of this review is to describe the function and mechanism of regulation of circRNAs on miRNAs’ expression in DLBCL. This will help us to better understand the regulatory network of circRNA/miRNA/mRNA, and to propose novel therapeutic targets to treat DLBCL. Full article

Candida utilis (CUM) possesses various biological effects, including anti-inflammatory, intestinal microbiota regulatory, and immunomodulatory activities. However, there has been little exploration regarding the effects of CUM on ulcerative colitis (UC). Therefore, this study aimed to investigate the beneficial effects of CUM on alleviating dextran sulfate sodium (DSS)-induced UC in mice and to explore the potential underlying mechanisms. Here, the effect of CUM on UC was analyzed using a DSS-induced colitis mouse model (n = 9), the results of which indicated a decrease in disease activity index (DAI) in DSS-induced UC mice. Furthermore, CUM alleviated colon shortening, minimized intestinal tissue damage, and preserved intestinal tight junction proteins (Claudin-3, Occludin, and ZO-1). CUM reduced the level of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), inhibited the activation of the NF-ĸB, MAPK and PPARγ signaling pathways, and decreased the level of oxidative mediators (MPO, SOD and MDA) in the colon of UC mice. Additionally, it mitigated the dysbiosis of intestinal microbiota in UC mice by increasing the abundance of Prevotellaceae and Lactobacillus while decreasing the abundance of Bacteroidaceae and Enterobacteriaceae. CUM alleviated the decrease in short-chain fatty acids (SCFAs) content in the colon of UC mice. The above results provide a scientific basis for CUM, as a natural supplement, to restore the balance of the gut inflammatory microbiota and promote gut health. Full article

Obesity is a risk factor for chronic kidney disease. The expansion of adipose tissues in obesity induces insulin resistance and low-grade systemic inflammation, promoting kidney damage. Our previous studies have demonstrated that agomelatine (AGOM) exerts renoprotective effects in experimental models of obesity and insulin resistance through various mechanisms, including the attenuation of ER stress and oxidative stress. This study aimed to further explore the effects of agomelatine on renal inflammation, insulin signaling, and necroptosis in obese, insulin-resistant rats. Obesity was induced in rats with a high-fat diet for 16 weeks, followed by 4 weeks of treatment with 20 mg kg⁻¹ day⁻¹ of AGOM or 10 mg kg⁻¹ day⁻¹ of pioglitazone (PIO). The results showed that insulin resistance was improved after treatment with AGOM and PIO, as demonstrated by the reduction in fasting plasma glucose, insulin, and HOMA-IR. Both treatments restored the levels of renal insulin signaling proteins. Moreover, AGOM inhibited TNFα, TNFR1, NF-ĸB, COX2, and IL1β, which attenuated the necroptosis-related proteins RIPK3 and MLKL. AGOM also prevented kidney DNA fragmentation, as detected by the TUNEL assay. In an obese condition, the level of the tight junction protein claudin-1 (CLDN1) was enhanced after being treated with AGOM. In conclusion, the novel mechanisms associated with AGOM and involved in limiting kidney injury were the inhibition of the TNFα/NF-ĸB/p-RIPK3 pathway and a reduction in inflammation and necroptosis. This suggested that AGOM could be an effective treatment for inhibiting kidney dysfunction in cases of obesity and insulin resistance. These findings open new avenues for the management of renal dysfunction, with implications for personalized medicine. Full article

Vitamin D (VD), a crucial micronutrient, regulates bone health and immune responses. Recent studies suggest that VD may confer protective effects against chronic inflammatory diseases. Additionally, plant-based peptides can show biological activities. Furthermore, the supplementation of protein hydrolysates with VD could potentially enhance the bioactivity of peptides, leading to synergistic effects. In this study, THP-1 cells were exposed to low concentrations of Lipopolysaccharide (LPS) to induce inflammation, followed by treatment with vitamin D at different concentrations (10, 25, or 50 nM) or a chickpea protein hydrolysate (“H30BIO”) supplemented with VD. The cytotoxicity of VD was evaluated using viability assay to confirm its safety. The cytokine secretion of TNF-α, IL-1β, and IL6 was assessed in the cell supernatant, and the gene expression of TNF-α, IL-1β, IL6, IL8, CASP-1, COX2, NRF2, NF-ĸB, NLRP3, CCL2, CCR2, IP10, IL10, and RANTES was quantified by qRT-PCR. Treatment with VD alone significantly decreased the expression of the pro-inflammatory genes TNF-α and IL6, as well as their corresponding cytokine levels in the supernatants. While IL-1β gene expression remained unchanged, a reduction in its cytokine release was observed upon VD treatment. No dose-dependent effects were observed. Interestingly, the combination of VD with H30BIO led to an increase in TNF-α expression and secretion in contrast with the LPS control, coupled with a decrease in IL-1β levels. Additionally, genes such as IP10, NF-κB, CCL2, COX2, NRF2, and CASP-1 exhibited notable modulation, suggesting that the combination treatment primarily downregulates NF-κB-related gene activity. This study demonstrates a synergistic interaction between VD and H30BIO, suggesting that this combination may enhance pathways involving TNF-α, potentially aiding in the resolution and modulation of inflammation through adaptive processes. These findings open new avenues for research into the therapeutic applications of enriched protein hydrolysates with VD to manage low-grade inflammatory-related conditions. Full article

Gestational diabetes mellitus is characterised by an insufficient insulin response to hyperglycaemia and the development of insulin resistance. This state has adverse effects on the health outcomes of the mother and child. Existing hyperglycaemia triggers a state of inflammation that involves several tissues, including the placenta. In this study, we analysed the putative pathomechanism of GDM, with special emphasis on the role of chronic, sterile, pro-inflammatory pathways. The expression and regulation of the elements of IL-1β and Toll-like receptor (TLR) pathways in GDM maternal blood plasma, healthy placental explants and a choriocarcinoma cell line (BeWo cell line) stimulated with pro-inflammatory factors was evaluated. Our results indicate elevated expression of the IL-1β and TLR pathways in GDM patients. After stimulation with IL-1β or LPS, the placental explants and BeWo cell line showed increased production of pro-inflammatory IL-6, TNFa and IL-1β together with increased expression of the elements of the signalling pathways. The application of selected inhibitors of NF-ĸB, MAPK and recombinant interleukin 1 receptor antagonist (IL1RA) proved the key involvement of the IL-1β pathway and TLRs in the pathogenesis of GDM. Our results show the possible existence of loops of autocrine stimulation and a possible inflammatory pathomechanism in placentas affected by GDM. Full article

Cystathionine gamma-lyase (CSE) and TNF-α are now recognized as key regulators of intestinal homeostasis, inflammation, and wound healing. In colonic epithelial cells, both molecules have been shown to influence a variety of biological processes, but the specific interactions between intracellular signaling pathways regulated by CSE and TNF-α are poorly understood. In the present study, we investigated these interactions in normal colonocytes and an organoid model of the healthy human colon using CSE-specific pharmacological inhibitors and siRNA-mediated transient gene silencing in analytical and functional assays in vitro. We demonstrated that CSE and TNF-α mutually regulated each other’s functions in colonic epithelial cells. TNF-α treatment stimulated CSE activity within minutes and upregulated CSE expression after 24 h, increasing endogenous CSE-derived H₂S production. In turn, CSE activity promoted TNF-α-induced NF-ĸB and ERK1/2 activation but did not affect the p38 MAPK signaling pathway. Inhibition of CSE activity completely abolished the TNF-α-induced increase in transepithelial permeability and wound healing. Our data suggest that CSE activity may be essential for effective TNF-α-mediated intestinal injury response. Furthermore, CSE regulation of TNF-α-controlled intracellular signaling pathways could provide new therapeutic targets in diseases of the colon associated with impaired epithelial wound healing. Full article