Search Results (474)

We investigated the role of the intermediate-conductance, Ca²⁺-activated K⁺ channel K_Ca3.1 and volume-regulatory anion channel LRRC8A in regulating C-C motif chemokine ligand 2 (CCL2) expression in THP-1-differentiated M₂ macrophages (M₂-MACs), which serve as a useful model for studying tumor-associated macrophages (TAMs). CCL2 is a potent chemoattractant involved in the recruitment of immunosuppressive cells and its expression is regulated through intracellular signaling pathways such as ERK, JNK, and Nrf2 in various types of cells including macrophages. The transcriptional expression of CCL2 was suppressed in M₂-MACs following treatment with a K_Ca3.1 activator or an LRRC8A inhibitor via distinct signaling pathways: ERK–CREB2 and JNK–c-Jun pathways for K_Ca3.1, and the NOX2–Nrf2–CEBPB pathway for LRRC8A. Under in vitro conditions mimicking the elevated extracellular K⁺ concentration ([K⁺]_e) characteristic of the tumor microenvironment (TME), CCL2 expression was markedly upregulated, and this increase was reversed by treatment with them in M₂-MACs. Additionally, the WNK1–AMPK pathway was, at least in part, involved in the high [K⁺]_e-induced upregulation of CCL2. Collectively, modulating K_Ca3.1 and LRRC8A activities offers a promising strategy to suppress CCL2 secretion in TAMs, potentially limiting the CCL2-induced infiltration of immunosuppressive cells (TAMs, T_regs, and MDSCs) in the TME. Full article

Ischemic stroke is a serious disease that frequently occurs in the elderly and is characterized by a complex pathophysiology and a limited number of effective therapeutic agents. Salvianolic acid A (SAL-A) is a natural product derived from the rhizome of Salvia miltiorrhiza, which possesses diverse pharmacological activities. This study aims to investigate the effect and mechanisms of SAL-A in inhibiting ferroptosis to improve ischemic stroke. Brain injury, oxidative stress and ferroptosis-related analysis were performed to evaluate the effect of SAL-A on ischemic stroke in photochemical induction of stroke (PTS) in mice. Lipid peroxidation levels, antioxidant protein levels, tissue iron content, nuclear factor erythroid 2-related factor 2 (Nrf2), and mitochondrial morphology changes were detected to explore its mechanism. SAL-A significantly attenuated brain injury, reduced malondialdehyde (MDA) and long-chain acyl-CoA synthase 4 (ACSL4) levels. In addition, SAL-A also amplified the antioxidative properties of glutathione (GSH) when under glutathione peroxidase 4 (GPX4), and the reduction in ferrous ion levels. In vitro, brain microvascular endothelial cells (b.End.3) exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) were used to investigate whether the anti-stroke mechanism of SAL-A is related to Nrf2. Following OGD/R, ML385 (Nrf2 inhibitor) prevents SAL-A from inhibiting oxidative stress, ferroptosis, and mitochondrial dysfunction in b.End.3 cells. In conclusion, SAL-A inhibits ferroptosis to ameliorate ischemic brain injury, and this effect is mediated through Nrf2. Full article

Oxysterols such as 7-ketocholesterol (7KCh) contribute to the pathogenesis of autoimmune and chronic inflammatory diseases by inducing oxidative stress and promoting pro-inflammatory immune cell activation. Dendritic cells (DCs) play a central role in maintaining immune tolerance, and their dysregulation is a key driver of autoimmunity. Targeting DCs by using natural compounds offers a promising strategy to restore redox balance and suppress aberrant immune responses. This study investigated the immunomodulatory and antioxidant properties of Lupeol, a natural triterpenoid, in human monocyte-derived DCs exposed to 7KCh. Flow cytometry and cytokine profiling demonstrated that Lupeol preserved the immature, tolerogenic phenotype of DCs by promoting a dose-dependent increase in the anti-inflammatory cytokine IL-10. Lupeol also inhibited the 7KCh-induced upregulation of maturation markers (CD83, CD86) and suppressed the release of pro-inflammatory cytokines IL-1β and IL-12p70. Functionally, Lupeol-treated DCs directed T cell polarization toward an anti-inflammatory and regulatory profile while dampening the inflammatory responses triggered by 7KCh. This immunoregulatory effect was further supported by the decreased secretion of the pro-inflammatory cytokines IL-1β and IL-12p70 in DC culture supernatants. Mechanistic analyses using immunofluorescence showed that Lupeol alone significantly increased nuclear NRF2 levels and upregulated HO-1 expression. Western blot analysis further confirmed Lupeol’s ability to activate the KEAP1-NRF2 signaling pathway, as evidenced by increased expression of NRF2 and its downstream target, NQO1. The use of ML385, a selective NRF2 inhibitor, in ROS and cytokine assays supported the involvement of NRF2 in mediating the Lupeol antioxidant and anti-inflammatory effects in DCs. Notably, the oxidative burden induced by 7KCh limited the full activation of NRF2 signaling triggered by Lupeol. Furthermore, docking and MM/PBSA analyses revealed the specific interactions of Lupeol with the kelch domain of KEAP1. These findings suggest that Lupeol may serve as a promising orally available immunomodulatory agent capable of promoting tolerogenic DCs, offering potential applications in autoimmune and other chronic inflammatory diseases. Full article

HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis. 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

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

The current study investigates the chemical profiling, antioxidant activities, and enzyme inhibitory and cytotoxic potential of the water and methanolic extracts of different parts (flower, leaf, and bulb) of Muscari armeniacum. Chemical profiling was performed using UHPLC-MS/MS. At the same time, different in vitro assays were employed to support the results for antioxidant potential, such as DPPH, ABTS, FRAP, CUPRAC, metal chelation, and PBD, along with the measurement of total phenolic and flavonoid contents. Enzyme inhibition was investigated for cholinesterase (AChE and BChE), α-amylase, α-glucosidase, and tyrosinase enzymes. Additionally, the relative expression of NRF2, HMOX1, and YGS was evaluated by qPCR. LC-MS/MS analysis indicated the presence of some significant compounds, including apigenin, muscaroside, hyacinthacine A, B, and C, and luteolin. According to the results, the highest TPC and TFC were obtained with both extracts of the leaves, followed by the water extract (flower) and methanolic extract of the bulb. In contrast, the methanolic extract from the bulb exhibited the highest antioxidant potential using DPPH, ABTS, CUPRAC, and FRAP, followed by the extracts of leaves. In contrast, the leaf extracts had the highest values for the PBD assay and maximum chelation ability compared to other tested extracts. According to the enzyme inhibition studies, the methanolic extract from the bulb appeared to be the most potent inhibitor for all the tested enzymes, with the highest values obtained for AChE (1.96 ± 0.05), BChE (2.19 ± 0.33), α-amylase (0.56 ± 0.02), α-glucosidase (2.32 ± 0.01), and tyrosinase (57.19 ± 0.87). Interestingly, the water extract from the bulb did not inhibit most of the tested enzymes. The relative expression of NRF2 based on qPCR analysis was considerably greater in the flower methanol extract compared to the other extracts (p < 0.05). The relative expression of HMOX1 was stable in all the extracts, whereas YGS expression remained stable in all the treatments and had no statistical differences. The current results indicate that the components of M. armeniacum (leaves, flowers, and bulb) may be a useful source of natural bioactive compounds that are effective against oxidative stress-related conditions, including hyperglycemia, skin disorders, and neurodegenerative diseases. Complementary in silico approaches, including molecular docking, dynamics simulations, and transcription factor (TF) network analysis for NFE2L2, supported the experimental findings and suggested possible multi-target interactions for the selected compounds. Full article

Transcription factors (TFs) are proteins that control gene expression by binding to specific DNA sequences and are essential for cell development, differentiation, and homeostasis. Dysregulation of TFs is implicated in numerous diseases, including cancer, autoimmune disorders, and neurodegeneration. While TFs were traditionally considered “undruggable” due to their lack of well-defined binding pockets, recent advances have made it possible to modulate their activity using diverse pharmacological strategies. Major TF families include NF-κB, p53, STATs, HIF-1α, AP-1, Nrf2, and nuclear hormone receptors, which take part in the regulation of inflammation, tumor suppression, cytokine signaling, hypoxia and stress response, oxidative stress, and hormonal response, respectively. TFs can perform multiple functions, participating in the regulation of opposing processes depending on the context. NF-κB, for instance, plays dual roles in immunity and cancer, and is targeted by proteasome and IKKβ inhibitors. p53, often mutated in cancer, is reactivated using MDM2 antagonist Nutlin-3, refunctionalizing compound APR-246, or stapled peptides. HIF-1α, which regulates hypoxic responses and angiogenesis, is inhibited by agents like acriflavine or stabilized in anemia therapies by HIF-PHD inhibitor roxadustat. STATs, especially STAT3 and STAT5, are oncogenic and targeted via JAK inhibitors or novel PROTAC degraders, for instance SD-36. AP-1, implicated in cancer and arthritis, can be inhibited by T-5224 or kinase inhibitors JNK and p38 MAPK. Nrf2, a key antioxidant regulator, can be activated by agents like DMF or inhibited in chemoresistant tumors. Pharmacological strategies include direct inhibitors, activators, PROTACs, molecular glues, and epigenetic modulators. Challenges remain, including the structural inaccessibility of TFs, functional redundancy, off-target effects, and delivery barriers. Despite these challenges, transcription factor modulation is emerging as a viable and promising therapeutic approach, with ongoing research focusing on specificity, safety, and efficient delivery methods to realize its full clinical potential. Full article

Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), remains a therapeutic challenge due to its aggressive nature, limited treatment options, and high recurrence rates. Current therapies, including chemotherapy and immune checkpoint inhibitors, face resistance driven by tumor heterogeneity, immunosuppressive signaling, and dysregulated redox pathways. This review explores silibinin’s potential to modulate the tumor immune microenvironment (TIME) and overcome therapeutic resistance in TNBC. Silibinin exerts multifaceted anticancer effects by suppressing PD-L1 expression through the inhibition of JAK/STAT3 signaling and MUC1-C interaction, attenuating NF-κB-driven inflammation, and downregulating CCL2-mediated recruitment of tumor-associated macrophages (TAMs). Additionally, silibinin disrupts redox adaptation by targeting the Nrf2-EGFR-MYC-TXNIP axis, enhancing oxidative stress and chemosensitivity. Preclinical studies highlight its ability to inhibit epithelial–mesenchymal transition (EMT), reduce cancer stem cell (CSC) populations, and synergize with existing therapies like PD-1 inhibitors. Despite its low bioavailability, advanced formulations such as liposomes and nanoparticles show promise in improving delivery and efficacy. By reshaping TIME through dual antioxidant and immunomodulatory mechanisms, silibinin emerges as a viable adjunct therapy to reverse immunosuppression and chemoresistance in TNBC. 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

This study investigates the role of melatonin in alleviating the oxidative stress and apoptosis of TM3 Leydig cells induced by 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), the primary active metabolite of Bisphenol A, and clarifies its potential mechanisms involving the SIRT1/PGC-1α pathway. We found that melatonin effectively mitigated MBP-induced cytotoxicity in TM3 cells (p < 0.05). The testosterone levels and steroid hormone synthesis proteins were significantly restored by melatonin. Furthermore, there was a significant reduction in apoptosis after melatonin treatment both in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues (p < 0.05), along with a significant decrease in the pro-apoptotic markers Bax and cleaved caspase 3, and a significant increase in the anti-apoptotic Bcl-2 level and the Bcl-2/Bax ratio in TM3 cells (p < 0.05). Additionally, the mitochondrial membrane potential improved significantly, ROS and MDA levels were down-regulated, and ATP production was elevated following melatonin treatment in TM3 cells. Mechanistically, melatonin promoted PGC-1α expression and activated the SIRT1 signaling pathway in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues. This leads to increased expression of NRF2 and its downstream antioxidant genes, mitochondrial respiratory chain complex-related genes, mitochondrial biogenesis genes, and mitochondrial fusion genes while significantly reducing mitochondrial fission genes (p < 0.05). The PGC-1α inhibitor SR-18292 reversed these protective effects, confirming the critical role of this pathway. Conclusively, melatonin exerts a protective effect against MBP-induced oxidative stress and apoptosis in TM3 cells through the SIRT1/PGC-1α pathway, indicating its potential as a therapeutic agent for improving male reproductive health compromised by environmental toxins. Full article

Chronic exposure to arsenic via drinking water can induce bladder cancer in humans. Nevertheless, there is little knowledge about the precise mechanisms of this. Abnormal elevations in cell proliferation and migration have repeatedly been identified as the first cellular traits of carcinogenesis. The aims of this study are to uncover the molecular mechanisms underlying arsenic-induced aberrant proliferation and migration of uroepithelium cells by exploring the role of cellular redox modulation. Our results show significant elevations in the levels of ROS and GSH, Trx1, components of the Nrf2 system, and NLRP3 inflammasome activity in the cells chronically treated with arsenite, which also experienced markedly enhanced proliferation and migration capacities. Additionally, ROS inhibitors, NLRP3, and the above antioxidant system could suppress this enhancement of the proliferation and migration capacities and reverse overexpression in these cells. However, only the AKT and ERK inhibitors were capable of reversing EGF, TGFα, and HSP90 overexpression. In conclusion, our findings indicate that the cellular redox status in the uroepithelium following chronic treatment with low-level arsenite was rebalanced due to ROS overproduction and compensatory upregulation of the redox control systems, which may allow ROS and Trx1 to be maintained at higher levels to facilitate cell proliferation and migration via overstimulation of the related signaling pathways. Full article

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the BCR::ABL1 fusion gene, which codifies the BCR-ABL protein with increased tyrosine kinase activity. Despite the clinical results for the outstanding tyrosine kinase inhibitors (TKIs), drug resistance is a problem in CML management. Genetic variants that alter redox homeostasis by changing antioxidant enzyme expression or activity may influence patient responses and could enhance patient stratification. We aimed to assess the association of SOD2, CAT GPX1, NRF2, and KEAP1 genetic variants with TKI response and disease prognosis. For this purpose, we genotyped the variants rs4880 (SOD2), rs1050450 (GPX1), rs1001179 (CAT), rs6721961, rs4893819, rs35652124, rs6706649, rs13001694 (NFE2L2), and rs113540846 (KEAP1) via PCR in 187 CML patients. Our results show that variants in genes related to oxidative stress influence the development and degree of TKI resistance (allele G and GG genotypes of GPX1 and CT genotype of NFE2L2 rs4893819), the appearance of mutations in the BCR::ABL1 gene (AG genotype of NFE2L2 rs13001694 and genetic profile GGCTTCCCGG of the NFE2L2/KEAP1 axis), disease evolution (AG genotype of SOD2 and CT genotype of NFE2L2 rs4893819), and overall survival (CC genotype of CAT and GG genotype of NFE2L2 rs13001694) of CML patients. Our study found that variants in oxidative stress-related genes impact treatment response and outcomes in CML. Full article

Meloxicam has been identified as an adjuvant therapeutic component in the management of bovine uterine diseases, exhibiting anti-inflammatory and antioxidant effects. However, the mechanisms underlying its antioxidant actions in the context of bovine uterine diseases remain incompletely understood. The objective of this research was to determine whether meloxicam exerts its antioxidant effects through the Nrf2/HO-1 signaling pathway. By employing N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), along with inhibitors directed against heme oxygenase-1 (HO-1) or nuclear factor erythroid 2-related factor 2 (Nrf2), we investigated the dynamic changes in oxidative stress markers (ROS and malondialdehyde) and antioxidant indices (comprising catalase, superoxide dismutase, and glutathione), as well as the expression profiles of Nrf2 and inflammation-associated genes and proteins in bovine endometrial epithelial cells (BEECs) subjected to lipopolysaccharide (LPS) stimulation. As a result, meloxicam alleviated the LPS-induced elevation of oxidative stress marker levels and the reduction in antioxidant enzyme activities and antioxidant substance contents in BEECs. Compared to NAC, meloxicam demonstrated superior efficacy in activating the Nrf2 pathway, with the promotion of NRF2 expression (~1.6-fold) and nuclear translocation. The pretreatment of cells with HO-1 or Nrf2 inhibitors markedly attenuated the antioxidant activity of meloxicam. In summary, meloxicam primarily alleviates LPS-induced oxidative stress through the activation of the Nrf2/HO-1 pathway in BEECs. Full article