Search Results (3,522)

Human NAD(P)H-quinone oxidoreductase1 (HNQO1) is a two-electron reductase antioxidant enzyme whose expression is driven by the NRF2 transcription factor highly active in the prooxidant milieu found in human malignancies. The resulting abundance of NQO1 expression (up to 200-fold) in cancers and a barely detectable expression in body tissues makes it a selective marker of neoplasms. NQO1 can catalyze the repeated futile redox cycling of certain natural and synthetic quinones to their hydroxyquinones, consuming NADPH and generating rapid bursts of cytotoxic reactive oxygen species (ROS) and H₂O₂. A greater level of this quinone bioactivation due to elevated NQO1 content has been recognized as a tumor-specific therapeutic strategy, which, however, has not been clinically exploited. We review here the natural and new quinones activated by NQO1, the catalytic inhibitors, and the ensuing cell death mechanisms. Further, the cancer-selective expression of NQO1 has opened excellent opportunities for distinguishing cancer cells/tissues from their normal counterparts. Given this diagnostic, prognostic, and therapeutic importance, we and others have engineered a large number of specific NQO1 turn-on small molecule probes that remain latent but release intense fluorescence groups at near-infrared and other wavelengths, following enzymatic cleavage in cancer cells and tumor masses. This sensitive visualization/quantitation and powerful imaging technology based on NQO1 expression offers promise for guided cancer surgery, and the reagents suggest a theranostic potential for NQO1-targeted chemotherapy. Full article

Multiple sclerosis (MS) is a chronic and degenerative disease that impacts central nervous system (CNS) function. One of the major characteristics of the disease is the presence of regions lacking myelin and an oxidative and inflammatory environment. TGF-β1 and Nrf2 proteins play a fundamental role in different oxidative/inflammatory processes linked to neurodegenerative diseases such as MS. The evidence from different experimental settings has demonstrated a TGF-β1-Nrf2 signaling crosstalk under pathological conditions. However, this possibility has not been explored in experimental models of MS. Here, by using the cuprizone-induced demyelination model of MS, we report that the in vivo pharmacological blockage of the TGF-β1 receptor reduced Nrf2, catalase, and TGFβ-1 protein levels in the demyelination phase of cuprizone administration. In addition, ATP production, locomotor function and cognitive performance were diminished by the treatment. Altogether, our results provide evidence for a crosstalk between TGF-β1 and Nrf2 signaling pathways under CNS demyelination, highlighting the importance of the antioxidant cellular response of neurodegenerative diseases such as MS. Full article

Our preliminary study identified dairy cow placenta extract (CPE) as a mixture of peptides with potent antioxidant activity both in vivo and in vitro. However, the specific antioxidant peptides (AOPs) responsible for this activity were not yet identified. In the current study, we employed virtual screening and chromatography techniques to isolate two peptides, ANNGKQWAEVF (CP1) and QPGLPGPAG (CP2), from CPE. These peptides were found to be less stable under extreme conditions such as high temperature, strong acid, strong alkali, and simulated digestive conditions. Nevertheless, under normal physiological conditions, both CP1 and CP2 exhibited significant antioxidant properties, including free-radical scavenging, metal chelating, and the inhibition of lipid peroxidation. They also up-regulated the activities of intracellular antioxidant enzymes in response to hydrogen-peroxide-induced oxidative stress, resulting in reduced MDA levels, a decreased expression of the Keap1 gene and protein, and increased levels of the Nrf2 and HO-1 genes and proteins. Furthermore, CP1 demonstrated superior antioxidant activity compared to CP2. These findings suggest that CP1 and CP2 hold potential for mitigating oxidative stress in vitro and highlight the efficacy of virtual screening as a method for isolating AOPs within CPE. Full article

Liver disease is a global health problem that affects the well-being of tens of thousands of people. Dihydroquercetin (DHQ) is a flavonoid compound derived from various plants. Furthermore, DHQ has shown excellent activity in the prevention and treatment of liver injury, such as the inhibition of hepatocellular carcinoma cell proliferation after administration, the normalization of oxidative indices (like SOD, GSH) in this tissue, and the down-regulation of pro-inflammatory molecules (such as IL-6 and TNF-α). DHQ also exerts its therapeutic effects by affecting molecular pathways such as NF-κB and Nrf2. This paper discusses the latest research progress of DHQ in the treatment of various liver diseases (including viral liver injury, drug liver injury, alcoholic liver injury, non-alcoholic liver injury, fatty liver injury, and immune liver injury). It explores how to optimize the application of DHQ to improve its effectiveness in treating liver diseases, which is valuable for preparing potential therapeutic drugs for human liver diseases in conjunction with DHQ. Full article

Determining the gene expression and serum profile of the indicators linked to clinical endometritis susceptibility in Egyptian buffalo cows was the aim of this investigation. The buffalo cows that were enrolled were divided into two groups: forty infected buffalo cows with clinical endometritis and forty seemingly healthy buffalo cows that served as the control group. For the purposes of gene expression and biochemical analysis, ten milliliters of blood was obtained via jugular venipuncture from each buffalo cow. TLR4, IL-8, IL-17, NFKB, SLCA11A1, NCF4, Keap1, HMOX1, OXSR1, ST1P1, and SERP1 were manifestly expressed at much higher levels in the buffaloes with endometritis. On the other hand, the genes that encode SOD, CAT, NDUFS6, Nrf2, and PRDX2 were down-regulated. There was a significant (p < 0.05) elevation of the serum levels of non-esterified fatty acids (NEFAs), beta hydroxy butyric acid (BHBA), triglycerides (TGs), globulin, creatinine, and cortisol, along with a reduction in the serum levels of glucose, cholesterol, total protein albumin, urea, estrogen (E2), progesterone (P4), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroxine (T4), prostaglandin F2 α (PGF2α), calcium, iron, and selenium, in the endometritis group in comparison with the control. However, no significant change was observed in the values of phosphorus, magnesium, copper, or zinc in either group. Within the selective breeding of naturally resistant animals, the variation in the genes under study and the changes in the serum profiles of the indicators under investigation may serve as a reference guide for reducing endometritis in Egyptian buffalo cows. Full article

The pharmacological effects of the fruiting body of Ophiocordyceps sinensis (O. sinensis) such as antioxidant, anti-virus, and immunomodulatory activities have already been described, whereas the anti-inflammatory effects and active components of the submerged culture of O. sinesis (SCOS) still need to be further verified. This study aimed to investigate the active compounds in the fermented liquid (FLOS), hot water (WEOS), and 50–95% (EEOS-50, EEOS-95) ethanol extracts of SCOS and their anti-inflammatory effects and potential mechanisms in lipopolysaccharide (LPS)-stimulated microglial BV2 cells. The results demonstrated that all of the SCOS extracts could inhibit NO production in BV2 cells. EEOS-95 exhibited the strongest inhibitory effects (71% inhibitory ability at 500 µg/mL), and its ergosterol, γ-aminobutyric acid (GABA), total phenolic, and total flavonoid contents were significantly higher than those of the other extracts (18.60, 18.60, 2.28, and 2.14 mg/g, p < 0.05, respectively). EEOS-95 also has a strong inhibitory ability against IL-6, IL-1β, and TNF-α with an IC₅₀ of 617, 277, and 507 µg/mL, respectively, which is higher than that of 1 mM melatonin. The anti-inflammatory mechanism of EEOS-95 seems to be associated with the up-regulation of PPAR-γ/Nrf-2/HO-1 antioxidant-related expression and the down-regulation of NF-κB/COX-2/iNOS pro-inflammatory expression signaling. In summary, we demonstrated that EEOS-95 exhibits neuroinflammation-mediated neurodegenerative disorder activities in LPS-induced inflammation in brain microglial cells. Full article

This paper presents an energy-efficient and high-accuracy sampling synchronization approach for real-time synchronous data acquisition in wireless sensor networks (saWSNs). A proprietary protocol based on time-division multiple access (TDMA) and deep energy-efficient coding in sensor firmware is proposed. A real saWSN model based on 2.4 GHz nRF52832 system-on-chip (SoC) sensors was designed and experimentally tested. The obtained results confirmed significant improvements in data synchronization accuracy (even by several times) and power consumption (even by a hundred times) compared to other recently reported studies. The results demonstrated a sampling synchronization accuracy of 0.8 μs and ultra-low power consumption of 15 μW per 1 kb/s throughput for data. The protocol was well designed, stable, and importantly, lightweight. The complexity and computational performance of the proposed scheme were small. The CPU load for the proposed solution was <2% for a sampling event handler below 200 Hz. Furthermore, the transmission reliability was high with a packet error rate (PER) not exceeding 0.18% for TXPWR ≥ −4 dBm and 0.03% for TXPWR ≥ 3 dBm. The efficiency of the proposed protocol was compared with other solutions presented in the manuscript. While the number of new proposals is large, the technical advantage of our solution is significant. Full article

Radiation-induced salivary gland injury (RISGI) is a common complication of radiotherapy in patients with head and neck cancer. Intragland expression of the Sonic Hedgehog (Shh) gene may partially rescue irradiation (IR)-induced hyposalivation by preserving salivary stem/progenitor cells and parasympathetic innervation, maintaining resident macrophages, and maintaining microvascular density. Previous studies have revealed that Ad-Rat Shh transduction through the salivary glands of miniature pigs can ameliorate oxidative stress-induced microvascular dysfunction after radiotherapy. Changes in the parotid salivary flow rate were analyzed, and the parotid tissue was collected at 5 and 20 weeks after IR. Changes in the Hedgehog pathway and vascular function-related markers (vascular endothelial growth factor (VEGF) and CD31) and oxidative stress-related markers were detected via immunohistochemistry, immunofluorescence, and Western blotting. A stable Shh-overexpressing cell line was generated from human umbilical vein endothelial cells (HUVECs) and exposed to 10 Gy X-ray irradiation, after which endothelial cell proliferation, senescence, apoptosis, and vascular function were evaluated. We found that intragland expression of the Shh gene efficiently alleviated IR-induced parotid gland injury in a miniature pig model. Our results indicate that the antioxidative stress and microvascular-protective effects of the Hh pathway are regulated by nuclear factor-erythroid 2-related factor 2 (Nrf2). Full article

Lespedeza bicolor Turcz. (L. bicolor) honey, a monofloral honey, has garnered increased attention due to its origin in the L. bicolor plant. A previous study has shown that L. bicolor honey can ameliorate inflammation. In this study, we aimed to investigate the effects of L. bicolor honey extract and its biomarker (Trifolin) on DSS-induced ulcerative colitis (UC). Our results demonstrated that L. bicolor honey extract and Trifolin significantly increased the expression levels of the tight junction cytokines Claudin-1 and ZO-1. Additionally, they decreased the pro-inflammatory factors TNF-α and IL-6 and enhanced the antioxidant factors NQO1 and GSTA1. Based on metabolomic analyses, L. bicolor honey extract and Trifolin regulated the progression of UC by inhibiting ferroptosis. Mechanistically, they improved the levels of SOD and iron load, increased the GSH/GSSG ratio, reduced MDA content and ROS release, and upregulated the Nrf2/HO-1 pathway, thereby inhibiting DSS-induced UC. Moreover, the expression levels of ferroptosis-related genes indicated that they decreased FTL, ACSL4, and PTGS2 while increasing SLC7A11 expression to resist ferroptosis. In conclusion, our study found that L. bicolor honey improves DSS-induced UC by inhibiting ferroptosis by activating the Nrf2/HO-1 pathway. These findings further elucidate the understanding of anti-inflammatory and antioxidant activities of L. bicolor honey. Full article

Weaning is a critical stage in the growth and development of piglets, often inducing stress reactions. This study aims to investigate the effects of Parabacteroides distasonis (PBd) derived from Ningxiang pigs on growth performance, intestinal apoptosis, oxidative damage, and inflammation in ETEC-challenged weaned piglets. A total of 22 Duroc × Landrace × Yorkshire (DLY) piglets, 24 days old with similar body weights, were randomly divided into three groups: Control (n = 7), ETEC (n = 7), and PBd + ETEC (n = 8). The results show that, compared to the Control group, ETEC challenge led to decreased growth performance, reduced villus height in the duodenum and jejunum, increased crypt depth in the duodenum, a decreased villus-height-to-crypt-depth ratio, increased expression of apoptosis-related genes (Caspase-8 and Caspase-9), increased expression of oxidative damage-related genes (Nrf2, GSH-PX, mTOR, and Beclin1), increased expression of inflammation-related genes (Myd88, P65, TNF-α, and IL-6), and reduced the contents of SCFAs in the colonic chyme (acetate, propionate, butyrate, valerate, and total SCFAs). Compared to the ETEC group, the PBd + ETEC group alleviated the reduction in growth performance, mitigated intestinal morphological damage, and reduced the expression of the aforementioned apoptosis, oxidative damage, and inflammation-related genes with the increase in SCFAs. In conclusion, PBd derived from Ningxiang pigs effectively reduces ETEC-induced intestinal damage in weaned piglets, improves intestinal health, and increases the content of SCFAs in the colonic chyme, thereby enhancing growth performance. Full article

Sex differences may play a role in the etiopathogenesis and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), a disorder characterized by excessive fat accumulation associated with increased inflammation and oxidative stress. We previously observed the development of steatosis specifically in female rats fed a high-fat diet enriched with liquid fructose (HFHFr) for 12 weeks. The aim of this study was to better characterize the observed sex differences by focusing on the antioxidant and cytoprotective pathways related to the KEAP1/NRF2 axis. The KEAP1/NRF2 signaling pathway, autophagy process (LC3B and LAMP2), and endoplasmic reticulum stress response (XBP1) were analyzed in liver homogenates in male and female rats that were fed a 12-week HFHFr diet. In females, the HFHFr diet resulted in the initial activation of the KEAP1/NRF2 pathway, which was not followed by the modulation of downstream molecular targets; this was possibly due to the increase in KEAP1 levels preventing the nuclear translocation of NRF2 despite its cytosolic increase. Interestingly, while in both sexes the HFHFr diet resulted in an increase in the levels of LC3BII/LC3BI, a marker of autophagosome formation, only males showed a significant upregulation of LAMP2 and XBP1s; this did not occur in females, suggesting impaired autophagic flux in this sex. Overall, our results suggest that males are characterized by a greater ability to cope with an HFHFr metabolic stimulus mainly through an autophagic-mediated proteostatic process while in females, this is impaired. This might depend at least in part upon the fine modulation of the cytoprotective and antioxidant KEAP1/NRF2 pathway resulting in sex differences in the occurrence and severity of MASLD. These results should be considered to design effective therapeutics for MASLD. Full article

Calcification plays a key role in biological processes, and breakdown of the regulatory mechanism results in a pathological state such as ectopic calcification. We hypothesized that ENPP1, the enzyme that produces the calcification inhibitor pyrophosphate, is transcriptionally regulated by Nrf2, and that Nrf2 activation augments ENPP1 expression to inhibit ectopic calcification. Cell culture experiments were performed using mouse osteoblastic cell line MC3T3-E1. Nrf2 was activated by 5-aminolevulinic acid and sodium ferrous citrate. Nrf2 overexpression was induced by the transient transfection of an Nrf2 expression plasmid. ENPP1 expression was monitored by real-time RT-PCR. Because the promoter region of ENPP1 contains several Nrf2-binding sites, chromatin immunoprecipitation using an anti-Nrf2 antibody followed by real-time PCR (ChIP-qPCR) was performed. The relationship between Nrf2 activation and osteoblastic differentiation was examined by alkaline phosphatase (ALP) and Alizarin red staining. We used mice with a hypomorphic mutation in ENPP1 (ttw mice) to analyze whether Nrf2 activation inhibits ectopic calcification. Nrf2 and Nrf2 overexpression augmented ENPP1 expression and inhibited osteoblastic differentiation, as indicated by ALP expression and calcium deposits. ChIP-qPCR showed that some putative Nrf2-binding sites in the ENPP1 promoter region were bound by Nrf2. Nrf2 activation inhibited ectopic calcification in mice. ENPP1 gene expression was transcriptionally regulated by Nrf2, and Nrf2 activation augmented ENPP1 expression, leading to the attenuation of osteoblastic differentiation and ectopic calcification in vitro and in vivo. Nrf2 activation has a therapeutic potential for preventing ectopic calcification. Full article

Progression of metabolic dysfunction-associated steatites liver disease (MASLD) to steatohepatitis (MASH) is driven by stress-inducing lipids that promote liver inflammation and fibrosis, and MASH can lead to cirrhosis and hepatocellular carcinoma. Previously, we showed coordinated defenses regulated by transcription factors, nuclear factor erythroid 2-related factor-1 (Nrf1) and -2 (Nrf2), protect against hepatic lipid stress. Here, we investigated protective effects of hepatocyte Nrf1 and Nrf2 against MASH-linked liver fibrosis and tumorigenesis. Male and female mice with flox alleles for genes encoding Nrf1 (Nfe2l1), Nrf2 (Nfe2l2), or both were fed a MASH-inducing diet enriched with high fat, fructose, and cholesterol (HFFC) or a control diet for 24–52 weeks. During this period, hepatocyte Nrf1, Nrf2, or combined deficiency for ~7 days, ~7 weeks, and ~35 weeks was induced by administering mice hepatocyte-targeting adeno-associated virus (AAV) expressing Cre recombinase. The effects on MASH, markers of liver fibrosis and proliferation, and liver tumorigenesis were compared to control mice receiving AAV-expressing green fluorescent protein. Also, to assess the impact of Nrf1 and Nrf2 induction on liver fibrosis, HFFC diet-fed C57bl/6J mice received weekly injections of carbon tetrachloride, and from week 16 to 24, mice were treated with the Nrf2-activating drug bardoxolone, hepatocyte overexpression of human NRF1 (hNRF1), or both, and these groups were compared to control. Compared to the control diet, 24-week feeding with the HFFC diet increased bodyweight as well as liver weight, steatosis, and inflammation. It also increased hepatocyte proliferation and a marker of liver damage, p62. Hepatocyte Nrf1 and combined deficiency increased liver steatosis in control diet-fed but not HFFC diet-fed mice, and increased liver inflammation under both diet conditions. Hepatocyte Nrf1 deficiency also increased hepatocyte proliferation, whereas combined deficiency did not, and this also occurred for p62 level in control diet-fed conditions. In 52-week HFFC diet-fed mice, 35 weeks of hepatocyte Nrf1 deficiency, but not combined deficiency, resulted in more liver tumors in male mice, but not in female mice. In contrast, hepatocyte Nrf2 deficiency had no effect on any of these parameters. However, in the 15-week CCL4-exposed and 24-week HFFC diet-fed mice, Nrf2 induction with bardoxolone reduced liver steatosis, inflammation, fibrosis, and proliferation. Induction of hepatic Nrf1 activity with hNRF1 enhanced the effect of bardoxolone on steatosis and may have stimulated liver progenitor cells. Physiologic Nrf1 delays MASLD progression, Nrf2 induction alleviates MASH, and combined enhancement synergistically protects against steatosis and may facilitate liver repair. Full article

HT074, a multiherbal mixture containing extracts from Inula britannica flowers and Paeonia lactiflora roots, is used in Korean medicine for gastric disorders. This study investigated the protective mechanisms of HT074 against acute reflux esophagitis (RE) in rats. Nitric oxide (NO) production and mRNA expression of antioxidant-related genes (Nrf2, HO-1, SOD, CAT, and GPx2) were evaluated in LPS-induced RAW 264.7 cells. Gastroesophageal reflux (GER) was induced in rats, followed by HT074 (100, 300 mg/kg) or ranitidine (50 mg/kg) administration. Esophageal damage and histological changes were assessed. Gastric pH and protein expression levels of Nrf2, HO-1, SOD, CAT, and GPx-1/2 were measured. HT074 pretreatment reduced NO production and increased the expression of HO-1, CAT, and GPx2 in LPS-induced RAW 264.7 cells. In GER-induced rats, HT074 significantly decreased esophageal lesions and increased the expression of HO-1, SOD, GPx-1/2, and Nrf2. HT074 did not affect gastric pH. These findings suggest that HT074 protects against GER-induced esophagitis by inhibiting NO production and enhancing antioxidant activity. Therefore, HT074 could be a promising therapeutic agent for GER disease. Full article

Breast cancer is the second-leading cause of cancer death among women in the United States. Triple-negative breast cancer (TNBC), a subtype of breast cancer, is an aggressive phenotype that lacks estrogen (ER), progesterone (PR), and human epidermal growth (HER-2) receptors, which is challenging to treat with standardized hormonal therapy. Kaempferol is a natural flavonoid with antioxidant, anti-inflammatory, neuroprotective, and anticancer effects. Besides anti-tumorigenic, antiproliferative, and apoptotic effects, kaempferol protects non-cancerous cells. Kaempferol showed anti-breast cancer effects by inducing DNA damage and increasing caspase 3, caspase 9, and pAMT expression, modifying ROS production by Nrf2 modulation, inducing apoptosis by increasing cleaved PARP and Bax and downregulating Bcl-2 expression, inducing cell cycle arrest at the G2/M phase; inhibiting immune evasion by modulating the JAK-STAT3 pathway; and inhibiting the angiogenic and metastatic potential of tumors by downregulating MMP-3 and MMP-9 levels. Kaempferol holds promise for boosting the efficacy of anticancer agents, complementing their effects, or reversing developed chemoresistance. Exploring novel TNBC molecular targets with kaempferol could elucidate its mechanisms and identify strategies to overcome limitations for clinical application. This review summarizes the latest research on kaempferol’s potential as an anti-TNBC agent, highlighting promising but underexplored molecular pathways and delivery challenges that warrant further investigation to achieve successful clinical translation. Full article