Protective effects of syringic acid in nonalcoholic fatty liver in rats through regulation of Nrf2/HO-1 signaling pathway.

Nonalcoholic fatty liver disease (NAFLD) is an alarming ailment that leads to severe liver damage and increases the risk of serious health conditions. The prevalence of NAFLD due to oxidative stress could be mitigated by plant-derived antioxidants. This study aims to investigate the effects of syringic acid (SA) on NAFLD in a high-fat diet (HFD) rat model. Twenty-four rats were randomly divided into four groups (n = 6): normal control, HFD, SA-administered HFD, and positive control SA on a normal diet. Rats in the normal control and positive control groups received a normal diet, and the remaining groups received an HFD for 8 weeks. SA (20 mg/kg b.w.) was orally (gavage) administered for 8 weeks. Lipid profiles were controlled by SA against HFD-fed rats (p < 0.05). SA reduced the serum aspartate aminotransferase and alanine aminotransferase levels by 70%-190%. SA also suppressed pro-inflammatory cytokines and attenuated histopathological and immunohistochemical changes against HFD-fed rats. SA reversed oxidative stress by suppressing the malondialdehyde formation by 82% and replenished the nonenzymatic and enzymatic antioxidant activities (p < 0.05). Gene expressions of nuclear factor-erythroid 2-related factor/heme oxygenase 1 (Nrf2/HO-1) were elevated in SA-treated rats. Ameliorative effects of SA on NAFLD induced by an HFD in rats were prominent through the reversal of oxidative stress and inflammation, regulated by an intrinsic mechanism of defense against oxidative stress, the Nrf2/HO-1 pathway.

Vincamine exerts hepato-protective activity during colon ligation puncture-induced sepsis by modulating oxidative stress, apoptosis, and TNFα/Nrf-2/Keap-1 signaling pathways.

Sepsis is a pathological and biochemical disorder induced by numerous infections, leading to critical illness and a high mortality rate worldwide. Vincamine is an indole alkaloid compound obtained from the leaves of Vinca minor. The present study aims to investigate the hepato-protective activity of vincamine during colon ligation puncture (CLP)-induced sepsis at the molecular level. Sepsis was induced using the CLP model. Liver function enzymes such as ALT and AST were analyzed. The hepatic antioxidant status (SOD and GSH), lipid peroxidation (MDA), the pro-inflammatory cytokines (TNFα, IL-6, and IL-1ß), bax, bcl2, and cleaved caspase 3 proteins were estimated. Nrf-2 and Keap-1 protein expression was evaluated using western blotting. Histopathological investigation of liver tissues was also performed. CLP-induced sepsis led to liver injury through the elevation of ALT and AST liver enzymes. Oxidative stress was initiated during CLP via the suppression of hepatic GSH content and SOD activity and the elevation of MDA. The inflammatory condition was activated by the upregulation of TNFα, IL-6, IL-1ß, and Keap-1 and the downregulation of Nrf-2 proteins. The apoptosis was initiated through the activation of bax and cleaved caspase 3 protein expression and inhibition of bcl2 protein expression. However, vincamine significantly improved the hepatic histological abnormalities and decreased liver enzymes (ALT and AST). It ameliorated oxidative stress, as evidenced by reducing the hepatic MDA content and increasing the SOD activity and GSH content. Moreover, vincamine reduced the hepatic content of TNFα, IL-6, IL-1ß, and Keap-1 and increased Nrf-2 protein expression. Additionally, it upregulated bcl2 protein expression and downregulated bax and cleaved caspase 3 protein expression. Vincamine exhibited hepato-protective potential during CLP-induced sepsis via the cross-connection of antioxidant, anti-inflammatory, and anti-apoptotic activities by modulating TNFα/IL-6/IL-1ß/Nrf-2/Keap-1 and regulating bax/bcl2/cleaved caspase 3 signaling pathways.

Attenuation of chromium (VI) and arsenic (III)-induced oxidative stress and hepatic apoptosis by phloretin, biochanin-A, and coenzyme Q10 via activation of SIRT1/Nrf2/HO-1/NQO1 signaling.

Heavy metal contamination is an alarming concern on a global scale, as drinking tainted water significantly increases human susceptibility to heavy metals. In a realistic scenario, humans are often exposed to a combination of harmful chemicals rather than a single toxicant. Phloretin (PHL), biochanin-A (BCA), and coenzyme Q10 (CoQ10) are bioactive compounds owning plentiful pharmacological properties. Henceforth, the current research explored the putative energizing effects of selected nutraceuticals in combined chromium (Cr) and arsenic (As) intoxicated Swiss albino mice. Potassium dichromate (75 ppm) and sodium meta-arsenite (100 ppm) were given in the drinking water to induce hepatotoxicity, conjugated with PHL and BCA (50 mg/kg each), and CoQ10 (10 mg/kg) intraperitoneally for 2 weeks. After the statistical evaluation, it was observed that the hepato-somatic index, metal load, and antioxidant activity (lipid peroxidation and protein carbonyl content) increased along with the concomitant decrease in the antioxidants (catalase, glutathione-S-transferase, superoxide dismutase, reduced glutathione, and total thiol) in the Cr and As intoxicated mice. Additionally, light microscopy observations, DNA breakages, decreased silent information regulator 1 (SIRT1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) gene expressions, together with stimulated apoptotic cell death manifested by the increased expressions of caspase 8 and caspase 3, thus, proved consistency with the aforementioned outcomes. Importantly, the treatment with nutraceuticals not only restored the antioxidant activity but also favorably altered the expressions of SIRT1, Nrf2, HO-1, and NQO1 signaling and apoptosis markers. These findings highlight the crucial role of the PHL, BCA, and CoQ10 combination in reducing Cr and As-induced hepatotoxicity in mice. By averting the triggered apoptosis in conjunction with oxidative stress, this combination increases the SIRT1, Nrf2, HO-1, and NQO1 signaling, thereby reassuringly maintaining the cellular equilibrium.

Chinese medicine PaBing-II protects human iPSC-derived dopaminergic neurons from oxidative stress.

Background: PaBing-II Formula (PB-II) is a traditional Chinese medicine for treating Parkinson's disease (PD). However, owing to the complexity of PB-II and the difficulty in obtaining human dopaminergic neurons (DAn), the mechanism of action of PB-II in PD treatment remains unclear. The aim of this study was to investigate the mechanisms underlying the therapeutic benefits of PB-II in patients with PD. Methods: hiPSCs derived DAn were treated with H2O2 to construct the DAn oxidative damage model. SwissTargetPrediction was employed to predict the potential targets of the main compounds in serum after PB-II treatment. Metascape was used to analyze the pathways. Sprague-Dawley rats were used to construct the 6-hydroxydopamine (6-OHDA)-induced PD model, and the duration of administration was four weeks. RNA sequencing was used for Transcriptome analysis to find the signal pathways related to neuronal damage. The associated inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). We identified PB-II as an Nrf2 activator using antioxidant-responsive element luciferase assay in MDA-MB-231 cells. Results: In vitro experiments showed that the treatment of PB-II-treated serum increased the percentage of TH+ cells, decreased inflammation and the apoptosis, reduced cellular reactive oxygen species, and upregulated the expression of Nrf2 and its downstream genes. Pathway analysis of the RNA-seq data of samples before and after the treatment with PB-II-treated serum identified neuron-associated pathways. In vivo experiments demonstrated that PB-II treatment of PD rat model could activate the Nrf2 signaling pathway, protect the midbrain DAn, and improve the symptoms in PD rats. Conclusion: PB-II significantly protects DAn from inflammation and oxidative stress via Nrf2 pathway activation. These findings elucidate the roles of PB-II in PD treatment and demonstrate the application of hiPSC-derived DAn in research of Chinese medicine.

Evaluation of Phenazine Derivatives from the Lichen-Associated Streptomyces flavidovirens as Potent Antineuroinflammatory Agents In Vitro and In Vivo.

Eighteen nitrogen-containing compounds (1-18) were isolated from cultures of the lichen-associated Streptomyces flavidovirens collected from the Qinghai-Tibet Plateau, including seven phenazine derivatives with three new ones, named subphenazines A-C (2-4), two new furan pyrrolidones (8-9), and nine known alkaloids. The structures were elucidated by spectroscopic data analysis, and absolute configurations were determined by single-crystal X-ray diffraction and ECD calculations. The phenazine-type derivatives, in particular compound 3, exhibited significantly better antineuroinflammatory activity than other isolated compounds (8-18). Compound 3 inhibited the release of proinflammatory cytokines including IL-6, TNF-α, and PGE2, and the nuclear translocation of NF-κB; it also reduced the oxidative stress and activated the Nrf2 signaling pathway in LPS-induced BV2 microglia cells. In vivo anti-inflammatory activity in zebrafish indicated that 3 inhibited LPS-stimulated ROS generation. These findings suggested that compound 3 might be a potent antineuroinflammatory agent through the regulation of the NF-κB/Nrf2 signaling pathways.

TRIM44 enhances autophagy via SQSTM1 oligomerization in response to oxidative stress.

The deubiquitinase tripartite motif containing 44 (TRIM44) plays a critical role in linking the proteotoxic stress response with autophagic degradation, which is significant in the context of cancer and neurological diseases. Although TRIM44 is recognized as a prognostic marker in various cancers, the complex molecular mechanisms through which it facilitates autophagic degradation, particularly under oxidative stress conditions, have not been fully explored. In this study, we demonstrate that TRIM44 significantly enhances autophagy in response to oxidative stress, reducing cytotoxicity in cancer cells treated with arsenic trioxide. Our research emphasizes the critical role of the posttranslational modification of sequestosome-1 (SQSTM1) and its importance in improving sequestration during autophagic degradation under oxidative stress. We found that TRIM44 notably promotes SQSTM1 oligomerization in both PB1 domain-dependent and oxidation-dependent manners. Furthermore, TRIM44 amplifies the interaction between protein kinase A and oligomerized SQSTM1, leading to enhanced phosphorylation of SQSTM1 at S349. This phosphorylation event activates NFE2L2, a key transcription factor in the oxidative stress response, highlighting the importance of TRIM44 in modulating SQSTM1-mediated autophagy. Our findings support that TRIM44 plays pivotal roles in regulating autophagic sensitivity to oxidative stress, with implications for cancer, aging, aging-associated diseases, and neurodegenerative disorders.

Sarmentosin alleviates doxorubicin-induced cardiotoxicity and ferroptosis via the p62-Keap1-Nrf2 pathway.

Doxorubicin (Dox) is extensively used as an antitumor agent, but its severe cardiotoxicity significantly limits its clinical use. Current treatments for Dox-induced cardiotoxicity are inadequate, necessitating alternative solutions. This study evaluated the effects of sarmentosin, a compound from Sedum sarmentosum, on Dox-induced cardiotoxicity and dysfunction. Sarmentosin was administered as a pretreatment to both mice and H9c2 cells before Dox exposure. Subsequently, markers of Dox-induced cardiotoxicity and ferroptosis in serum and cell supernatants were measured. Western blot analysis was utilized to detect levels of ferroptosis, oxidative stress, and autophagy proteins. Additionally, echocardiography, hematoxylin-eosin staining, ROS detection, and immunofluorescence techniques were employed to support our findings. Results demonstrated that sarmentosin significantly inhibited iron accumulation, lipid peroxidation, and oxidative stress, thereby reducing Dox-induced ferroptosis and cardiotoxicity in C57BL/6 mice and H9c2 cells. The mechanism involved the activation of autophagy and the Nrf2 signaling pathway. These findings suggest that sarmentosin may prevent Dox-induced cardiotoxicity by mitigating ferroptosis. The study underscores the potential of compounds like sarmentosin in treating Dox-induced cardiotoxicity.

The involvement of the Stat1/Nrf2 pathway in exacerbating Crizotinib-induced liver injury: implications for ferroptosis.

Crizotinib carries an FDA hepatotoxicity warning, yet analysis of the FAERS database suggests that the severity of its hepatotoxicity risks, including progression to hepatitis and liver failure, might be underreported. However, the underlying mechanism remains poorly understood, and effective intervention strategies are lacking. Here, mRNA-sequencing analysis, along with KEGG and GO analyses, revealed that DEGs linked to Crizotinib-induced hepatotoxicity predominantly associate with the ferroptosis pathway which was identified as the principal mechanism behind Crizotinib-induced hepatocyte death. Furthermore, we found that ferroptosis inhibitors, namely Ferrostatin-1 and Deferoxamine mesylate, significantly reduced Crizotinib-induced hepatotoxicity and ferroptosis in both in vivo and in vitro settings. We have also discovered that overexpression of AAV8-mediated Nrf2 could mitigate Crizotinib-induced hepatotoxicity and ferroptosis in vivo by restoring the imbalance in glutathione metabolism, iron homeostasis, and lipid peroxidation. Additionally, both Stat1 deficiency and the Stat1 inhibitor NSC118218 were found to reduce Crizotinib-induced ferroptosis. Mechanistically, Crizotinib induces the phosphorylation of Stat1 at Ser727 but not Tyr701, promoting the transcriptional inhibition of Nrf2 expression after its entry into the nucleus to promote ferroptosis. Meanwhile, we found that MgIG and GA protected against hepatotoxicity to counteract ferroptosis without affecting or compromising the anti-cancer activity of Crizotinib, with a mechanism potentially related to the Stat1/Nrf2 pathway. Overall, our findings identify that the phosphorylation activation of Stat1 Ser727, rather than Tyr701, promotes ferroptosis through transcriptional inhibition of Nrf2, and highlight MgIG and GA as potential therapeutic approaches to enhance the safety of Crizotinib-based cancer therapy.

The protective effect of vinpocetine against Estradiol-benzoate induced cervical hyperkeratosis in female rats via modulation of SIRT1/Nrf2, and NLRP3 inflammasome.

The current study was assigned to determine the putative preventive role of vinpocetine (VIN) in cervical hyperkeratosis (CHK) in female rats. Estradiol Benzoate (EB) was utilized in a dose f (60 µg/100 g, i.m) three times/week for 4 weeks to induce cervical hyperkeratosis. VIN was administered alone in a dose of (10 mg/kg/day, orally) for 4 weeks and in the presence of EB. Levels of malondialdehyde (MDA), total nitrites (NOx), reduced glutathione (GSH), interleukin-18 (IL-18), IL-1ß, tumor necrosis factor-alpha (TNF-α) were measured in cervical tissue. The expression of NLRP3/GSDMD/Caspase-1, and SIRT1/Nrf2 was determined using ELISA. Cervical histopathological examination was also done. EB significantly raised MDA, NOx, TNF-α, IL-18, IL-1ß, and GSDMD and up-regulated NLRP3/Caspase-1 proteins. However, GSH, SIRT1, and Nrf2 levels were reduced in cervical tissue. VIN significantly alleviates all biochemical and histopathological abnormalities. VIN considerably mitigates EB-induced cervical hyperkeratosis via NLRP3-induced pyroptosis and SIRT1/Nrf2 signaling pathway.

Advancing osteoarthritis therapy with GMOCS hydrogel-loaded BMSCs-exos.

This study investigated the mechanism of the extracellular matrix-mimicking hydrogel-mediated TGFB1/Nrf2 signaling pathway in osteoarthritis using bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos). A GMOCS-Exos hydrogel was synthesized and evaluated for its impact on chondrocyte viability and neutrophil extracellular traps (NETs) formation. In an OA rat model, GMOCS-Exos promoted cartilage regeneration and inhibited NETs formation. Transcriptome sequencing identified TGFB1 as a key gene, with GMOCS-Exos activating Nrf2 signaling through TGFB1. Depletion of TGFB1 hindered the cartilage-protective effect of GMOCS-Exos. This study sheds light on a promising therapeutic strategy for osteoarthritis through GMOCS-Exos-mediated TGFB1/Nrf2 pathway modulation.

Isoliensinine activated the Nrf2/GPX4 pathway to inhibit glutamate-induced ferroptosis in HT-22 cells.

Isoliensinine (ISO), a natural compound, is a bibenzyl isoquinoline alkaloid monomer in lotus seed, which has strong antioxidant and free radical scavenging activities. The oxidative toxicity caused by glutamic acid overdose is one of the important mechanisms of nerve cell injury, and the oxidative toxicity caused by glutamic acid is related to ferroptosis. This study aims to establish a glutamate-induced injury model of mouse hippocampal neurons HT-22 cells, and investigate the protective effect of ISO on the neurotoxicity of glutamate-induced HT-22 cells. The results showed that ISO inhibited glutamate-induced ferroptosis of neuronal cells through nuclear factor E2-related factor 2/glutathione peroxidase 4 (Nrf2/GPX4) signaling pathway. Pretreatment of HT-22 cells with ISO significantly reduced glutamate-induced cell death. Ferroptosis inhibitors have the same effect. ISO inhibited the decrease of mitochondrial membrane potential detection and the increase of iron content induced by glutamate, the increase of malondialdehyde and reactive oxygen species in cytoplasm and lipid, and protected the activities of GPx and superoxide dismutase enzymes. In addition, WB showed that glutamic acid could induce the upregulated expression of long-chain esteryl coA synthase 4 (ACSL4) protein and the downregulated expression of SLC7A11 and GPX4 protein in HT-22 cells, while ISO could prevent the abnormal expression of these proteins induced by glutamic acid. The nuclear translocation of Nrf2 in HT-22 cells was increased, and the expression of downstream heme oxygenase-1 protein was upregulated. In summary, ISO protects HT-22 cells from glutamate-induced ferroptosis through a novel mechanism of the Nrf2/GPX4 signaling pathway.

A Nanozyme-Boosted MOF-CRISPR Platform for Treatment of Alzheimer's Disease.

Rectifying the aberrant microenvironment of a disease through maintenance of redox homeostasis has emerged as a promising perspective with significant therapeutic potential for Alzheimer's disease (AD). Herein, we design and construct a novel nanozyme-boosted MOF-CRISPR platform (CMOPKP), which can maintain redox homeostasis and rescue the impaired microenvironment of AD. By modifying the targeted peptides KLVFFAED, CMOPKP can traverse the blood-brain barrier and deliver the CRISPR activation system for precise activation of the Nrf2 signaling pathway and downstream redox proteins in regions characterized by oxidative stress, thereby reinstating neuronal antioxidant capacity and preserving redox homeostasis. Furthermore, cerium dioxide possessing catalase enzyme-like activity can synergistically alleviate oxidative stress. Further in vivo studies demonstrate that CMOPKP can effectively alleviate cognitive impairment in 3xTg-AD mouse models. Therefore, our design presents an effective way for regulating redox homeostasis in AD, which shows promise as a therapeutic strategy for mitigating oxidative stress in AD.

The C5AR1/TNFSF13B axis alleviates osteoarthritis by activating the PI3K/Akt/GSK3ß/Nrf2/HO-1 pathway to inhibit ferroptosis.

Chondrocyte ferroptosis induces the occurrence of osteoarthritis (OA). As a key gene of OA, C5a receptor 1 (C5AR1) is related to ferroptosis. Here, we investigated whether C5AR1 interferes with chondrocyte ferroptosis during OA occurrence. C5AR1 was downregulated in PA-treated chondrocytes. Overexpression of C5AR1 increased the cell viability and decreased ferroptosis in chondrocytes. Moreover, Tumor necrosis factor superfamily member 13B (TNFSF13B) was downregulated in PA-treated chondrocytes, and knockdown of TNFSF13B eliminated the inhibitory effect of C5AR1 on ferroptosis in chondrocytes. More importantly, the PI3K/Akt/GSK3ß/Nrf2/HO-1 pathway inhibitor LY294002 reversed the inhibition of C5AR1 or TNFSF13B on ferroptosis in chondrocytes. Finally, we found that C5AR1 alleviated joint tissue lesions and ferroptosis in rats and inhibited the progression of OA in the rat OA model constructed by anterior cruciate ligament transection (ACLT), which was reversed by interfering with TNFSF13B. This study shows that C5AR1 reduces the progression of OA by upregulating TNFSF13B to activate the PI3K/Akt/GSK3ß/Nrf2/HO-1 pathway and thereby inhibiting chondrocyte sensitivity to ferroptosis, indicating that C5AR1 may be a potential therapeutic target for ferroptosis-related diseases.

Exploring the Underlying Mechanisms of Preventive Treatment Related to Dietary Factors for Gastric Diseases.

Gastric diseases have emerged as one of the main chronic diseases in humans, leading to considerable health, social, and economic burdens. As a result, using food or "food and medicinal homologous substances" has become an effective strategy to prevent gastric diseases. Diet may play a crucial role in the prevention and mitigation of gastric diseases, particularly long-term and regular intake of specific dietary components that have a protective effect on the stomach. These key components, extracted from food, include polysaccharides, alkaloids, terpenoids, polyphenols, peptides, probiotics, etc. The related mechanisms involve regulating gastric acid secretion, protecting gastric mucosa, increasing the release of gastric defense factors, decreasing the level of inflammatory factors, inhibiting Helicobacter pylori infection, producing antioxidant effects or reducing oxidative damage, preventing gastric oxidative stress by inhibiting lipid peroxides, activating Nrf2 signaling pathway, and inhibiting NF-κB, TLR4, and NOS/NO signaling pathways.

DDX5 deficiency drives non-canonical NF-κB activation and NRF2 expression, influencing sorafenib response and hepatocellular carcinoma progression.

In advanced hepatocellular carcinoma (HCC), RNA helicase DDX5 regulates the Wnt/ß-catenin-ferroptosis axis, influencing the efficacy of the multi-tyrosine kinase inhibitor (mTKI) sorafenib. DDX5 inhibits Wnt/ß-catenin signaling, preventing sorafenib-induced ferroptosis escape. Sorafenib/mTKIs reduce DDX5 expression, correlating with poor patient survival post-sorafenib treatment. Notably, DDX5-knockout in HCC cells activates Wnt/ß-catenin signaling persistently. Herein, we investigate the mechanistic impact of Wnt/ß-catenin activation resulting from DDX5 downregulation in the progression and treatment of HCC. RNAseq analyses identified shared genes repressed by DDX5 and upregulated by sorafenib, including Wnt signaling genes, NF-κB-inducing kinase (NIK) essential for non-canonical NF-κB (p52/RelB) activation, and cytoprotective transcription factor NRF2. We demonstrate, Wnt/ß-catenin activation induced NIK transcription, leading to non-canonical NF-κB activation, which subsequently mediated NRF2 transcription. Additionally, DDX5 deficiency extended NRF2 protein half-life by inactivating KEAP1 through p62/SQSTM1 stabilization. In a preclinical HCC mouse model, NRF2 knockdown or DDX5 overexpression restricted tumor growth upon sorafenib treatment, via induction of ferroptosis. Importantly, DDX5-knockout HCC cells exhibited elevated expression of Wnt signaling genes, NIK, p52/RelB, and NRF2-regulated genes, regardless of sorafenib treatment. Transcriptomic analyses of HCCs from TCGA and the Stelic Animal Model (STAM) of non-alcoholic steatohepatitis revealed elevated expression of these interconnected pathways in the context of DDX5 downregulation. In conclusion, DDX5 deficiency triggers Wnt/ß-catenin signaling, promoting p52/RelB and NRF2 activation, thereby enabling ferroptosis evasion upon sorafenib treatment. Similarly, independent of sorafenib, DDX5 deficiency in liver tumors enhances activation and gene expression of these interconnected pathways, underscoring the clinical relevance of DDX5 deficiency in HCC progression and therapeutic response.

The impact of consuming different types of high-caloric fat diet on the metabolic status, liver, and aortic integrity in rats.

Consumption of high-caloric diets contributes to the alarming number of overweight and obese individuals worldwide, which in turn leads to several diseases and multiple organ dysfunction. Not only has the number of calories taken per day but also the type of fat in the diet has an important impact on health. Accordingly, the purpose of the current study was to examine the impact of different types of high-caloric fat diets on the metabolic status and the integrity of the liver and aorta in albino rats. Adult male albino rats were divided into 6 groups: Control group, long chain-saturated fat group (SFD), long chain-monounsaturated fat (MUFAs) group, long chain-polyunsaturated fat (PUFAs) group, medium-chain fat (MCFAs) group, and short-chain fat (SCFAs) group. Body mass index (BMI), Lee index, and visceral fat amount were reported. Serum levels of insulin, liver transaminases, lipid profile, and different oxidative stress and inflammatory markers were evaluated. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and adiponectin/leptin ratio were also calculated. Histopathological examinations of liver and aorta with Masson's trichrome stain, and immune-staining for Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) were also done. SFD group showed significantly elevated liver transaminases, inflammatory markers, HOMA-IR, dyslipidemia, reduced adiponectin, and deficient anti-oxidative response compared to other groups together with disturbed hepatic and aortic architecture. Other treated groups showed an improvement. PUFAs group showed the highest level of improvement. Not all high-fat diets are hazardous. Diets rich in PUFAs, MUFAs, MCFAs, or SCFAs may protect against the hazards of high caloric diet.

Protective function of albiflorin against ferroptosis in exhaustive exerciseinduced myocardial injury via the AKT/Nrf2/HO-1 signaling.

PURPOSE: It has been reported that exhaustive exercise (EE) causes myocyte injury, and eventually damages the function of the myocardia. Albiflorin (AF) has anti-inflammatory, antioxidant, and anti-apoptosis effects. In this study, we determined whether AF could mitigate the EE-induced myocardial injury and research the potential mechanisms. METHODS: The rat model of EE was built by forced treadmill running method. Rats were intraperitoneally injected with AF before EE once daily for one week. The relative factors levels were examined by commercial kits. The apoptosis was appraised using a TdT-mediated dUTP nick end labeling assay kit. The ACSL4, GPX4, Nrf2, pAKT/AKT, and HO-1 contents were assessed by western blot. RESULTS: AF lessened EE-induced cardiac myocytes ischemic/hypoxic injury and reduced the contents of myocardial injury biomarkers in the serum. AF lessened EE-induced cardiac myocyte apoptosis, inflammatory response, oxidative stress, and ferroptosis in myocardial tissues. However, the influences of AF were overturned by the co-treatment of AF and LY294002. AF activated the AKT/Nrf2/HO-1 signaling pathway in myocardial tissues in vivo. CONCLUSIONS: AF could curb cardiac myocytes ferroptosis, thus diminishing the EE-induced myocardial injury through activating the AKT/Nrf2/HO-1 cascade.

Puerarin alleviates oxaliplatin-induced neuropathic pain by promoting Nrf2/GPX4-mediated antioxidative response.

Oxaliplatin (OXA) as the platinum-based agent induces the cumulative neuropathy including functional impairment and neuropathic pain. OXA treatment triggered oxidative stress and inflammatory reaction in the spinal cord. Puerarin as a natural product has the neuroprotective effect on neuropathic pain. Hence, the roles and mechanisms of Pue on OXA induced neuropathic pain were studied. In this study, OXA-induced neuropathic pain mouse model was constructed by oxaliplatin injection for 5 consecutive days and two cycles. Pue (10 mg/kg) was administered intraperitoneally for seven consecutive days. The changes of behavior, morphology and levels of related proteins were detected. As a result, OXA-induced mice exhibited as the increased pain hypersensitivity, the impaired motor coordination, the activated NLRP3 inflammasome mediated inflammation and the suppressed nuclear factor erythroid 2-related factor 2 (Nrf2) mediated antioxidative reaction in the spinal cord (P<0.05 vs Control). After Pue administration, the mechanical pain threshold, thermal pain latency, spontaneous pain number and motor latency were improved (P<0.05 vs OXA). In the spinal cord, Pue administration reduced the levels of inflammatory elements, increased the levels of antioxidative elements and decreased the levels of oxidative factors (P<0.05 vs OXA). Furthermore, Pue also bind with Nrf2 and increased the association of Nrf2 to glutathione peroxidase 4 (GPX4). In summary, Pue alleviates oxaliplatin induced neuropathic pain by enhancing Nrf2/GPX4-mediated antioxidant response and suppressing inflammatory reaction in the spinal cord.

Molecular basis of the interactions between the disordered Neh4 and Neh5 domains of Nrf2 and CBP/p300 in oxidative stress response.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor that functions in maintaining redox homeostasis in cells. It mediates the transcription of cytoprotective genes in response to environmental and endogenous stresses to prevent oxidative damage. Thus, Nrf2 plays a significant role in chemoprevention. However, aberrant activation of Nrf2 has been shown to protect cancer cells from apoptosis and contribute to their chemoresistance. The interaction between Nrf2 and CBP is critical for the gene transcription activation. CBP and its homologue p300 interact with two transactivation domains in Nrf2, Neh4, and Neh5 domains through their TAZ1 and TAZ2 domains. To date, the molecular basis of this crucial interaction is not known, hindering a more detailed understanding of the regulation of Nrf2. To close this knowledge gap, we have used a set of biophysical experiments to dissect the Nrf2-CBP/p300 interactions. Structural properties of Neh4 and Neh5 and their binding with the TAZ1 and TAZ2 domains of CBP/p300 were characterized. Our results show that the Neh4 and Neh5 domains of Nrf2 are intrinsically disordered, and they both can bind the TAZ1 and TAZ2 domains of CBP/p300 with micromolar affinities. The findings provide molecular insight into the regulation of Nrf2 by CBP/p300 through multi-domain interactions.

Micafungin protects mouse heart against doxorubicin-induced oxidative injury via suppressing MALT1-dependent k48-linked ubiquitination of Nrf2.

Oxidative stress contributes greatly to doxorubicin (DOX)-induced cardiotoxicity. Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor in DOX-induced myocardial oxidative injury. Recently, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)-dependent k48-linked ubiquitination was responsible for down-regulation of myocardial Nrf2 in DOX-treated mice. Micafungin, an antifungal drug, was identified as a potential MALT1 inhibitor. This study aims to explore whether micafungin can reduce DOX-induced myocardial oxidative injury and if its anti-oxidative effect involves a suppression of MALT1-dependent k48-linked ubiquitination of Nrf2. To establish the cardiotoxicity models in vivo and in vitro, mice were treated with a single dose of DOX (15 mg/kg, i.p.) and cardiomyocytes were incubated with DOX (1 µM) for 24 h, respectively. Using mouse model of DOX-induced cardiotoxicity, micafungin (10 or 20 mg/kg) was shown to improve cardiac function, concomitant with suppression of oxidative stress, mitochondrial dysfunction, and cell death in a dose-dependent manner. Similar protective roles of micafungin (1 or 5 µM) were observed in DOX-treated cardiomyocytes. Mechanistically, micafungin weakened the interaction between MALT1 and Nrf2, decreased the k48-linked ubiquitination of Nrf2 while elevated the protein levels of Nrf2 in both DOX-treated mice and cardiomyocytes. Furthermore, MALT1 overexpression counteracted the cardioprotective effects of micafungin. In conclusion, micafungin reduces DOX-induced myocardial oxidative injury via suppression of MALT1, which decreases the k48-linked ubiquitination of Nrf2 and elevates Nrf2 protein levels. Thus, micafungin may be repurposed for treating DOX-induced cardiotoxicity.