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Ischemia/hypoxia (I/H)-induced myocardial injury has a large burden worldwide. Hesperetin (HSP) has a cardioprotective effect, but the molecular mechanism underlying this is not clearly established. Here, we focused on the protective mechanisms of HSP against I/H-induced myocardium injury. H9c2 cardiomyocytes were challenged with CoCl 2 for 22 h to imitate hypoxia after treatment groups received HSP for 4 h. The viability of H9c2 cardiomyocytes was evaluated, and cardiac function indices, reactive oxygen species, apoptosis, mitochondrial membrane potential (MMP), and intracellular Ca 2+ concentration ([Ca 2+ ] i ) were measured. L-type Ca 2+ current (I Ca-L ), myocardial contraction, and Ca 2+ transients in isolated ventricular myocytes were also recorded. We found that HSP significantly increased the cell viability, and MMP while significantly decreasing cardiac impairment, oxidative stress, apoptosis, and [Ca 2+ ] i caused by CoCl 2 . Furthermore, HSP markedly attenuated I Ca-L , myocardial contraction, and Ca 2+ transients in a concentration-dependent manner. Our findings suggest a protective mechanism of HSP on I/H-induced myocardium injury by restoring oxidative balance, inhibiting apoptosis, improving mitochondrial function, and reducing Ca 2+ influx via L-type Ca 2+ channels (LTCCs). These data provide a new direction for HSP applied research as a LTCC inhibitor against I/H-induced myocardium injury., (© 2022 John Wiley & Sons Ltd.)

Hesperetin (HSP) is a natural flavonoid that offers useful curative effects for cardiovascular diseases, but its effect on myocardial ischemia and its precise mechanism remains unclear. The aim of this study is to explore the potential cardioprotective mechanism of HSP on myocardial ischemia caused by isoproterenol (ISO). Adult male Kunming mice were randomly divided into five groups: control, ISO, low-dose HSP (L-HSP, 25 mg/kg/d), high-dose HSP (H-HSP, 50 mg/kg/d), and verapamil (VER) group. Treatment groups of mice received HSP or VER for seven days, and the groups other than the control group were injected with ISO (100 mg/kg/d) subcutaneously for two consecutive days to establish a model of myocardial ischemia. Electrocardiogram and heart-histology changes were used to assess changes in myocardial architecture. The activities and the content of oxidative stress markers and inflammatory cytokines were determined and assayed using kits respectively. The expressions of proteins associated with apoptosis and the Sirt1/Nrf2 pathway were evaluated by Western blotting. The results demonstrate that VER, L-HSP and H-HSP significantly reduced the J-point displacement, heart rate, cardiac pathomorphological changes, and the levels of creatine kinase, lactated dehydrogenase, malonaldehyde, interleukin-6, and tumor necrosis factor-α in serum while promoting the activation of superoxide dismutase, catalase, glutathione in serum in the ISO-treated animals. Furthermore, L-HSP and H-HSP also reversed the ISO-induced apoptosis and the changes in the Sirt1/Nrf2 signaling pathway, as evident from the levels of proteins Bax, Bcl-2, caspase-3, Sirt1, Nrf2, NQO-1, and HO-1. In conclusion, HSP plays a protective role in ISO-induced myocardial ischemia by modulating oxidative stress, inflammation, and apoptosis via Sirt1/Nrf2 pathway activation., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease. Dietary supplementation has become a promising strategy for managing NAFLD. Hesperetin, a citrus flavonoid, is mainly found in citrus fruits (oranges, grapefruit, and lemons) and possesses multiple pharmacological properties, including anti-cancer, anti-Alzheimer and anti-diabetic effects. However, the anti-NAFLD effect and mechanisms of hesperetin remain unclear. In this study, we investigated the therapeutic effect of hesperetin against NAFLD and the underlying mechanism in vitro and in vivo. In oleic acid (OA)-induced HepG2 cells, hesperetin upregulated antioxidant levels (SOD/GPx/GR/GCLC/HO-1) by triggering the PI3 K/AKT-Nrf2 pathway, alleviating OA-induced reactive oxygen species (ROS) overproduction and hepatotoxicity. Furthermore, hesperetin suppressed NF-κB activation and reduced inflammatory cytokine secretion (TNF-α and IL-6). More importantly, we revealed that this anti-inflammatory effect is attributed to reduced ROS overproduction by the Nrf2 pathway, as pre-treatment with Nrf2 siRNA or an inhibitor of superoxide dismutase (SOD) or/and glutathione peroxidase (GPx) abolished hesperetin-induced NF-κB inactivation and reductions in inflammatory cytokine secretion. In a rat model of high-fat diet (HFD)-induced NAFLD, we confirmed that hesperetin relieved hepatic steatosis, oxidative stress, inflammatory cell infiltration and fibrosis. Moreover, hesperetin activated the PI3 K/AKT-Nrf2 pathway in the liver, increasing antioxidant expression and inhibiting NF-κB activation and inflammatory cytokine secretion. In summary, our results demonstrate that hesperetin ameliorates hepatic oxidative stress through the PI3 K/AKT-Nrf2 pathway and that this antioxidative effect further suppresses NF-κB-mediated inflammation during NAFLD progression. Thus, our study suggests that hesperetin may be an effective dietary supplement for improving NAFLD by suppressing hepatic oxidative stress and inflammation.

The present study was performed to investigate the protective effects of tannic acid (TA) on liver injury induced by arsenic trioxide (ATO) and to elucidate the mechanism involved as related to the Kelch‑like ECH‑associated protein 1 (Keap1)‑nuclear factor erythroid 2‑related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway. Adult rats were intraperitoneally injected with TA, while ATO was administered 1 h later. On the 11th day, the rats were euthanized to determine any liver histological changes, liver function, and the activities of antioxidant, antiapoptosis and proinflammatory cytokines in the liver. Furthermore, the protein expression levels of nuclear Nrf2, total Nrf2, Keap1, Heme oxygenase‑1 (HO‑1), NADPH quinine oxidoreductase‑1 (NQO1), and γ‑glutamylcysteine synthetase (γ‑GCS) were determined using western blot analysis. The results showed that TA treatment ameliorated ATO‑induced liver histological changes and decreased the ATO‑induced increased alanine aminotransferase (ALT) and aspartate transaminase (AST) serum levels. Activities of the antioxidant enzymes significantly were increased, while the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were attenuated following TA treatment. In addition, TA treatment inhibited ATO‑induced liver apoptosis and inflammatory responses, increased Bcl‑2 protein expression level and reduced the levels of Bax, caspase‑3, interleukin (IL)‑1β, IL‑6 and tumor necrosis factor (TNF)‑α. Furthermore, TA treatment increased the protein expression levels of Nrf2 and Keap1, HO‑1, NQO1 and γ‑GCS. The results demonstrated that TA has a protective effect on ATO‑treated hepatic toxicity and that its underlying mechanism could be due to TA activation of the Keap1‑Nrf2/ARE signaling pathway, to reduce oxidative stress, apoptosis and inflammation in ATO‑intoxicated rats.

Scope: [6]-Gingerol is one of the primary pungent constituents of ginger. While [6]-gingerol has many pharmacological effects, its benefits for myocardial fibrosis, including its exact role and underlying mechanisms, remain largely unexplored. The present study is designed to characterize the cardio-protective effects of [6]-gingerol in myocardial fibrosis mice and possible underlying mechanisms., Methods and Results: Mice are subcutaneously injected with isoproterenol (ISO, 10 mg kg -1 ) and gavaged with [6]-gingerol (10, 20 mg kg -1 day -1 ) for 14 days. Pathological alterations, fibrosis, oxidative stress, inflammation response, and apoptosis are examined. In ISO-induced myocardial fibrosis, [6]-gingerol treatment decreases the J-point, heart rate, cardiac weight index, left ventricle weight index, creatine kinase (CK), and lactate dehydrogenase serum levels, calcium concentration, reactive oxygen species, malondialdehyde, and glutathione disulfide (GSSG), and increases levels of superoxide dismutase, catalase, glutathione, and GSH/GSSG. Further, [6]-gingerol improved ISO-induced morphological pathologies, inhibited inflammation and apoptosis, and suppressed the toll-like receptor-4 (TLR4)/mitogen-activated protein kinases (MAPKs)/nuclear factor κB (NF-κB) signaling pathways., Conclusion: The protective effect of [6]-gingerol in mice with ISO-induced myocardial fibrosis may be related to the inhibition of oxidative stress, inflammation, and apoptosis, potentially through the TLR4/MAPKs/NF-κB signaling pathway., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Zuota is regarded as the king of Tibetan medicine. However, the major starting material of Zuota is mercury, which is one very toxic heavy metal. This has aroused serious doubts on the biosafety of Zuota containing drugs. In this study, we quantified the Hg contents in four Zuota samples, monitored the release of Hg in simulated gastric/intestinal juice and evaluated their cytotoxicity to Caco-2 cells. Our results showed that the Hg contents in Zuota samples were in the range of 566-676 mg/g. Fortunately, the release of Hg from Zuota samples was very low in simulated gastric juice, and much lower in simulated intestinal juice. Direct contact of Zuota with Caco-2 cells led to dose-dependent cytotoxicity, including activity loss and membrane leakage. The toxicity was closely related to apoptosis, because the caspase 3/7 levels of Caco-2 cells increased after the exposure to Zuota. Interestingly, Zuota samples inhibited the oxidative stress at low concentrations, but the toxicity could be relived by antioxidants. The possible toxicity should be attributed to the cellular uptake of Zuota particulates. Beyond the cytotoxicity, significant differences among Zuota samples from different institutions were observed, suggesting that the preparation process of Zuota had meaningful influence of its biosafety. The implications to the safety and clinical applications of Zuota are discussed.

To investigate the effects of dexmedetomidine combined with intravenous anesthesia on oxidative emergency indicators, postoperative sleep quality, and brain function in patients with hypertensive cerebral hemorrhage (HICH), a total of 285 HICH patients admitted to our hospital from February 2020 to February 2021 were selected. The combined anesthesia group (n = 142) and the control group (n = 143) were established by the random number table method. The control group received conventional intravenous anesthesia, and the combined anesthesia group received dexmedetomidine combined intravenous anesthesia. Two groups of patients before and after operation was observed vital signs, oxidative stress index difference, comparing each time, the change of the two groups of brain function index, adverse reactions occurred between observation group, and the postoperative period of Pittsburgh Sleep Quality Index Scale (PSQI) score as a result, the Pearson correlation coefficient analysis of oxidative stress level and the correlation of HICH patients sleep quality. After operation, the mean arterial pressure (MAP) and heart rate (HR) of patients in both groups decreased significantly. The MAP level in the combined anesthesia group significantly increased compared to the control group, and the HR level decreased significantly than the control group (all P < 0.05). The levels of TNF-α, IL-6 and MDA in both groups increased significantly on day 7 after operation compared with before operation, but the indexes in the combined anesthesia group significantly decreased compared with the control group (P < 0.05). The level of superoxide dismutase (SOD) in both groups significantly decreased compared to that before operation, and the index value in combined anesthesia group significantly increased compared to that in the control group (P < 0.05). After surgery, the levels of central nerve specific protein (S100-β) and neuron specific enolase (NSE) in 2 groups increased with time, and the indexes in the combined anesthesia group significantly decreased compared to the control group (all P < 0.05). The incidence of adr in combined anesthesia group decreased significantly than that in control group (P < 0.05). After surgery, PSQI scores of the two groups showed a downward trend with time extension, and scores of the combined anesthesia group decreased significantly than those of the control group at 24 h, 48 h and 7 d after surgery (all P < 0.05). Pearson's correlation coefficient was used to analyze that TNF-α, IL-6, and MDA levels were positively correlated with PSQI score, while SOD level was negatively correlated with PSQI score (all P < 0.05). Dexmedetomidine combined with intravenous anesthesia can significantly improve the vital signs and oxidative stress response of HICH patients, effectively reduce the risk of adverse reactions, have little impact on the brain function of patients, and can improve the postoperative sleep quality of patients. This operation is worthy of clinical application. In addition, this study further analyzed the influence mechanism of postoperative sleep quality in patients with HICH and showed that TNF-α, IL-6, MDA, and SOD were all correlated with sleep quality in patients with HICH, suggesting that follow-up detection of these indicators has positive significance in improving the prognosis of patients. [ABSTRACT FROM AUTHOR]

Background: Hesperidin (HES) is a flavonoid glycoside found in the tangerine peel and has antioxidant properties. Arsenic trioxide (ATO) is an anti-tumour drug; however, its serious cardiotoxicity limits its clinical application. In addition, the protection of HES against ATO-induced cardiotoxicity has not been explored. Objective: The study aims to investigate and identify the underlying effect and mechanism of HES on ATO-induced cardiotoxicity. Methods: Fifty mice were randomly assigned to five groups. Mice were orally given HES:100 or 300 mg/kg/day concurrently and given ATO intraperitoneal injections: 7.5 mg/kg/day for 1 week. Blood and heart tissues were collected for examination. Evaluated in serum was the levels of creatine kinase (CK), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI). In addition, evaluated in heart tissues were the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, cleaved-Caspase-3, p62, Kelch-like ECH-associated protein 1 (Keap1), and nuclear factor erythroid 2-related factor 2 (Nrf2). The heart tissues were also examined for histopathology and mitochondrial ultrastructure. Results: Compared with the ATO group, the HES treatment groups reduced the levels of CK, LDH, cTnI, ROS, MDA, TNF-α, IL-6, Bax, Caspase-3, cleaved-Caspase-3 and Keap1 and enhanced the levels of SOD, GSH, CAT, Bcl-2, p62 and Nrf2. Conclusions: The results demonstrate that HES protects against ATO-induced cardiotoxicity, through inhibiting oxidative stress, and subsequent inflammation and apoptosis. The underlying results are closely related to the regulation of the p62-Keap1-Nrf2 signalling pathway. [ABSTRACT FROM AUTHOR]

The widespread use of pesticides performs a vital role in safeguarding crop yields and quality, providing the opportunity for multiple pesticides to co-exist, which poses a significant potential risk to human health. To assess the toxic effects caused by exposures to individual pesticides (chlorpyrifos, carbofuran and acetamiprid), binary combinations and ternary combinations, individual and combined exposure models were developed using HepG2 cells and the types of combined effects of pesticide mixtures were assessed using concentration addition (CA), independent action (IA) and combination index (CI) models, respectively, and the expression of biomarkers related to oxidative stress, apoptosis and cell necrosis was further examined. Our results showed that both individual pesticides and mixtures exerted toxic effects on HepG2 cells. The CI model indicated that the toxic effects of pesticide mixtures exhibited synergistic effects. The results of the lactate dehydrogenase (LDH) release and apoptosis assay revealed that the pesticide mixture increased the release of LDH and apoptosis levels. Moreover, our results also showed that individual pesticides and mixtures disrupted redox homeostasis and that pesticide mixtures produced more intense oxidative stress effects. In conclusion, we have illustrated the enhanced combined toxicity of pesticide mixtures by in-vitro experiments, which provides a theoretical basis and scientific basis for further toxicological studies. [Display omitted] • Co-existence of multiple pesticides poses potentially greater risk to human health. • CI model showed that the toxic effects of pesticide mixtures exhibited synergistic effects. • Individual pesticides and mixtures disrupted various biological processes on HepG2 cells. • Pesticide mixtures have a synergistic effect on the expression of multiple biomarkers. [ABSTRACT FROM AUTHOR]

Main conclusion: Hydrogen peroxide-responsive pathways in roots of alkaligrass analyzed by proteomic studies and PutGLP enhance the plant tolerance to saline-, alkali- and cadmium-induced oxidative stresses.Oxidative stress adaptation is critical for plants in response to various stress environments. The halophyte alkaligrass (Puccinellia tenuiflora) is an outstanding pasture with strong tolerance to salt and alkali stresses. In this study, iTRAQ- and 2DE-based proteomics approaches, as well as qRT-PCR and molecular genetics, were employed to investigate H2O2-responsive mechanisms in alkaligrass roots. The evaluation of membrane integrity and reactive oxygen species (ROS)-scavenging systems, as well as abundance patterns of H2O2-responsive proteins/genes indicated that Ca2+-mediated kinase signaling pathways, ROS homeostasis, osmotic modulation, and transcriptional regulation were pivotal for oxidative adaptation in alkaligrass roots. Overexpressing a P. tenuiflora germin-like protein (PutGLP) gene in Arabidopsis seedlings revealed that the apoplastic PutGLP with activities of oxalate oxidase and superoxide dismutase was predominantly expressed in roots and played important roles in ROS scavenging in response to salinity-, alkali-, and CdCl2-induced oxidative stresses. The results provide insights into the fine-tuned redox-responsive networks in halophyte roots. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO)-induced hepatotoxicity limits the therapeutic effect of acute myelogenous leukemia treatment. Magnesium isoglycyrrhizinate (MgIG) is a natural compound extracted from licorice and a hepatoprotective drug used in liver injury. It exhibits anti-oxidant, anti-inflammatory and anti-apoptotic properties. The aim of the present study was to identify the protective action and underlying mechanism of MgIG against ATO-induced hepatotoxicity. A total of 50 mice were randomly divided into five groups (n=10/group): Control; ATO; MgIG and high- and low-dose MgIG + ATO. Following continuous administration of ATO for 7 days, the relative weight of the liver, liver enzyme, histological data, antioxidant enzymes, pro-inflammatory cytokines, cell apoptosis and changes in Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) signaling pathway were observed. MgIG decreased liver injury, decreased the liver weight and liver index, inhibited oxidative stress and decreased the activity of glutathione, superoxide dismutase and catalase, production of reactive oxygen species and levels of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α. Western blotting showed a decrease in Bax and caspase-3. There was decreased cleaved caspase-3 expression and increased Bcl-2 expression. MgIG notably activated ATO-mediated expression of Keap1 and Nrf2 in liver tissue. MgIG administration was an effective treatment to protect the liver from ATO-induced toxicity. MgIG maintained the level of Nrf2 in the liver and protected the antioxidative defense system to attenuate oxidative stress and prevent ATO-induced liver injury. [ABSTRACT FROM AUTHOR]

• Crocetin attenuates oxidative stress, inflammation and apoptosis in the kidney. • Crocetin activates the expression of the PI3K/AKT pathway related genes. • Crocetin has a protective action on arsenic trioxide-induced nephrotoxicity. Arsenic trioxide (ATO)-induced renal toxicity through oxidative stress and apoptosis restricts the therapeutic action of acute myelogenous leukemia. Crocetin (Crt) possesses antioxidant and antiapoptosis properties, and has certain renal protective effects, but it has not been reported that it has protective effect on renal injury caused by ATO. The current study explored the effects and mechanisms of Crt on kidney damage induced by ATO. Fifty Sprague-Dawley rats were randomly divided into five groups. Adult rats were given Crt concurrently with ATO for 1 week. On the 8th day, rats were killed and blood and kidney tissues were collected. Histopathological changes were measured, and kidney tissues and serum were used to determine renal function and antioxidant enzyme activity. In addition, the protein expression levels of P-PI3K, PI3K, P-AKT, AKT, CytC, Bax, Bcl-2 and Caspase-3 were determined via western blot analysis. Results revealed ATO induced renal morphological alterations and activated serum BUN and CRE. Compared with the control group, ROS, MDA, IL-1β, TNF-α, protein carbonyls (PC), lipid hydroperoxides (LOOH) and arsenic concentration levels were found to be significantly increased and SOD, CAT, GSH-Px, GSH and total sulphydryl groups (TSH) levels were attenuated in the ATO group. Crt markedly reduced oxidative stress in ATO-induced nephrotoxicity. Further, ATO induced apoptosis by significantly enhancing CytC, Bax and Caspase-3 and inhibiting Bcl-2. Administration with Crt markedly improved the expression of apoptosis factor. Moreover, Crt treatment stimulated the expressions of P-PI3K, PI3K, P-AKT, AKT induced by ATO. This study indicates Crt could prevent renal injury caused by ATO through inhibiting oxidative stress, inflammation and apoptosis, and its mechanism may be related to activation of PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Recent study suggests that auranofin (AF), a US Food and Drug Administration (FDA)-approved drug for treatment of rheumatoid arthritis, has selective anticancer activity in various experimental models. Its clinical applications in cancer treatment, however, have been hampered due in part to its relatively moderate activity as a single agent. In this study, we performed a high-throughput screening of the FDA-approved drug library for clinical compounds that potentiate the anticancer activity auranofin, and unexpectedly identified an anti-inflammatory drug celecoxib (CE) that potently enhanced the therapeutic activity of AF in vitro and in vivo. Mechanistically, AF/CE combination induced severe oxidative stress that caused ROS-mediated inhibition of hexokinase (HK) and a disturbance of mitochondrial redox homeostasis, resulting in a significant decrease of ATP generation. The CE-induced ROS increase together with AF-medicated inhibition of thioredoxin reductase cause a shift of Trx2 to an oxidized state, leading to degradation of MTCO2 and dysfunction of the electron transport chain. Our study has identified a novel drug combination that effectively eliminates cancer cells in vivo. Since AF and CE are FDA-approved drugs that are currently used in the clinic, it is feasible to translate the findings of this study into clinical applications for cancer treatment. [ABSTRACT FROM AUTHOR]