Dahuang Danshen Decoction Inhibits Pancreatic Fibrosis by Regulating Oxidative Stress and Endoplasmic Reticulum Stress

Background. In Traditional Chinese Medicine (TCM), Dahuang Danshen decoction (DD) is used to treat pancreatic fibrosis. Pancreatic fibrosis is a typical manifestation of chronic pancreatitis (CP), which affects the digestive system. The therapeutic mechanisms of DD in pancreatic fibrosis are unclear. Aim. This study aimed to investigate the regulatory mechanisms of DD on oxidative stress and endoplasmic reticulum stress in CP. Materials and Methods. Experimental rats were intraperitoneally injected with 500 mg/kg BW of diethyldithiocarbamate (DDC) twice a week for six weeks to induce CP. At the same time, DD was administered orally at daily doses of 1.37 g/kg BW, 2.74 g/kg BW, and 5.48 g/kg BW to evaluate its treatment effects on CP. After all treatments, pancreatic tissues were harvested and subjected to H&E staining. Transmission electron microscopy (TEM) was also performed to show the endoplasmic reticulum structure in the pancreatic tissues. Immunohistochemistry was used to detect the α-SMA expression level in the pancreatic tissues. Metabolomics analysis of the serum and proteomics analysis of the pancreatic tissues were performed to reveal the changes of endogenous metabolites and proteins, respectively. Concentrations of GSH, MDA, SOD, ROS, col-1, and col-3 were determined using corresponding kits. The western blotting method was used to determine the protein levels of Keap-1, HO-1, NQO1, Nrf2, GRP, JNK, and caspase 12. The pancreatic mRNA levels of NQO1, GPX1, HO-1, GST-π, GRP, JNK, and caspase 12 were also determined by quantitative PCR. The interactions between TCM components and Keap-1 were investigated by molecular docking modeling. Results. The pathohistological results demonstrated that DD could ameliorate DDC-induced CP in vivo, indicated by reduction of α-SMA, col-1, col-3, TNF-α, and IL-6. DD increased serum levels of GSH and SOD but reduced pancreatic ROS. DD decreased cytoplasmic Keap-1 and increased Nrf2 nuclear localization. Correspondingly, DD increased the expression levels of Nrf2 downstream antioxidant genes NQO1, GPX1, HO-1, and GST-π. DD also decreased ERS hallmarks caspase 12 cleavage and GRP expression. Eventually, DD inhibited PSC activation by reducing JNK phosphorylation and MMK-3/p38 expression. Molecular docking analysis showed that salvianolic acid B and emodin had a good binding affinity toward Keap-1. Conclusions. These results demonstrated that DD could ameliorate the oxidative and endoplasmic reticulum stress through releasing Nrf2 from Keap-1 binding and inducing the downstream antioxidant enzymes. As a result, DD could thwart pancreatic fibrosis by inhibiting PSCs activation, which was induced by OS and ERS through JNK and MMK3/p38 pathways.

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Ginkgo biloba Leaf Extract Protects against Myocardial Injury via Attenuation of Endoplasmic Reticulum Stress in Streptozotocin-Induced Diabetic ApoE−/− Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2370617 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 6

Author(s):

Jinfan Tian ◽

Yanfei Liu ◽

Yue Liu ◽

Keji Chen ◽

Shuzheng Lyu

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Myocardial Injury ◽

Caspase 3 ◽

Interstitial Fibrosis ◽

Serum Levels ◽

Cardiomyocyte Apoptosis ◽

Mrna Levels ◽

Caspase 12 ◽

Apoptosis Pathways

Diabetes was induced in high-fat diet-fed ApoE−/− mice via administration of low-dose streptozotocin (STZ) for five days. Mice were then treated with GBE (200 or 400 mg/kg) by gastric gavage daily for 12 weeks. Mice in the untreated diabetic group received saline instead, and nondiabetic C57BL/6J mice served as controls. Collagen І and ІІІ mRNA expression was measured by real-time PCR. TNF-α, IL-1β mRNA levels, and NF-κB expression were determined to analyze intramyocardial inflammation. Hallmarks of endoplasmic reticulum stress- (ERS-) related apoptosis pathways, including phosphorylated c-Jun N-terminal kinase (p-JNK), C/EBP homologous protein (CHOP), caspase-12, and cleaved caspase-3, were analyzed by Western blotting. Diabetic ApoE−/− myocardial injury was associated with increased cardiomyocyte apoptosis (increased expression of p-JNK, CHOP, caspase-12, and cleaved caspase-3), interstitial fibrosis (increased mRNA levels of collagen І and ІІІ), and inflammation (increased mRNA levels of TNF-α and IL-1β, and NF-κB expression). GBE at 200 and 400 mg/kg/day significantly attenuated cardiomyocyte apoptosis, collagen deposition, and inflammation in diabetic mice via inhibition of the p-JNK, CHOP, and caspase-12 pathways. Serum levels of the proinflammatory cytokines (IL-6, IL-1β, and TNF-α), blood glucose, and lipid profiles were also regulated by GBE treatment. GBE might be beneficial in the treatment of diabetic myocardial injury.

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Endoplasmic reticulum stress-dependent oxidative stress mediated vascular injury induced by silica nanoparticles in vivo and in vitro

NanoImpact ◽

10.1016/j.impact.2019.100169 ◽

2019 ◽

Vol 14 ◽

pp. 100169 ◽

Cited By ~ 7

Author(s):

Yanbo Li ◽

Ru Ma ◽

Xiaoying Liu ◽

Yi Qi ◽

Alimire Abulikemu ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Silica Nanoparticles ◽

Vascular Injury ◽

Stress Dependent

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Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

Cellular Physiology and Biochemistry ◽

10.1159/000486165 ◽

2017 ◽

Vol 44 (6) ◽

pp. 2407-2421 ◽

Cited By ~ 20

Author(s):

Yanhua Cui ◽

Lipeng Ren ◽

Bo Li ◽

Jia Fang ◽

Yuanxin Zhai ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Caspase 3 ◽

Survival Rates ◽

Underlying Mechanism ◽

Pcr Analysis ◽

Caspase 12 ◽

Apoptosis Proteins

Background/Aims: Busulfan is commonly used for cancer chemotherapy. Although it has the advantage of increasing the survival rate of patients, it can cause male infertility via damaging the testes and reducing sperm counts. Therefore, the underlying mechanism should be explored, and new agents should be developed to protect the male reproductive system from busulfan-induced damage. Endoplasmic reticulum stress (ERS) is considered a key contributor to numerous pathologies. Despite several studies linking ERS to toxicants, studies have yet to determine whether ERS is a contributing factor to busulfan-induced testicular damage. Melatonin is a well-known broad-spectrum antioxidant, anti-inflammatory and antitumour agent, but the effects of melatonin on busulfan-induced ERS in mouse testes damage are less documented. Methods: The effects of melatonin were measured by immunofluorescence staining, Western blot, qRT-PCR analysis and flow cytometry assay. The underlying mechanism was investigated by measuring ERS. Results: We found that ERS was strongly activated in mouse testes (in vivo) and the C18-4 cell line (in vitro) after busulfan administration. ERS-related apoptosis proteins such as caspase-12, CHOP and caspase-3 were activated, and the expression of apoptotic proteins such as P53 and PUMA were upregulated. Furthermore, we investigated whether melatonin reduced the extent of damage to mouse testes and improved the survival rates of busulfan-treated mice. When exploring the underlying mechanisms, we found melatonin could counteract ERS by decreasing the expression levels of the ERS markers GRP78, ATF6, pIRE1 and XBP1 in mouse testes and mouse SSCs (C18-4 cells). Moreover, it blocked the activation of ERS-related apoptosis proteins caspase-12, CHOP and caspase-3 and suppressed P53 and PUMA expression stimulated by busulfan both in vivo and in vitro. Conclusion: Our results demonstrate that ERS is an important mediator for busulfan-induced apoptosis. The attenuation of ERS by melatonin can prevent busulfan-treated SSCs apoptosis and protect busulfan-treated testes from damage. Thus, this study suggests that melatonin may alleviate the side effects of busulfan for male patients during clinical treatment.

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In Vitro and In Vivo Protective Effects of Lentil (Lens culinaris) Extract against Oxidative Stress-Induced Hepatotoxicity

Molecules ◽

10.3390/molecules27010059 ◽

2021 ◽

Vol 27 (1) ◽

pp. 59

Author(s):

Yeon-Seop Jung ◽

So-Hee Lee ◽

So Young Chun ◽

Dae Hwan Kim ◽

Byung Ik Jang ◽

...

Keyword(s):

Oxidative Stress ◽

Serum Levels ◽

Liver Cells ◽

Dependent Manner ◽

Protective Effects ◽

H2o2 Treatment ◽

Antioxidant Genes ◽

Hepatic Diseases

Excessive oxidative stress plays a role in hepatotoxicity and the pathogenesis of hepatic diseases. In our previous study, the phenolic extract of beluga lentil (BLE) showed the most potent in vitro antioxidant activity among extracts of four common varieties of lentils; thus, we hypothesized that BLE might protect liver cells against oxidative stress-induced cytotoxicity. BLE was evaluated for its protective effects against oxidative stress-induced hepatotoxicity in AML12 mouse hepatocytes and BALB/c mice. H2O2 treatment caused a marked decrease in cell viability; however, pretreatment with BLE (25–100 μg/mL) for 24 h significantly preserved the viability of H2O2-treated cells up to about 50% at 100 μg/mL. As expected, BLE dramatically reduced intracellular reactive oxygen species (ROS) levels in a dose-dependent manner in H2O2-treated cells. Further mechanistic studies demonstrated that BLE reduced cellular ROS levels, partly by increasing expression of antioxidant genes. Furthermore, pretreatment with BLE (400 mg/kg) for 2 weeks significantly reduced serum levels of alanine transaminase and triglyceride by about 49% and 40%, respectively, and increased the expression and activity of glutathione peroxidase in CCl4-treated BALB/c mice. These results suggest that BLE protects liver cells against oxidative stress, partly by inducing cellular antioxidant system; thus, it represents a potential source of nutraceuticals with hepatoprotective effects.

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Oleoylethanolamide Reduces Hepatic Oxidative Stress and Endoplasmic Reticulum Stress in High-Fat Diet-Fed Rats

Antioxidants ◽

10.3390/antiox10081289 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1289

Author(s):

Anna Maria Giudetti ◽

Daniele Vergara ◽

Serena Longo ◽

Marzia Friuli ◽

Barbara Eramo ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

High Fat Diet ◽

Free Access ◽

High Fat ◽

Alcoholic Fatty Liver ◽

Antioxidant Genes ◽

Diet Induced Obesity ◽

Hepatic Oxidative Stress

Long-term high-fat diet (HFD) consumption can cause weight gain and obesity, two conditions often associated with hepatic non-alcoholic fatty liver and oxidative stress. Oleoylethanolamide (OEA), a lipid compound produced by the intestine from oleic acid, has been associated with different beneficial effects in diet-induced obesity and hepatic steatosis. However, the role of OEA on hepatic oxidative stress has not been fully elucidated. In this study, we used a model of diet-induced obesity to study the possible antioxidant effect of OEA in the liver. In this model rats with free access to an HFD for 77 days developed obesity, steatosis, and hepatic oxidative stress, as compared to rats consuming a low-fat diet for the same period. Several parameters associated with oxidative stress were then measured after two weeks of OEA administration to diet-induced obese rats. We showed that OEA reduced, compared to HFD-fed rats, obesity, steatosis, and the plasma level of triacylglycerols and transaminases. Moreover, OEA decreased the amount of malondialdehyde and carbonylated proteins and restored the activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, which decreased in the liver of HFD-fed rats. OEA had also an improving effect on parameters linked to endoplasmic reticulum stress, thus demonstrating a role in the homeostatic control of protein folding. Finally, we reported that OEA differently regulated the expression of two transcription factors involved in the control of lipid metabolism and antioxidant genes, namely nuclear factor erythroid-derived 2-related factor 1 (Nrf1) and Nrf2, thus suggesting, for the first time, new targets of the protective effect of OEA in the liver.

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Reactive Oxygen Species-Triggered Trophoblast Apoptosis Is Initiated by Endoplasmic Reticulum Stress via Activation of Caspase-12, CHOP, and the JNK Pathway in Toxoplasma gondii Infection in Mice

Infection and Immunity ◽

10.1128/iai.06295-11 ◽

2012 ◽

Vol 80 (6) ◽

pp. 2121-2132 ◽

Cited By ~ 46

Author(s):

Xiucai Xu ◽

Tingting Liu ◽

Aimei Zhang ◽

Xingxing Huo ◽

Qingli Luo ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Endoplasmic Reticulum ◽

Toxoplasma Gondii ◽

Endoplasmic Reticulum Stress ◽

Reactive Oxygen ◽

Oxygen Species ◽

Jnk Pathway ◽

Content Type ◽

Caspase 12

ABSTRACTToxoplasma gondiiinfection in pregnant women may result in abortion or in fetal teratogenesis; however, the underlying mechanisms are still unclear. In this paper, based on a murine model, we showed that maternal infection with RH strainT. gondiitachyzoites induced elevated production of reactive oxygen species (ROS), local oxidative stress, and subsequent apoptosis of placental trophoblasts. PCR array analysis of 84 oxidative stress-related genes demonstrated that 27 genes were upregulated at least 2-fold and that 9 genes were downregulated at least 2-fold in theT. gondiiinfection group compared with levels in the control group. The expression of NADPH oxidase 1 (Nox1) and glutathione peroxidase 6 (Gpx6) increased significantly, about 25-fold. The levels of malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) increased significantly withT. gondiiinfection, and levels of glutathione (GSH) decreased rapidly.T. gondiiinfection increased the early expression of endoplasmic reticulum stress (ERS) markers, followed by cleavage of caspase-12, activation of ASK1/JNK, and increased apoptosis of trophoblasts, bothin vivoandin vitro. The apoptosis of trophoblasts, the activation of caspase-12 and the ASK1/JNK pathway, and the production of peroxides were dramatically inhibited by pretreatment withN-acetylcysteine (NAC). The upregulation of Nox1 was contact dependent and preceded the increase in levels of ERS markers and the activation of the proapoptosis cascade. Thus, we concluded that apoptosis in placental trophoblasts was initiated predominantly by ROS-mediated ERS via activation of caspase-12, CHOP, and the JNK pathway in acuteT. gondiiinfection. Elevated ROS production is the central event inT. gondii-induced apoptosis of placental trophoblasts.

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The Sodium-Glucose Co-Transporter 2 Inhibitor, Empagliflozin, Protects against Diabetic Cardiomyopathy by Inhibition of the Endoplasmic Reticulum Stress Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000475942 ◽

2017 ◽

Vol 41 (6) ◽

pp. 2503-2512 ◽

Cited By ~ 20

Author(s):

Yang Zhou ◽

Wei Wu

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Diabetic Cardiomyopathy ◽

Left Ventricular ◽

High Dose ◽

Mrna Levels ◽

Caspase 12 ◽

Endoplasmic Reticulum Stress Pathway ◽

Systolic And Diastolic Function ◽

Stress Pathway

Background/Aims: This study aimed to determine whether or not the sodium-glucose co-transporter 2 inhibitor, empagliflozin (EMPA), can protect against diabetic cardiomyopathy (DCM) and to elucidate the related mechanism. Methods: Rats were divided into the following four groups: a non-diabetic group; diabetic cardiomyopathy rats without EMPA treatment; and diabetic cardiomyopathy rats with EMPA treatment (low- and high-dose EMPA). Hemodynamic measurements were performed to evaluate left ventricular systolic and diastolic function. The histopathology of the heart was examined with hematoxylin-eosin staining. Expression of glucose-regulated protein (GRP)78, enhancer-binding protein homologous protein (CHOP), and caspase-12 was detected by Western blot, and the mRNA levels of XBP1, ATF4, and TRAF2 were analysed by real-time PCR. Results: EMPA significantly decreased the blood glucose level when compared with vehicle. EMPA strongly improved cardiac function based on hemodynamic and histopathologic analyses. Moreover, EMPA can significantly down-regulate the expression of GRP78, CHOP, and caspase-12 (P < 0.01). Additionally, the mRNA levels of XBP1, ATF4, and TRAF2 were markedly decreased by administration of EMPA (P < 0.01). Conclusion: EMPA protects against DCM by inactivating the endoplasmic reticulum stress pathway.

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Berberine Improved Aldo-Induced Podocyte Injury via Inhibiting Oxidative Stress and Endoplasmic Reticulum Stress Pathways both In Vivo and In Vitro

Cellular Physiology and Biochemistry ◽

10.1159/000445618 ◽

2016 ◽

Vol 39 (1) ◽

pp. 217-228 ◽

Cited By ~ 11

Author(s):

Bin Wang ◽

Xianlin Xu ◽

Xiaozhou He ◽

Zhigang Wang ◽

Min Yang

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Annexin V ◽

Isoquinoline Alkaloid ◽

Sprague Dawley ◽

Podocyte Injury ◽

Transmission Electron

Background/Aims: Berberine, a naturally occurring isoquinoline alkaloid, acts against oxidative stress (OS) and endoplasmic reticulum stress (ERS), both of which are responsible for Aldosterone (Aldo) -induced podocyte injury. However, the direct effects of berberine on Aldo-induced OS, ERS, and podocyte injury are not well defined. Methods: Uninephrectomized Sprague-Dawley rats were given 1% NaCl (salt) in their water and an Aldo infusion (0.75 µg/h) for 28 days to induce podocyte injury in the Aldo group. In the Aldo/berberine group, in addition to Aldo infusion, rats were administered 150 mg/kg berberine per day by gastric gavage for 4 weeks. Podocytes were incubated in media containing either buffer or Aldo in the presence or absence of berberine for variable time periods. The kidney tissues and podocytes were then investigated using morphological analysis, immunohistochemistry, transmission electron microscopy, western blot, DHE staining, DCFDA fluorescence, and Annexin V staining. Results: Here, we have reported that berberine attenuated Aldo-induced OS, ERS, and podocyte injury both in vivo and in vitro. Additionally, berberine treatment improved the extensive fusion of foot processes in electron micrographs resulting from Aldo/salt infusion in rats. Conclusion: Berberine may be examined as an effective agent against Aldo-induced podocyte injury.

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