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Liu JJ, Xu Y, Chen S, Hao CF, Liang J, Li ZL. The mechanism of Yinchenhao decoction in treating obstructive-jaundice-induced liver injury based on Nrf2 signaling pathway. World J Gastroenterol 2022; 28:4635-4648. [PMID: 36157920 PMCID: PMC9476870 DOI: 10.3748/wjg.v28.i32.4635] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 06/08/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obstructive jaundice (OJ) is caused by bile excretion disorder after partial or complete bile duct obstruction. It may cause liver injury through various mechanisms. Traditional Chinese medicine (TCM) has a lot of advantages in treating OJ. The recovery of liver function can be accelerated by combining Chinese medicine treatment with existing clinical practice. Yinchenhao decoction (YCHD), a TCM formula, has been used to treat jaundice. Although much progress has been made in recent years in understanding the mechanism of YCHD in treating OJ-induced liver injury, it is still not clear. AIM To investigate chemical components of YCHD that are effective in the treatment of OJ and predict the mechanism of YCHD. METHODS The active components and putative targets of YCHD were predicted using a network pharmacology approach. Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes path enrichment analysis were carried out by cluster profile. We predicted the biological processes, possible targets, and associated signaling pathways that YCHD may involve in the treatment of OJ. Thirty male Sprague-Dawley rats were randomly divided into three groups, each consisting of 10 rats: the sham group (Group S), the OJ model group (Group M), and the YCHD-treated group (Group Y). The sham group only received laparotomy. The OJ model was established by ligating the common bile duct twice in Groups M and Y. For 1 wk, rats in Group Y were given a gavage of YCHD (3.6 mL/kg) twice daily, whereas rats in Groups S and M were given the same amount of physiological saline after intragastric administration daily. After 7 d, all rats were killed, and the liver and blood samples were collected for histopathological and biochemical examinations. Total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), and aspartate transaminase (AST) levels in the blood samples were detected. The gene expression levels of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), and the nucleus positive rate of NF-E2 related factor 2 (Nrf2) protein were measured. Western blot analyses were used to detect the protein and gene expression levels of Nrf2, Kelch-like ECH-associated protein 1, NAD(P)H quinone dehydrogenase 1 (NQO1), and glutathione-S-transferase (GST) in the liver tissues. One-way analysis of variance was used to evaluate the statistical differences using the statistical package for the social sciences 23.0 software. Intergroup comparisons were followed by the least significant difference test and Dunnett's test. RESULTS The effects of YCHD on OJ involve biological processes such as DNA transcription factor binding, RNA polymerase II specific regulation, DNA binding transcriptional activator activity, and nuclear receptor activity. The protective effects of YCHD against OJ were closely related to 20 pathways, including the hepatitis-B, the mitogen-activated protein kinase, the phosphatidylinositol 3-kinase/protein kinase B, and tumor necrosis factor signaling pathways. YCHD alleviated the swelling and necrosis of hepatocytes. Following YCHD treatment, the serum levels of TBIL (176.39 ± 17.03 μmol/L vs 132.23 ± 13.88 μmol/L, P < 0.01), DBIL (141.41 ± 14.66 μmol/L vs 106.43 ± 10.88 μmol/L, P < 0.01), ALT (332.07 ± 34.34 U/L vs 269.97 ± 24.78 U/L, P < 0.05), and AST (411.44 ± 47.64 U/L vs 305.47 ± 29.36 U/L, P < 0.01) decreased. YCHD promoted the translocation of Nrf2 into the nucleus (12.78 ± 0.99 % vs 60.77 ± 1.90 %, P < 0.001). After YCHD treatment, we found a decrease in iNOS (0.30 ± 0.02 vs 0.20 ± 0.02, P < 0.001) and an increase in eNOS (0.18 ± 0.02 vs 0.32 ± 0.02, P < 0.001). Meanwhile, in OJ rats, YCHD increased the expressions of Nrf2 (0.57 ± 0.03 vs 1.18 ± 0.10, P < 0.001), NQO1 (0.13 ± 0.09 vs 1.19 ± 0.07, P < 0.001), and GST (0.12 ± 0.02 vs 0.50 ± 0.05, P < 0.001), implying that the potential mechanism of YCHD against OJ-induced liver injury was the upregulation of the Nrf2 signaling pathway. CONCLUSION OJ-induced liver injury is associated with the Nrf2 signaling pathway. YCHD can reduce liver injury and oxidative damage by upregulating the Nrf2 pathway.
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Affiliation(s)
- Jun-Jian Liu
- The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, Tianjin 300102, China
| | - Yan Xu
- Graduate School, Tianjin Medical University, Tianjin 3000070, China
| | - Shuai Chen
- Department of Thoracic Surgery, Xuzhou City Hospital of Traditional Chinese Medicine, Xuzhou 221000, Jiangsu Province, China
| | - Cheng-Fei Hao
- The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, Tianjin 300102, China
| | - Jing Liang
- School of Foreign Languages, Chengdu University of Traditional Chinese Medicine, Chengdu 610000, Sichuan Province, China
| | - Zhong-Lian Li
- The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, Tianjin 300102, China
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Stupin V, Abramov I, Gahramanov T, Kovalenko A, Manturova N, Litvitskiy P, Balkizov Z, Silina E. Comparative Study of the Results of Operations in Patients with Tumor and Non-Tumor Obstructive Jaundice Who Received and Did Not Receive Antioxidant Therapy for the Correction of Endotoxemia, Glycolysis, and Oxidative Stress. Antioxidants (Basel) 2022; 11:antiox11061203. [PMID: 35740100 PMCID: PMC9219634 DOI: 10.3390/antiox11061203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/10/2022] [Accepted: 06/17/2022] [Indexed: 02/04/2023] Open
Abstract
Purpose: To compare the results of surgical treatment and changes in biomarkers of cholestasis, endotoxicosis, cytolysis, lipid peroxidation, glycolysis disorders, and inflammation in patients with benign and malignant obstructive jaundice (OJ) in patients receiving and not receiving antioxidant pharmacotherapy (AOT). Patients and methods: The study included 113 patients (aged 21–90 years; 47 males and 66 females) who received surgical intervention for OJ due to non-malignant (71%) or malignant tumor (29%) etiologies. Patients were divided into two groups: Group I (n = 61) who did not receive AOT and Group II (n = 51) who received AOT (succinate-containing drug Reamberin) as part of detoxification infusion therapy. The surgical approach and scope of interventions in both groups were identical. Dynamic indicators of endotoxicosis, cholestasis, and cytolysis (total, direct, and indirect bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [AP] and gamma-glutamyltransferase [GGT]), kidney function (urea), lipid peroxidation (malonic dialdehyde, MDA), inflammation (leukocytosis), and glycolysis disorders (lactate dehydrogenase (LDH), glucose) were evaluated. Results: Tumor jaundice, unlike non-tumor jaundice, persisted and was characterized by a more severe course, a higher level of hyperbilirubinemia, and lipid peroxidation. The prognostic value of the direct (and total) bilirubin, MDA, glycemia, and leukocytosis levels on the day of hospitalization, which increased significantly in severe jaundice and, especially, in deceased patients, was established. Decompression interventions significantly reduced levels of markers of liver failure, cytolysis, cholestasis, and lipid peroxidation on day 3 after decompression by 1.5–3 times from initial levels; this is better achieved in non-tumor OJ. However, 8 days after decompression, most patients did not normalize the parameters studied in both groups. AOT favorably influenced the dynamics (on day 8 after decompression) of total and direct bilirubin, ALT, AST, MDA, and leukocytosis in non-tumor jaundice, as well as the dynamics of direct bilirubin, AST, MDA, glucose, and LDH in tumor jaundice. Clinically, in the AOT group, a two-fold reduction in the operative and non-operative complications was recorded (from 23% to 11.5%), a reduction in the duration of biliary drainage by 30%, the length of stay in intensive care units was reduced by 5 days, and even hospital mortality decreased, especially in malignancy-induced OJ. Conclusion: A mechanism for the development of liver failure in OJ is oxidative stress with the appearance of enhanced lipid peroxidation and accompanied by hepatocyte necrosis. Inclusion of AOT in perioperative treatment in these patients improves treatment outcomes.
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Affiliation(s)
- Victor Stupin
- Department of Hospital Surgery No.1, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (V.S.); (I.A.); (T.G.); (N.M.); (Z.B.)
| | - Igor Abramov
- Department of Hospital Surgery No.1, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (V.S.); (I.A.); (T.G.); (N.M.); (Z.B.)
| | - Teymur Gahramanov
- Department of Hospital Surgery No.1, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (V.S.); (I.A.); (T.G.); (N.M.); (Z.B.)
| | - Alexey Kovalenko
- Chemical Analytical Department, Institute of Toxicology of the Federal Medical and Biological Agency of Russia, 192019 Saint Petersburg, Russia;
| | - Natalia Manturova
- Department of Hospital Surgery No.1, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (V.S.); (I.A.); (T.G.); (N.M.); (Z.B.)
| | - Petr Litvitskiy
- Institute of Biodesign and Modeling of Complex Systems, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
| | - Zalim Balkizov
- Department of Hospital Surgery No.1, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (V.S.); (I.A.); (T.G.); (N.M.); (Z.B.)
| | - Ekaterina Silina
- Institute of Biodesign and Modeling of Complex Systems, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
- Correspondence: ; Tel.: +7-9689559784
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Silina EV, Stupin VA, Abramov IS, Bolevich SB, Deshpande G, Achar RR, Sinelnikova TG. Oxidative Stress and Free Radical Processes in Tumor and Non-Tumor Obstructive Jaundice: Influence of Disease Duration, Severity and Surgical Treatment on Outcomes. PATHOPHYSIOLOGY 2022; 29:32-51. [PMID: 35366288 PMCID: PMC8948772 DOI: 10.3390/pathophysiology29010005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/25/2022] [Accepted: 01/27/2022] [Indexed: 01/04/2023] Open
Abstract
The aim of this study was to assess the patterns and pattern disruptions of free radical processes in patients with obstructive jaundice of various origins, and the severity of jaundice before and after decompression. Oxidative stress markers were determined in 128 patients with obstructive jaundice with a tumor genesis (23.4%) or non-tumor genesis (76.6%). The patients were hospitalized at different stages of clinical signs of jaundice. We studied the anti-peroxide activity in plasma, basal and stimulated indicators of the chemiluminescence intensity in leukocytes, leukocyte activity coefficients reflecting the level of reactive oxygen species generated by leukocytes, malondialdehyde levels indicative of the degree of lipid peroxidation and cellular destruction, liver enzymes (markers of cytolysis) and bilirubin levels. Data for hepatocyte death and markers of oxidative stress correlated with the severity of jaundice, its duration and the method of its surgical correction. It is proposed that using markers of free radical processes to assess the prognosis and effectiveness of treatment and to personalize treatment measures will improve the results of jaundice treatment.
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Affiliation(s)
- Ekaterina Vladimirovna Silina
- Department of Human Pathology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (S.B.B.); (T.G.S.)
- Correspondence: ; Tel.: +7-916-7101265
| | - Victor Alexandrovich Stupin
- Department of Hospital Surgery No. 1, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (V.A.S.); (I.S.A.)
| | - Igor Sergeevich Abramov
- Department of Hospital Surgery No. 1, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (V.A.S.); (I.S.A.)
| | - Sergey Brankovich Bolevich
- Department of Human Pathology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (S.B.B.); (T.G.S.)
| | - Gouri Deshpande
- Division of Biochemistry, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru 570 015, India; (G.D.); (R.R.A.)
- Department of Biochemisty, Karnatak University, Dharwad 580 003, India
| | - Raghu Ram Achar
- Division of Biochemistry, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru 570 015, India; (G.D.); (R.R.A.)
| | - Tatiana Georgievna Sinelnikova
- Department of Human Pathology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (S.B.B.); (T.G.S.)
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Abdoli N, Sadeghian I, Azarpira N, Ommati MM, Heidari R. Taurine mitigates bile duct obstruction-associated cholemic nephropathy: effect on oxidative stress and mitochondrial parameters. Clin Exp Hepatol 2021; 7:30-40. [PMID: 34027113 PMCID: PMC8122090 DOI: 10.5114/ceh.2021.104675] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 10/30/2020] [Indexed: 12/19/2022] Open
Abstract
AIM OF THE STUDY Cholestasis is a serious complication affecting other organs such as the liver and kidney. Oxidative stress and mitochondrial impairment are proposed as the primary mechanisms for cholestasis-induced organ injury. Taurine (TAU) is the most abundant free amino acid in the human body, which is not incorporated in the structure of proteins. Several pharmacological effects have been attributed to TAU. It has been reported that TAU effectively mitigated oxidative stress and modulated mitochondrial function. The current study aimed to evaluate the impact of TAU on oxidative stress biomarkers and mitochondrial parameters in the kidney of cholestatic animals. MATERIAL AND METHODS Bile duct ligated (BDL) rats were used as an antioxidant model of cholestasis. Animals were treated with TAU (500 and 1000 mg/kg, oral) for seven consecutive days. Animals were anesthetized (thiopental 80 mg/kg, i.p.), and kidney and blood specimens were collected. RESULTS Severe elevation in serum and urine biomarkers of renal injury was evident in the BDL group. Significant lipid peroxidation, reactive oxygen species (ROS) formation, and protein carbonylation were detected in the kidney of BDL animals. Furthermore, depleted glutathione reservoirs and a significant decrease in the antioxidant capacity of renal tissue were detected in cholestatic rats. Renal tubular atrophy and interstitial inflammation were evident in BDL animals. Cholestasis also caused significant mitochondrial dysfunction in the kidney. TAU significantly prevented cholestasis-induced renal injury by inhibiting oxidative stress and mitochondrial impairment. CONCLUSIONS These data indicate TAU as a potential therapeutic agent in the management of cholestasis-induced renal injury.
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Affiliation(s)
- Narges Abdoli
- Iran Food and Drug Administration, Ministry of Health, Tehran, Iran
| | - Issa Sadeghian
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Xiong Y, Yin Q, Li J, He S. Oxidative Stress and Endoplasmic Reticulum Stress Are Involved in the Protective Effect of Alpha Lipoic Acid Against Heat Damage in Chicken Testes. Animals (Basel) 2020; 10:ani10030384. [PMID: 32120945 PMCID: PMC7142828 DOI: 10.3390/ani10030384] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/23/2020] [Accepted: 02/25/2020] [Indexed: 12/16/2022] Open
Abstract
Simple Summary In male animals, heat stress causes injury to the testes, resulting in an increase in the number of deformed sperm, a reduction in testosterone production, and consequently, reduced reproductive performance. As an important antioxidant, alpha lipoic acid (ALA) has been reported to have a protective effect against testicular injury caused by various pathological factors. However, few studies have focused on the role of ALA in heat-induced testicular lesions. In this study, the effects of ALA on histopathological parameters, the activity of key antioxidant enzymes involved in oxidative stress, biomarkers of endoplasmic reticulum stress signaling in the testicular tissue, and testosterone levels in serum were evaluated in heat-stressed chickens. The results showed that ALA significantly alleviated heat stress-induced adverse effects by affecting the activities of antioxidant enzymes, the expression of endoplasmic reticulum stress-related apoptotic modulators, and the protein levels of steroidogenic genes in the testes of chickens exposed to heat stress. These results suggest that in chickens, ALA may be beneficial for ameliorating decreased reproductive performance caused by heat stress and this study provides the basis for the design of novel therapies for heat-induced testicular damage. Abstract Heat stress (HS) causes testicular injury, resulting in decreased fertility. Alpha-lipoic acid (ALA) is a well-known antioxidant. The aim of this study was to investigate the protective effects of ALA on HS-induced testicular damage in chickens. Histological changes; biomarkers of oxidative stress, including glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA); markers of endoplasmic reticulum (ER) stress, including glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP); apoptosis-related modulators, including Bax, Bcl-2, and caspase 3, in testicular tissue and serum testosterone levels were evaluated in chickens under heat stress. Heat stress induces spermatogenic cell abnormalities in chicken testes. Compared to the HS group, the histomorphological abnormalities in testicular tissue were visibly ameliorated, with significant increases in the enzyme activities of GPx, SOD, and CAT, increased serum testosterone concentration, and decreased MDA levels in the ALA + HS group. Consistent with these results, compared with the HS group, the protein levels of GRP78, CHOP, caspase 3, and Bax were significantly decreased, whereas Bcl-2, StAR, and 3β-HSD protein levels were increased in the ALA + HS group. Collectively, these findings suggest that ALA significantly ameliorates the heat-induced histomorphological abnormalities in the testes and decreased testosterone production by potentiating the activities of anti-oxidative enzymes (GPx, SOD, and CAT), inhibiting ER stress-related apoptotic pathways (Bax, Bcl-2, and caspase 3), and increasing steroidogenic gene (StAR and 3β-HSD) expression in chickens.
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Affiliation(s)
- Yongjie Xiong
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; (Y.X.); (Q.Y.); (J.L.)
- Key Laboratory of the Quality and Safety Control for Pork of the Ministry of Agriculture, Anhui Science and Technology University, Fengyang 233100, China
| | - Qirun Yin
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; (Y.X.); (Q.Y.); (J.L.)
- Key Laboratory of the Quality and Safety Control for Pork of the Ministry of Agriculture, Anhui Science and Technology University, Fengyang 233100, China
| | - Jing Li
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; (Y.X.); (Q.Y.); (J.L.)
- Key Laboratory of the Quality and Safety Control for Pork of the Ministry of Agriculture, Anhui Science and Technology University, Fengyang 233100, China
| | - Shaojun He
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China; (Y.X.); (Q.Y.); (J.L.)
- Key Laboratory of the Quality and Safety Control for Pork of the Ministry of Agriculture, Anhui Science and Technology University, Fengyang 233100, China
- Correspondence: ; Tel.: +86-550-6732-040; Fax: +86-550-6732-040
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