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Mao B, Yuan W, Wu F, Yan Y, Wang B. Autophagy in hepatic ischemia-reperfusion injury. Cell Death Discov 2023; 9:115. [PMID: 37019879 PMCID: PMC10076300 DOI: 10.1038/s41420-023-01387-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/23/2023] [Accepted: 02/27/2023] [Indexed: 04/07/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a major complication of liver resection or liver transplantation that can seriously affect patient's prognosis. There is currently no definitive and effective treatment strategy for HIRI. Autophagy is an intracellular self-digestion pathway initiated to remove damaged organelles and proteins, which maintains cell survival, differentiation, and homeostasis. Recent studies have shown that autophagy is involved in the regulation of HIRI. Numerous drugs and treatments can change the outcome of HIRI by controlling the pathways of autophagy. This review mainly discusses the occurrence and development of autophagy, the selection of experimental models for HIRI, and the specific regulatory pathways of autophagy in HIRI. Autophagy has considerable potential in the treatment of HIRI.
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Affiliation(s)
- Benliang Mao
- College of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Wei Yuan
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China
| | - Fan Wu
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China
| | - Yong Yan
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China
| | - Bailin Wang
- College of Clinical Medicine, Guizhou Medical University, Guiyang, China.
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China.
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Yu B, Zhang Y, Wang T, Guo J, Kong C, Chen Z, Ma X, Qiu T. MAPK Signaling Pathways in Hepatic Ischemia/Reperfusion Injury. J Inflamm Res 2023; 16:1405-1418. [PMID: 37012971 PMCID: PMC10065871 DOI: 10.2147/jir.s396604] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/16/2023] [Indexed: 03/29/2023] Open
Abstract
The mitogen-activated protein kinase signaling pathway can be activated by a variety of growth factors, cytokines, and hormones, and mediates numerous intracellular signals related to cellular activities, including cell proliferation, motility, and differentiation. It has been widely studied in the occurrence and development of inflammation and tumor. Hepatic ischemia-reperfusion injury (HIRI) is a common pathophysiological phenomenon that occurs in surgical procedures such as lobectomy and liver transplantation, which is characterized by severe inflammatory reaction after ischemia and reperfusion. In this review, we mainly discuss the role of p38, ERK1/2, JNK in MAPK family and TAK1 and ASK1 in MAPKKK family in HIRI, and try to find an effective treatment for HIRI.
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Affiliation(s)
- Bo Yu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Yalong Zhang
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Tianyu Wang
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Jiayu Guo
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Chenyang Kong
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Zhongbao Chen
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Xiaoxiong Ma
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
| | - Tao Qiu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China
- Correspondence: Tao Qiu, Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China, Tel +86-13995632367, Email
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Li Z, Wu Z, Xi X, Zhao F, Liu H, Liu D. Cellular communication network factor 1 interlinks autophagy and ERK signaling to promote osteogenesis of periodontal ligament stem cells. J Periodontal Res 2022; 57:1169-1182. [PMID: 36199215 DOI: 10.1111/jre.13054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/23/2022] [Accepted: 09/07/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To investigate the effects of cellular communication network factor 1 (CCN1), a critical matricellular protein, on alveolar bone regeneration, and to elucidate the underlying molecular mechanism. BACKGROUND In the process of orthodontic tooth movement, bone deposition on the tension side of human periodontal ligament stem cells (hPDLSCs) ensured high efficiency and long-term stability of the treatment. The matricellular protein CCN1 is responsive to mechanical stimulation, exhibiting important tasks in bone homoeostasis. However, the role and mechanism of CCN1 on alveolar bone remodeling of hPDLSCs remains unclear. METHODS The expression and distribution of CCN1 in rat periodontal ligament were detected by immunofluorescence staining and immunohistochemical staining. ELISA verified the secretion of CCN1 triggered by stretch loading. To examine the mineralization ability of hPDLSCs induced by CCN1, Western blotting, qRT-PCR, ARS, and ALP staining were performed. CCK-8 and cell migration assay were performed to detect the cell proliferation rate and the wound healing. PI3K/Akt, MAPK, and autophagy activation were examined via Western blotting and immunofluorescence. RESULTS Mechanical stimuli induced the release of CCN1 into extracellular environment by hPDLSCs. Knockdown of CCN1 attenuated the osteogenesis of hPDLSCs while rhCCN1 enhanced the expression of Runx2, Col 1, ALPL, and promoted the mineralization nodule formation. CCN1 activated PI3K/Akt and ERK signaling, and blockage of PI3K/Akt signaling reversed the accelerated cell migration triggered by CCN1. The enhanced osteogenesis induced by CCN1 was abolished by ERK signaling inhibitor PD98059 or autophagy inhibitor 3-MA. Further investigation demonstrated PD98059 abrogated the activation of autophagy. CONCLUSION This study demonstrated that CCN1 promotes osteogenesis in hPDLSCs via autophagy and MAPK/ERK pathway.
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Affiliation(s)
- Zixuan Li
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Zuping Wu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China
| | - Xun Xi
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Fang Zhao
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Hong Liu
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Dongxu Liu
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
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Tang Q, Zeng M, Chen L, Fu N. Targeting Thyroid Hormone/Thyroid Hormone Receptor Axis: An Attractive Therapy Strategy in Liver Diseases. Front Pharmacol 2022; 13:871100. [PMID: 35721201 PMCID: PMC9201453 DOI: 10.3389/fphar.2022.871100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/19/2022] [Indexed: 12/24/2022] Open
Abstract
Thyroid hormone/thyroid hormone receptor (TH/TR) axis is characterized by TH with the assistance of plasma membrane transporters to combine with TR and mediate biological activities. Growing evidence suggests that TH/TR participates in plenty of hepatic metabolism. Thus, this review focuses on the role of the TH/TR axis in the liver diseases. To be specific, the TH/TR axis may improve metabolic-associated fatty liver disease, hepatitis, liver fibrosis, and liver injury while exacerbating the progression of acute liver failure and alcoholic liver disease. Also, the TH/TR axis has paradoxical roles in hepatocellular carcinoma. The TH/TR axis may be a prospecting target to cure hepatic diseases.
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Affiliation(s)
- Qianyu Tang
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, China
| | - Min Zeng
- Department of Gastroenterology, Liuyang Hospital of Chinese Medicine, Changsha, China
| | - Linxi Chen
- Department of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang, China
| | - Nian Fu
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, China
- The Affiliated Nanhua Hospital, Laboratory of Liver Disease, Institute of Clinical Research, Hengyang Medical School, University of South China, Hengyang, China
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Effects of Thyroid Hormone on Tissue Hypoxia: Relevance to Sepsis Therapy. J Clin Med 2021; 10:jcm10245855. [PMID: 34945151 PMCID: PMC8703810 DOI: 10.3390/jcm10245855] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 11/29/2021] [Accepted: 12/10/2021] [Indexed: 01/14/2023] Open
Abstract
Tissue hypoxia occurs in various conditions such as myocardial or brain ischemia and infarction, sepsis, and trauma, and induces cellular damage and tissue remodeling with recapitulation of fetal-like reprogramming, which eventually results in organ failure. Analogies seem to exist between the damaged hypoxic and developing organs, indicating that a regulatory network which drives embryonic organ development may control aspects of heart (or tissue) repair. In this context, thyroid hormone (TH), which is a critical regulator of organ maturation, physiologic angiogenesis, and mitochondrial biogenesis during fetal development, may be of important physiological relevance upon stress (hypoxia)-induced fetal reprogramming. TH signaling has been implicated in hypoxic tissue remodeling after myocardial infarction and T3 prevents remodeling of the postinfarcted heart. Similarly, preliminary experimental evidence suggests that T3 can prevent early tissue hypoxia during sepsis with important physiological consequences. Thus, based on common pathways between different paradigms, we propose a possible role of TH in tissue hypoxia after sepsis with the potential to reduce secondary organ failure.
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6
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Hu C, Zhao L, Zhang F, Li L. Regulation of autophagy protects against liver injury in liver surgery-induced ischaemia/reperfusion. J Cell Mol Med 2021; 25:9905-9917. [PMID: 34626066 PMCID: PMC8572770 DOI: 10.1111/jcmm.16943] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 08/10/2021] [Accepted: 09/08/2021] [Indexed: 12/16/2022] Open
Abstract
Transient ischaemia and reperfusion in liver tissue induce hepatic ischaemia/reperfusion (I/R) tissue injury and a profound inflammatory response in vivo. Hepatic I/R can be classified into warm I/R and cold I/R and is characterized by three main types of cell death, apoptosis, necrosis and autophagy, in rodents or patients following I/R. Warm I/R is observed in patients or animal models undergoing liver resection, haemorrhagic shock, trauma, cardiac arrest or hepatic sinusoidal obstruction syndrome when vascular occlusion inhibits normal blood perfusion in liver tissue. Cold I/R is a condition that affects only patients who have undergone liver transplantation (LT) and is caused by donated liver graft preservation in a hypothermic environment prior to entering a warm reperfusion phase. Under stress conditions, autophagy plays a critical role in promoting cell survival and maintaining liver homeostasis by generating new adenosine triphosphate (ATP) and organelle components after the degradation of macromolecules and organelles in liver tissue. This role of autophagy may contribute to the protection of hepatic I/R‐induced liver injury; however, a considerable amount of evidence has shown that autophagy inhibition also protects against hepatic I/R injury by inhibiting autophagic cell death under specific circumstances. In this review, we comprehensively discuss current strategies and underlying mechanisms of autophagy regulation that alleviates I/R injury after liver resection and LT. Directed autophagy regulation can maintain liver homeostasis and improve liver function in individuals undergoing warm or cold I/R. In this way, autophagy regulation can contribute to improving the prognosis of patients undergoing liver resection or LT.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingfei Zhao
- Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, Institute of Nephrology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fen Zhang
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Zang X, Zhou J, Zhang X, Han Y, Chen X. Ischemia Reperfusion Injury: Opportunities for Nanoparticles. ACS Biomater Sci Eng 2020; 6:6528-6539. [PMID: 33320610 DOI: 10.1021/acsbiomaterials.0c01197] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Ischemia reperfusion (IR)-induced oxidative stress, accompanied by inflammatory responses, contributes to morbidity and mortality in numerous diseases such as acute coronary syndrome, stroke, organ transplantation, and limb injury. Ischemia results in profound hypoxia and tissue dysfunction, whereas subsequent reperfusion further aggravates ischemic tissue damage through inducing cell death and activating inflammatory responses. In this review, we highlight recent studies of therapeutic strategies against IR injury. Furthermore, nanotechnology offers significant improvements in this area. Hence, we also review recent advances in nanomedicines for IR therapy, suggesting them as potent and promising strategies to improve drug delivery to IR-injured tissues and achieve protective effects.
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Affiliation(s)
- Xinlong Zang
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao 110016, P.R. China
| | - Jingyi Zhou
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao 110016, P.R. China
| | - Xiaoxu Zhang
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao 110016, P.R. China
| | - Yantao Han
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao 110016, P.R. China
| | - Xuehong Chen
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao 110016, P.R. China
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Bruton's Tyrosine Kinase Inhibitor Attenuates Warm Hepatic Ischemia/Reperfusion Injury via Modulation of the NLR Family Pyrin Domain Containing 3 Inflammasome. Transplant Proc 2020; 52:2947-2954. [PMID: 33131902 DOI: 10.1016/j.transproceed.2019.10.024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 10/06/2019] [Indexed: 11/24/2022]
Abstract
The NLR family pyrin domain containing 3 (NLRP3) inflammasome is a widely studied inflammasome that plays a critical role in inflammatory responses. Many triggers, including microbial pathogens (ie, bacteria and viruses) and other signals (ie, reactive oxygen species, adenosine triphosphate, urate, silicon, and asbestos), can stimulate the NLRP3 inflammasome. Liver ischemia/reperfusion (I/R) injury is a common pathologic process during liver surgery and shock and can induce severe liver damage. Although its pathogenesis is still unclear, oxidative stress and overproduction of the inflammatory response are likely to contribute to I/R injury. The NLRP3 inflammasome is activated during the I/R process, resulting in further recruitment and activation of caspase-1. Activated caspase-1 cleaves the pro-forms of interleukin-1β and interleukin-18 and results in their maturation, triggering a proinflammatory cytokine cascade and causing liver damage. Bruton's tyrosine kinase is a critical molecule involved in diverse cellular pathways, such as proliferation, apoptosis, inflammation, and angiogenesis. Intrahepatic Bruton's tyrosine kinase is mainly expressed on Kupffer cells and sinusoidal endothelial cells, and the inflammasome is activated in Kupffer cells. Our study found that inhibition of Bruton's tyrosine kinase effectively attenuated liver I/R injury by suppressing activation of the NLRP3 inflammasome in Kupffer cells.
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Yi L, Zhong T, Huang Y, Huang S. Triiodothyronine promotes the osteoblast formation by activating autophagy. Biophys Chem 2020; 267:106483. [PMID: 33010728 DOI: 10.1016/j.bpc.2020.106483] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/08/2020] [Accepted: 09/20/2020] [Indexed: 11/24/2022]
Abstract
Based on the osteogenic effect, triiodothyronine (T3) plays an important role in bone growth and development. Autophagy contributes to osteoblast formation and subsequent osteogenesis. Our study aims to explore the relationship among T3, autophagy and osteogenesis. In this study, cranial primary osteoblasts were obtained from 2 to 3 weeks-old Sprague Dawley (SD) rat fetuses. Osteoblasts were treated with T3, and then the autophagic parameters of Osteoblasts (including autophagic proteins, LC3 conversion rate and autophagosome formation) were observed through Western Blotting and Transmission Electron Microscopy. Next, after using autophagic pharmacological inhibitors (3-MA and chloroquine) and silencing vectors of autophagic genes (BECN1, Atg5 and Atg7) to downregulate autophagic activity, osteoblast proliferation and osteoblastic gene expression were detected using cell counting kit-8 (CCK-8) and quantitative real-time PCR (qRT-PCR) assays, respectively. Ultimately, the mice treated with partial thyroidectomy (PTx mice) were used to further observe the effect of T3 on the formation and autophagy of osteoblasts in trabecular bone in vivo. Our results show that T3 enhances osteoblast autophagy. Autophagy suppression with 3-MA, chloroquine or autophagy-genes knockdown reverses T3-promoted osteoblast formation. In vivo assays showed that the formation and autophagy of osteoblasts in bone tissue were reduced in T3-deficient young mice. Overall, T3 can promote osteoblast formation by activation of autophagy.
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Affiliation(s)
- Ling Yi
- Department of Pediatrics, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Tao Zhong
- Department of Pediatrics, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Yubo Huang
- Department of Pediatrics, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Shuping Huang
- Department of Pediatrics, Ganzhou People's Hospital, Ganzhou 341000, China.
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Low-free triiodothyronine is associated with poor prognosis of portal hypertension in cirrhosis. Eur J Gastroenterol Hepatol 2020; 32:1358-1363. [PMID: 31895910 DOI: 10.1097/meg.0000000000001658] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS The role of thyroid function in the portal hypertension development and prognosis remains unclear. This study aimed to investigate the correlation between serum-free triiodothyronine (fT3) levels and the outcomes of cirrhotic portal hypertension. METHODS A total of 385 cirrhotic patients with confirmed portal hypertension underwent computed tomography angiography and thyroid function test at a tertiary care referral center from January 2009 to December 2017. The patients were assigned to the low-fT3 (n = 98) and normal-fT3 groups (n = 287). RESULTS Child-Pugh (8.88 ± 0.22 vs. 7.09 ± 0.12, P < 0.001) and model for end-stage liver disease (MELD) scores (14.75 ± 0.57 vs. 10.59 ± 0.23, P < 0.001) significantly increased in the low-fT3 group. The hemoglobin level correlated with fT3 (R = 0.299, P < 0.0001) and fT4 (R = 0.310, P < 0.0001), while only fT3 significantly correlated with the albumin level (R = 0.537, P < 0.001). The Kaplan-Meier analysis indicated that the two-year survival rate was 74.51% in the low-fT3 group vs. 94.25% in the normal-fT3 group (P < 0.0001). The Cox regression analysis demonstrated that the serum level of fT3 [hazard ratio: 0.478; 95% confidence interval (CI) 0.391-0.758; P = 0.002] and prothrombin time (hazard ratio: 2.247; 95% CI: 1.316-3.838; P = 0.003) were independent prognostic factors in cirrhotic patients. CONCLUSION The low fT3 level was associated with poor prognosis and the progression of cirrhotic portal hypertension.
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Yang J, Liu H, Han S, Fu Z, Wang J, Chen Y, Wang L. Melatonin pretreatment alleviates renal ischemia-reperfusion injury by promoting autophagic flux via TLR4/MyD88/MEK/ERK/mTORC1 signaling. FASEB J 2020; 34:12324-12337. [PMID: 32662527 DOI: 10.1096/fj.202001252r] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 12/18/2022]
Abstract
Autophagy is an important mechanism for cellular homeostasis and survival during pathologic stress conditions in the kidney, such as ischemia-reperfusion (IR) injury. In this study, renal IR was induced in female C57BL/6 mice after melatonin administration. Renal function, histological damage, inflammatory infiltration, cytokine production, oxidative stress, antioxidant capacity, autophagy changing, apoptosis levels, and autophagy-associated intracellular signaling pathway were assessed to evaluate the impact of antecedent melatonin treatment on IR-induced renal injury. The administration of melatonin resulted in significantly preserved renal function, and the protective effect was associated with ameliorated oxidative stress, limited pro-inflammatory cytokine production, and neutrophil and macrophage infiltration. Moreover, autophagic flux was increased after melatonin administration while the apoptosis levels were decreased in the melatonin-pretreated mice. Using TAK-242 and CRX-527, we confirmed that MyD88-dependent TLR4 and MEK/ERK/mTORC1 signaling participated in melatonin-induced autophagy in IR mice. Collectively, our results provide novel evidence that antecedent melatonin treatment provides protection for the kidney against IR injury by enhancing autophagy, as regulated by the TLR4/MyD88/MEK/ERK/mTORC1 signaling pathway. Therefore, melatonin preconditioning offers a potential therapeutic approach to prevent renal IR injury related to various clinical conditions.
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Affiliation(s)
- Jinghui Yang
- Department of Organ Transplantation, Shanghai ChangZheng Hospital, Second Military Medical University, Shanghai, China
| | - Hao Liu
- Department of Organ Transplantation, Shanghai ChangZheng Hospital, Second Military Medical University, Shanghai, China
| | - Shu Han
- Department of Organ Transplantation, Shanghai ChangZheng Hospital, Second Military Medical University, Shanghai, China
| | - Zhiren Fu
- Department of Organ Transplantation, Shanghai ChangZheng Hospital, Second Military Medical University, Shanghai, China
| | - Jiyuan Wang
- Department of Organ Transplantation, Shanghai ChangZheng Hospital, Second Military Medical University, Shanghai, China
| | - Yu Chen
- Department of Organ Transplantation, Shanghai ChangZheng Hospital, Second Military Medical University, Shanghai, China
| | - Liming Wang
- Department of Organ Transplantation, Shanghai ChangZheng Hospital, Second Military Medical University, Shanghai, China
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Cai LL, Xu HT, Wang QL, Zhang YQ, Chen W, Zheng DY, Liu F, Yuan HB, Li YH, Fu HL. EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition. Int J Mol Med 2020; 45:1825-1837. [PMID: 32186754 PMCID: PMC7169940 DOI: 10.3892/ijmm.2020.4544] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 02/04/2020] [Indexed: 12/11/2022] Open
Abstract
Prostaglandin E receptor subtype 4 (EP4) is widely distributed in the heart, but its role in hepatic ischemia/reperfusion (I/R), particularly in mitochondrial permeability transition pore (MPTP) modulation, is yet to be elucidated. In the present study, an EP4 agonist (CAY10598) was used in a rat model to evaluate the effects of EP4 activation on liver I/R and the mechanisms underlying this. I/R insult upregulated hepatic EP4 expression during early reperfusion. In addition, subcutaneous CAY10598 injection prior to the onset of reperfusion significantly increased hepatocyte cAMP concentrations and decreased serum ALT and AST levels and necrotic and apoptotic cell percentages, after 6 h of reperfusion. Moreover, CAY10598 protected mitochondrial morphology, markedly inhibited mitochondrial permeability transition pore (MPTP) opening and decreased liver reactive oxygen species levels. This occurred via activation of the ERK1/2-GSK3β pathway rather than the janus kinase (JAK)2-signal transducers and activators of transcription (STAT)3 pathway, and resulted in prevention of mitochondria-associated cell injury. The MPTP opener carboxyatractyloside (CATR) and the ERK1/2 inhibitor PD98059 also partially reversed the protective effects of CAY10598 on the liver and mitochondria. The current findings indicate that EP4 activation induces ERK1/2-GSK3β signaling and subsequent MPTP inhibition to provide hepatoprotection, and these observations are informative for developing new molecular targets and preventative therapies for I/R in a clinical setting.
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Affiliation(s)
- Lin-Lin Cai
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Hai-Tao Xu
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Qi-Long Wang
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Ya-Qing Zhang
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Wei Chen
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Dong-Yu Zheng
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Fang Liu
- National Key Laboratory of Medical Immunology and Department of Immunology, Second Military Medical University, Shanghai 200433, P.R. China
| | - Hong-Bin Yuan
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Yong-Hua Li
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Hai-Long Fu
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
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Wang H, Liu Y, Wang D, Xu Y, Dong R, Yang Y, Lv Q, Chen X, Zhang Z. The Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases. Cells 2019; 8:E1597. [PMID: 31835352 PMCID: PMC6953127 DOI: 10.3390/cells8121597] [Citation(s) in RCA: 177] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/29/2019] [Accepted: 12/03/2019] [Indexed: 12/11/2022] Open
Abstract
Autophagy, originally found in liver experiments, is a cellular process that degrades damaged organelle or protein aggregation. This process frees cells from various stress states is a cell survival mechanism under stress stimulation. It is now known that dysregulation of autophagy can cause many liver diseases. Therefore, how to properly regulate autophagy is the key to the treatment of liver injury. mechanistic target of rapamycin (mTOR)is the core hub regulating autophagy, which is subject to different upstream signaling pathways to regulate autophagy. This review summarizes three upstream pathways of mTOR: the phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) signaling pathway, the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, and the rat sarcoma (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-extracellular activated protein kinase kinase (MEK)/ extracellular-signal-regulated kinase (ERK) signaling pathway, specifically explored their role in liver fibrosis, hepatitis B, non-alcoholic fatty liver, liver cancer, hepatic ischemia reperfusion and other liver diseases through the regulation of mTOR-mediated autophagy. Moreover, we also analyzed the crosstalk between these three pathways, aiming to find new targets for the treatment of human liver disease based on autophagy.
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Affiliation(s)
- Haojie Wang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Yumei Liu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Dongmei Wang
- College of Medical, Henan University of Science and Technology, Luoyang 471000, China;
| | - Yaolu Xu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Ruiqi Dong
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Yuxiang Yang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Qiongxia Lv
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Xiaoguang Chen
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Ziqiang Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
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Protective Role of mTOR in Liver Ischemia/Reperfusion Injury: Involvement of Inflammation and Autophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7861290. [PMID: 31827701 PMCID: PMC6885218 DOI: 10.1155/2019/7861290] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 08/24/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023]
Abstract
Liver ischemia/reperfusion (IR) injury is a common phenomenon after liver resection and transplantation, which often results in liver graft dysfunction such as delayed graft function and primary nonfunction. The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved serine/threonine protein kinase, which coordinates cell growth and metabolism through sensing environmental inputs under physiological or pathological conditions, involved in the pathophysiological process of IR injury. In this review, we mainly present current evidence of the beneficial role of mTOR in modulating inflammation and autophagy under liver IR to provide some evidence for the potential therapies for liver IR injury.
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Liu H, Dong J, Song S, Zhao Y, Wang J, Fu Z, Yang J. Spermidine ameliorates liver ischaemia-reperfusion injury through the regulation of autophagy by the AMPK-mTOR-ULK1 signalling pathway. Biochem Biophys Res Commun 2019; 519:227-233. [PMID: 31493865 DOI: 10.1016/j.bbrc.2019.08.162] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 08/31/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hepatic ischaemia-reperfusion (IR) injury is a common clinical challenge lacking effective therapy. The aim of this study was to investigate whether spermidine has protective effects against hepatic IR injury through autophagy. METHODS Liver ischaemia reperfusion was induced in male C57BL/6 mice. Then, liver function, histopathology, cytokine production and immunofluorescence were evaluated to assess the impact of spermidine pre-treatment on IR-induced liver injury. Autophagosome formation was observed by transmission electron microscopy. Western blotting was used to explore the underlying mechanism and its relationship with autophagy, and TUNEL staining was conducted to determine the relationship between apoptosis and autophagy in the ischaemic liver. RESULTS The results of the transaminase assay, histopathological examination, and pro-inflammatory cytokine production and immunofluorescence evaluations demonstrated that mice pre-treated with spermidine showed significantly preserved liver function. Further experiments demonstrated that mice administered spermidine before the induction of IR exhibited increased autophagy via the AMPK-mTOR-ULK1 pathway, and TUNEL staining revealed that spermidine attenuated IR-induced apoptosis in the liver. CONCLUSIONS Our results provide the first line of evidence that spermidine provides protection against IR-induced injury in the liver by regulating autophagy through the AMPK-mTOR-ULK1 signalling pathway. These results suggest that spermidine may be beneficial for hepatic IR injury.
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Affiliation(s)
- Hao Liu
- Department of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Jiayong Dong
- Department of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Shaohua Song
- Department of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Yuanyu Zhao
- Department of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Jiyuan Wang
- Department of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Zhiren Fu
- Department of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
| | - Jinghui Yang
- Department of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
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Protective Effects of Euthyroidism Restoration on Mitochondria Function and Quality Control in Cardiac Pathophysiology. Int J Mol Sci 2019; 20:ijms20143377. [PMID: 31295805 PMCID: PMC6678270 DOI: 10.3390/ijms20143377] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/05/2019] [Accepted: 07/08/2019] [Indexed: 12/18/2022] Open
Abstract
Mitochondrial dysfunctions are major contributors to heart disease onset and progression. Under ischemic injuries or cardiac overload, mitochondrial-derived oxidative stress, Ca2+ dis-homeostasis, and inflammation initiate cross-talking vicious cycles leading to defects of mitochondrial DNA, lipids, and proteins, concurrently resulting in fatal energy crisis and cell loss. Blunting such noxious stimuli and preserving mitochondrial homeostasis are essential to cell survival. In this context, mitochondrial quality control (MQC) represents an expanding research topic and therapeutic target in the field of cardiac physiology. MQC is a multi-tier surveillance system operating at the protein, organelle, and cell level to repair or eliminate damaged mitochondrial components and replace them by biogenesis. Novel evidence highlights the critical role of thyroid hormones (TH) in regulating multiple aspects of MQC, resulting in increased organelle turnover, improved mitochondrial bioenergetics, and the retention of cell function. In the present review, these emerging protective effects are discussed in the context of cardiac ischemia-reperfusion (IR) and heart failure, focusing on MQC as a strategy to blunt the propagation of connected dangerous signaling cascades and limit adverse remodeling. A better understanding of such TH-dependent signaling could provide insights into the development of mitochondria-targeted treatments in patients with cardiac disease.
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Xi J, Yan M, Li S, Song H, Liu L, Shen Z, Cai JZ. NOD1 activates autophagy to aggravate hepatic ischemia-reperfusion injury in mice. J Cell Biochem 2019; 120:10605-10612. [PMID: 30644583 DOI: 10.1002/jcb.28349] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 11/29/2018] [Indexed: 01/06/2023]
Abstract
Hepatic ischemia/reperfusion injury (IRI) is tissue damage resulting from return of the blood supply to the tissue after a period of ischemia or lack of oxygen. Much of the morbidity associated with liver transplantation and major hepatic resections is, in part, due to IRI. Both innate immunity and autophagy play important roles in hepatic IRI. With regard to innate immunity, one factor that plays a key role is NOD1, an intracellular pattern recognition receptor. NOD1 has recently been shown to be associated with autophagy, but the mechanisms involved with this process remain obscure. This relationship between NOD1 and autophagy prompted us to examine the role and potential mechanisms of NOD1 in regulating autophagy as related to hepatic IRI. We found that NOD1 was upregulated during hepatic IRI and was associated with an activation of the autophagic signaling pathway. Moreover, levels of Atg5, a critical protein associated with autophagy, were decreased when NOD1 was inhibited by NOD1 small interfering RNA. We conclude that NOD1 appears to exert a pivotal role in hepatic IRI by activating autophagy to aggravate hepatic IRI, and Atg5 was required for this process. The identification of this novel pathway, that links expression levels of NOD1 with Atg5-mediated autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI.
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Affiliation(s)
- Jiri Xi
- Department of Liver Transplantion, Oriental Organ Transplant Center, Tianjin First Central Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China
| | - Meiling Yan
- Department of Pharmacy, Oriental Organ Transplant Center, Tianjin First Central Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China
| | - Shipeng Li
- Department of General Surgery, Jiaozuo People's Hospital, Xinxiang Medical University, Jiaozuo, People's Republic of China
| | - Hu Song
- Department of Liver Transplantion, First Central Clinical College of Tianjin Medical University, Tianjin, People's Republic of China
| | - Lei Liu
- Department of Liver Transplantion, Oriental Organ Transplant Center, Tianjin First Central Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China
| | - Zhongyang Shen
- Department of Liver Transplantion, Oriental Organ Transplant Center, Tianjin First Central Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China
| | - Jin-Zhen Cai
- Department of Liver Transplantion, Oriental Organ Transplant Center, Tianjin First Central Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China
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18
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Sun X, Zhang Y, Xi S, Ma L, Li S. MiR‐330‐3p suppresses phosphoglycerate mutase family member 5 ‐inducted mitophagy to alleviate hepatic ischemia‐reperfusion injury. J Cell Biochem 2018; 120:4255-4267. [DOI: 10.1002/jcb.27711] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 08/29/2018] [Indexed: 12/29/2022]
Affiliation(s)
- Xiang‐Li Sun
- Department of Biochemistry and Molecular Biology Medical College, Henan University of Science and Technology Luoyang China
| | - Yan‐Le Zhang
- Department of Biochemistry and Molecular Biology Medical College, Henan University of Science and Technology Luoyang China
| | - Shou‐Min Xi
- Department of Biochemistry and Molecular Biology Medical College, Henan University of Science and Technology Luoyang China
| | - Ling‐Jun Ma
- Department of Biochemistry and Molecular Biology Medical College, Henan University of Science and Technology Luoyang China
| | - Shi‐Peng Li
- Department of General Surgery Jiaozuo People’s Hospital, Xinxiang Medical University Jiaozuo China
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19
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Han YF, Zhao YB, Li J, Li L, Li YG, Li SP, Li ZD. Stat3-Atg5 signal axis inducing autophagy to alleviate hepatic ischemia-reperfusion injury. J Cell Biochem 2017; 119:3440-3450. [PMID: 29143976 DOI: 10.1002/jcb.26516] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 11/13/2017] [Indexed: 12/16/2022]
Abstract
In performing our experiment, impaired autophagy increased hepatocellular damage during the reperfusion period. It was demonstrated by the effect of blocking autophagy using bafilomycin A1 or knocking Atg5 gene out reduces the anti-apoptotic effect of Stat3. Here we focus on the role of signal transducer and activator of transcription 3 (Stat3) in regulating autophagy to alleviate hepatic IRI. We found that Stat3 was up-regulated during hepatic IRI and was associated with an activation of the autophagic signaling pathway. This increased Stat3 expression, which was allied with high autophagic activity, alleviated liver damage to IR, an effect which was abrogated by Stat3 epletion as demonstrated in both in vivo and in vitro methods. The levels of Atg5 protein were decreased when Stat3 was inhibited by HO 3867 or siStat3. We conclude that Stat3 appeared to exert a pivotal role in hepatic IRI, by activating autophagy to alleviate hepatic IRI, and Atg5 was required for this process. The identification of this novel pathway, that links expression levels of Stat3 with Atg5-mediated autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI.
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Affiliation(s)
- Yu-Fang Han
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Yan-Bing Zhao
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Jun Li
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Li Li
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Yong-Gan Li
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Shi-Peng Li
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Zhong-Dong Li
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
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20
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Singh BK, Sinha RA, Ohba K, Yen PM. Role of thyroid hormone in hepatic gene regulation, chromatin remodeling, and autophagy. Mol Cell Endocrinol 2017; 458:160-168. [PMID: 28216439 DOI: 10.1016/j.mce.2017.02.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 02/09/2017] [Accepted: 02/10/2017] [Indexed: 01/21/2023]
Abstract
Thyroid hormone (TH) actions on development and metabolism have been studied ever since the discovery of thyroxine almost a century ago. Initial studies focused on the physiological and biochemical actions of TH. Later, the cloning of the thyroid hormone receptor (THR) isoforms and the development of techniques enabled the study of TH regulation of complex cellular processes (such as gene transcription). Recently we found that TH activates secondary transcription factors such as FOXO1, to amplify gene transcription; and also is a potent inducer of autophagy that was critical for fatty acid β-oxidation in the liver. This review summarizes the recent advancements in our understanding of TH regulation of gene expression of metabolic genes (via co-regulators/transcription factors and epigenetic control) and autophagy in the liver. Our deeper understanding of TH action recently has led to the development of tissue- and THR isoform-specific TH mimetics that may be useful for the treatment of metabolic disorders.
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Affiliation(s)
- Brijesh Kumar Singh
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 169857, Singapore
| | - Rohit Anthony Sinha
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 169857, Singapore
| | - Kenji Ohba
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 169857, Singapore; Department of Internal Medicine, Enshu Hospital, Hamamatsu, Shizuoka 430-0929, Japan
| | - Paul Michael Yen
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 169857, Singapore.
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21
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El-Hamoly T, El-Sharawy DM, El Refaye MS, Abd El-Rahman SS. L-thyroxine modifies nephrotoxicity by regulating the apoptotic pathway: The possible role of CD38/ADP-ribosyl cyclase-mediated calcium mobilization. PLoS One 2017; 12:e0184157. [PMID: 28892514 PMCID: PMC5593187 DOI: 10.1371/journal.pone.0184157] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 08/18/2017] [Indexed: 11/18/2022] Open
Abstract
Thyroid hormones are well-established as a key regulator of many cellular metabolic pathways developed in various pathogeneses. Here, we dedicated the current work to investigate the role of thyroid hormone analogue (L-thyroxine, L-TH) in regulating the renal cytotoxicity using in vivo and in vitro models. Swiss mice were exposed to gamma radiation (IRR, 6Gy) or treated with cisplatin (CIS, 15 mg/kg, i.p.) for induction of nephrotoxicity. Remarkably, pretreatment with L-TH (1μg/kg) ameliorated the elevated kidney function biomarkers, oxidative stress and protected the renal tissue from the subsequent cellular damage. Likewise, L-TH inhibited the apoptotic cascade by down-regulating the extreme consumption of the cellular energy (ATP), the expression of caspase-3 and Bax, and the stimulation of cyclic ADP ribose (cADPR)/calcium mobilization. Moreover, incubation with L-TH (120nM/4h) significantly blocked the cytotoxicity of CIS on Vero cells and the depletion of NAD+ content as well as modified the ADP-ribose cyclase (CD38) enzymatic activity. High doses of L-TH (up to30 nM/4h) inversely increased the radiosensitivity of Vero cells towards IRR (up to 6Gy). On the other hand, L-TH did not interfere CIS-induced cytotoxicity of colorectal adenocarcinoma (Caco-2) cell line. In conclusion, pretreatment with L-TH could be a promising protective approach to the renal cellular damage induced during either CIS or IRR therapy by regulating the unbalanced oxidative status, the expression of pro-apoptotic biomarkers via modulation of cADPR mediated-calcium mobilization.
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Affiliation(s)
- Tarek El-Hamoly
- Drug Radiation Research Department, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
- Cyclotron Project, Center of Nuclear Researches, Atomic Energy Authority, Cairo, Egypt
| | - Dina M. El-Sharawy
- Cyclotron Project, Center of Nuclear Researches, Atomic Energy Authority, Cairo, Egypt
| | - Marwa S. El Refaye
- Cyclotron Project, Center of Nuclear Researches, Atomic Energy Authority, Cairo, Egypt
| | - Sahar S. Abd El-Rahman
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
- * E-mail: ,
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22
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Sinha RA, Singh BK, Yen PM. Reciprocal Crosstalk Between Autophagic and Endocrine Signaling in Metabolic Homeostasis. Endocr Rev 2017; 38:69-102. [PMID: 27901588 DOI: 10.1210/er.2016-1103] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 11/28/2016] [Indexed: 12/19/2022]
Abstract
Autophagy is a cellular quality control and energy-providing process that is under strict control by intra- and extracellular stimuli. Recently, there has been an exponential increase in autophagy research and its implications for mammalian physiology. Autophagy deregulation is now being implicated in many human diseases, and its modulation has shown promising results in several preclinical studies. However, despite the initial discovery of autophagy as a hormone-regulated process by De Duve in the early 1960s, endocrine regulation of autophagy still remains poorly understood. In this review, we provide a critical summary of our present understanding of the basic mechanism of autophagy, its regulation by endocrine hormones, and its contribution to endocrine and metabolic homeostasis under physiological and pathological settings. Understanding the cross-regulation of hormones and autophagy on endocrine cell signaling and function will provide new insight into mammalian physiology as well as promote the development of new therapeutic strategies involving modulation of autophagy in endocrine and metabolic disorders.
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Affiliation(s)
- Rohit A Sinha
- Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School Singapore, Singapore 169016
| | - Brijesh K Singh
- Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School Singapore, Singapore 169016
| | - Paul M Yen
- Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School Singapore, Singapore 169016
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23
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Long Q, Li X, He H, He D. Autophagy activation protects shock wave induced renal tubular epithelial cell apoptosis may through modulation of Akt/ GSK-3β pathway. Int J Biol Sci 2016; 12:1461-1471. [PMID: 27994511 PMCID: PMC5166488 DOI: 10.7150/ijbs.16864] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 09/17/2016] [Indexed: 01/06/2023] Open
Abstract
Purpose: Extracorporeal shock wave lithotripsy (ESWL) is well documented to exert destructive effect to renal cells and its mechanism is not clear. Autophagy is one of cell basic response for stressful conditions and it is important to determine cell's fate. The aim of this study is to elucidate the role of autophagy in the process of shock wave-induced renal cells injury. Methods: NRK-52E cell, a rat renal tubular epithelial cell, was exposed to shock wave at the voltage of 14KV. GFP-LC3 puncta was used to monitor Autophagy flux in the process of shock wave injury. Autophagic relative proteins, such as light chain 3 (LC3), beclin-1 and p62, were also examined. Cell variability and apoptosis were detected when inhibition autophagy with 3-methyladenine (3MA) or stimulating its activity with rapamycin during the process of shock wave injury. The role of Akt/ GSK-3β and its connection with autophagy in the process of shock wave injury were also investigated. Results: Shock wave was confirmed to activate autophagy in renal cells, which was manifested in LC3-II turnover, beclin-1 induction and degradation of p62. Inhibition autophagy enhanced cell damage or apoptosis, whereas its stimulating was able to exert protection from shock wave injury. Akt/ GSK-3β, a cell-survival signaling pathway, can also be activated during the process. And its activation could be suppressed by blockade autophagy. Conclusion: Autophagy is a self-protective response for renal cells from shock wave injury. The cyto-protection of autophagy may be connected with modulation Akt/ GSK-3β pathway.
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Affiliation(s)
- Qingzhi Long
- Department of Urology, First affiliated hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Xiang Li
- Department of Urology, First affiliated hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Hui He
- Department of Urology, First affiliated hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Dalin He
- Department of Urology, First affiliated hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
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24
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Liu Y, Lu Z, Cui M, Yang Q, Tang Y, Dong Q. Tissue kallikrein protects SH-SY5Y neuronal cells against oxygen and glucose deprivation-induced injury through bradykinin B2 receptor-dependent regulation of autophagy induction. J Neurochem 2016; 139:208-220. [PMID: 27248356 DOI: 10.1111/jnc.13690] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Revised: 05/21/2016] [Accepted: 05/24/2016] [Indexed: 12/22/2022]
Affiliation(s)
- Yanping Liu
- Department of Neurology; Huashan Hospital; State Key Laboratory of Medical Neurobiology; Fudan University; Shanghai China
| | - Zhengyu Lu
- Department of Neurology; Yueyang Hospital of Integrated Traditional Chinese and Western Medicine; Shanghai University of Traditional Chinese Medicine; Shanghai China
| | - Mei Cui
- Department of Neurology; Huashan Hospital; State Key Laboratory of Medical Neurobiology; Fudan University; Shanghai China
| | - Qi Yang
- Department of Neurology; Huashan Hospital; State Key Laboratory of Medical Neurobiology; Fudan University; Shanghai China
| | - Yuping Tang
- Department of Neurology; Huashan Hospital; State Key Laboratory of Medical Neurobiology; Fudan University; Shanghai China
| | - Qiang Dong
- Department of Neurology; Huashan Hospital; State Key Laboratory of Medical Neurobiology; Fudan University; Shanghai China
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Li SP, He JD, Wang Z, Yu Y, Fu SY, Zhang HM, Zhang JJ, Shen ZY. miR-30b inhibits autophagy to alleviate hepatic ischemia-reperfusion injury via decreasing the Atg12-Atg5 conjugate. World J Gastroenterol 2016; 22:4501-14. [PMID: 27182160 PMCID: PMC4858632 DOI: 10.3748/wjg.v22.i18.4501] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 01/30/2016] [Accepted: 03/01/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the role and potential mechanism of miR-30b regulation of autophagy in hepatic ischemia-reperfusion injury (IRI). METHODS An animal model of hepatic IRI was generated in C57BL/6 mice. For in vitro studies, AML12 cells were immersed in mineral oil for 1 h and then cultured in complete Dulbecco's Modified Eagle's Medium (DMEM)/F12 to simulate IRI. Mice and cells were transfected with miR-30b agomir/mimics or antagomir/inhibitor to examine the effect of miR-30b on autophagy to promote hepatic IRI. The expression of miR-30b was measured by real-time polymerase chain reaction. Apoptotic cells were detected by terminal uridine nick-end labeling (TUNEL) staining, and cell viability was detected by methylthiazole tetrazolium assay. The expression of light chain 3, autophagy-related gene (Atg)12, Atg5, P62, and caspase-3 were detected by western blotting analysis. RESULTS miR-30b levels were significantly downregulated after hepatic IRI, and the numbers of autophagosomes were increased in response to IRI both in vivo and in vitro. These findings demonstrate that low levels of miR-30b could promote hepatic IRI. Furthermore, we found that miR-30b interacted with Atg12-Atg5 conjugate by binding to Atg12. Overexpression of miR-30b diminished Atg12 and Atg12-Atg5 conjugate levels, which promoted autophagy in response to IR. In contrast, downregulation of miR-30b was associated with increased Atg12-Atg5 conjugate levels and increased autophagy. CONCLUSION miR-30b inhibited autophagy to alleviate hepatic ischemia-reperfusion injury via decreasing the Atg12-Atg5 conjugate.
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