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Shi X, Zhang J, Gao J, Guo D, Zhang S, Chen X, Tang H. Melatonin attenuates liver ischemia-reperfusion injury via inhibiting the PGAM5-mPTP pathway. PLoS One 2024; 19:e0312853. [PMID: 39471139 PMCID: PMC11521291 DOI: 10.1371/journal.pone.0312853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 10/14/2024] [Indexed: 11/01/2024] Open
Abstract
Phosphoglycerate mutase/protein phosphatase (PGAM5)-mediated cell death plays an important role in multiple liver diseases. However, few studies have confirmed the regulatory mechanism of melatonin acting on PGAM5-mediated cell death in the context of liver ischemia-reperfusion (I/R) injury. The liver I/R injury model and cell hypoxia-reoxygenation model were established after melatonin pretreatment. Liver injury, cell activity, cell apoptosis, oxidative stress index, and PGAM5 protein expression were detected. To investigate the role of PGAM5 in melatonin-mediated liver protection during I/R injury, PGAM5 silencing, and overexpression were performed before melatonin pretreatment. Our results indicated that PGAM5 was significantly elevated by I/R injury, and predominantly localized in the necrosis area. However, treatment with melatonin blocked PGAM5 activation and conferred a survival advantage of hepatocytes in liver I/R injury, similar to the results achieved by silencing PGAM5. In terms of mechanism, we illustrated that activated PGAM5 promoted mitochondrial permeability transition pore (mPTP) opening, and administration of melatonin inhibited mPTP opening and interrupted hepatocytes death via blocking PGAM5. Our data indicated that the PGAM5-mPTP axis is responsible for I/R-induced liver injury. In contrast, melatonin supplementation blocked the PGAM5-mPTP axis and thus decreased cell death, providing a protective advantage to hepatocytes in I/R. These results established a new paradigm in melatonin-mediated hepatocyte protection under the burden of I/R attack.
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Affiliation(s)
- Xiaoyi Shi
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Jiakai Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Jie Gao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Danfeng Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Xu Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Hongwei Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
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Liu J, Luo R, Zhang Y, Li X. Current status and perspective on molecular targets and therapeutic intervention strategy in hepatic ischemia-reperfusion injury. Clin Mol Hepatol 2024; 30:585-619. [PMID: 38946464 PMCID: PMC11540405 DOI: 10.3350/cmh.2024.0222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/02/2024] Open
Abstract
Hepatic ischemia‒reperfusion injury (HIRI) is a common and inevitable complication of hepatic trauma, liver resection, or liver transplantation. It contributes to postoperative organ failure or tissue rejection, eventually affecting patient prognosis and overall survival. The pathological mechanism of HIRI is highly complex and has not yet been fully elucidated. The proposed underlying mechanisms include mitochondrial damage, oxidative stress imbalance, abnormal cell death, immune cell hyperactivation, intracellular inflammatory disorders and other complex events. In addition to serious clinical limitations, available antagonistic drugs and specific treatment regimens are still lacking. Therefore, there is an urgent need to not only clarify the exact etiology of HIRI but also reveal the possible reactions and bottlenecks of existing drugs, helping to reduce morbidity and shorten hospitalizations. We analyzed the possible underlying mechanism of HIRI, discussed various outcomes among different animal models and explored neglected potential therapeutic strategies for HIRI treatment. By thoroughly reviewing and analyzing the literature on HIRI, we gained a comprehensive understanding of the current research status in related fields and identified valuable references for future clinical and scientific investigations.
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Affiliation(s)
- Jia Liu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Ranyi Luo
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yinhao Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaojiaoyang Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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Deng RM, Zhou J. Targeting NF-κB in Hepatic Ischemia-Reperfusion Alleviation: from Signaling Networks to Therapeutic Targeting. Mol Neurobiol 2024; 61:3409-3426. [PMID: 37991700 DOI: 10.1007/s12035-023-03787-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a major complication of liver trauma, resection, and transplantation that can lead to liver dysfunction and failure. Scholars have proposed a variety of liver protection methods aimed at reducing ischemia-reperfusion damage, but there is still a lack of effective treatment methods, which urgently needs to find new effective treatment methods for patients. Many studies have reported that signaling pathway plays a key role in HIRI pathological process and liver function recovery mechanism, among which nuclear transfer factor-κB (NF-κB) signaling pathway is one of the signal transduction closely related to disease. NF-κB pathway is closely related to HIRI pathologic process, and inhibition of this pathway can delay oxidative stress, inflammatory response, cell death, and mitochondrial dysfunction. In addition, NF-κB can also interact with PI3K/Akt, MAPK, and Nrf2 signaling pathways to participate in HIRI regulation. Based on the role of NF-κB pathway in HIRI, it may be a potential target pathway for HIRI. This review emphasizes the role of inhibiting the NF-κB signaling pathway in oxidative stress, inflammatory response, cell death, and mitochondrial dysfunction in HIRI, as well as the effects of related drugs or inhibitors targeting NF-κB on HIRI. The objective of this review is to elucidate the role and mechanism of NF-κB pathway in HIRI, emphasize the important role of NF-κB pathway in the prevention and treatment of HIRI, and provide a theoretical basis for the target NF-κB pathway as a therapy for HIRI.
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Affiliation(s)
- Rui-Ming Deng
- Department of Anesthesiology, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China
- The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China
| | - Juan Zhou
- The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China.
- Department of Thyroid and Breast Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China.
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Ali FF, Mohammed MM, Hussein Y, Ibrahim MFG. Targeting PI3K/p-Akt/eNOS, Nrf2/HO-1, and NF-κB/p53 signaling pathways by angiotensin 1-7 protects against liver injury induced by ischemia-reperfusion in rats. Cell Biochem Funct 2024; 42:e3938. [PMID: 38269514 DOI: 10.1002/cbf.3938] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 12/13/2023] [Accepted: 01/10/2024] [Indexed: 01/26/2024]
Abstract
The liver is an important organ, and hepatic ischemia-reperfusion (IR) injury is a frequent pathophysiological process that can cause significant morbidity and mortality. Thus, our study aimed to investigate the effect of targeting PI3K/p-Akt/eNOS (phosphoinositide 3-kinase/phospho-protein kinase B/endothelial nitric oxide synthase), Nrf2/HO-1 (nuclear factor-erythroid 2-related factor-2/heme oxygenase-1), and NF-κB/p53 (nuclear factor-κB/tumor protein 53) signaling pathways by using angiotensin (1-7) [ang-(1-7)] against hepatic injury induced by IR. Thirty-two male rats were included in sham group, ang-(1-7)-treated group, hepatic IR group, and hepatic IR group treated with ang-(1-7). The levels of hepatic ang-(1-7), angiotensin II (Ang II), angiotensin-converting enzyme 2 (ACE2), HO-1, malondialdehyde (MDA), PI3K, and p-Akt were assessed. The expressions of eNOS and B-cell leukemia/lymphoma-2 (BCL-2) in the liver were determined. Histological assessment and immunohistochemical expression of NF-κB, p53, and Nrf2 were carried out. The levels of reduced glutathione (GSH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in serum were estimated. Results showed that administration of ang-(1-7) to hepatic IR rats led to significant amelioration of hepatic damage through a histological evaluation that was associated with significant upregulation of the expressions of PI3K/p-Akt/eNOS and Nrf2/HO-1 with downregulation of NF-κB/p53 signaling pathways. In conclusion, PI3K/p-Akt/eNOS and Nrf2/HO-1 signaling pathways are involved in the protective effects of ang-(1-7) against hepatic damage induced by IR. Therefore, ang-(1-7) can be used to prevent hepatic IR, which occurs in certain conditions such as liver transplantation, hemorrhagic shock, and severe infection.
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Affiliation(s)
- Fatma Farrag Ali
- Medical Physiology Department, Faculty of Medicine, Minia University, Minia, Egypt
- Biochemistry and Physiology Department, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | | | - Youssef Hussein
- Anatomy, Histology and Embryology Department, Faculty of Medicine, Mutah University, Al-Karak, Jordan
- Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Huang W, Paul D, Calin GA, Bayraktar R. miR-142: A Master Regulator in Hematological Malignancies and Therapeutic Opportunities. Cells 2023; 13:84. [PMID: 38201290 PMCID: PMC10778542 DOI: 10.3390/cells13010084] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/29/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
MicroRNAs (miRNAs) are a type of non-coding RNA whose dysregulation is frequently associated with the onset and progression of human cancers. miR-142, an ultra-conserved miRNA with both active -3p and -5p mature strands and wide-ranging physiological targets, has been the subject of countless studies over the years. Due to its preferential expression in hematopoietic cells, miR-142 has been found to be associated with numerous types of lymphomas and leukemias. This review elucidates the multifaceted role of miR-142 in human physiology, its influence on hematopoiesis and hematopoietic cells, and its intriguing involvement in exosome-mediated miR-142 transport. Moreover, we offer a comprehensive exploration of the genetic and molecular landscape of the miR-142 genomic locus, highlighting its mutations and dysregulation within hematological malignancies. Finally, we discuss potential avenues for harnessing the therapeutic potential of miR-142 in the context of hematological malignancies.
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Affiliation(s)
- Wilson Huang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (W.H.); (G.A.C.)
| | - Doru Paul
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - George A. Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (W.H.); (G.A.C.)
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Recep Bayraktar
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Shao JL, Wang LJ, Xiao J, Yang JF. Non-coding RNAs: The potential biomarker or therapeutic target in hepatic ischemia-reperfusion injury. World J Gastroenterol 2023; 29:4927-4941. [PMID: 37731999 PMCID: PMC10507504 DOI: 10.3748/wjg.v29.i33.4927] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/22/2023] [Accepted: 08/18/2023] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is the major complication of liver surgery and liver transplantation, that may increase the postoperative morbidity, mortality, tumor progression, and metastasis. The underlying mechanisms have been extensively investigated in recent years. Among these, oxidative stress, inflammatory responses, immunoreactions, and cell death are the most studied. Non-coding RNAs (ncRNAs) are defined as the RNAs that do not encode proteins, but can regulate gene expressions. In recent years, ncRNAs have emerged as research hotspots for various diseases. During the progression of HIRI, ncRNAs are differentially expressed, while these dysregulations of ncRNAs, in turn, have been verified to be related to the above pathological processes involved in HIRI. ncRNAs mainly contain microRNAs, long ncRNAs, and circular RNAs, some of which have been reported as biomarkers for early diagnosis or assessment of liver damage severity, and as therapeutic targets to attenuate HIRI. Here, we briefly summarize the common pathophysiology of HIRI, describe the current knowledge of ncRNAs involved in HIRI in animal and human studies, and discuss the potential of ncRNA-targeted therapeutic strategies. Given the scarcity of clinical trials, there is still a long way to go from pre-clinical to clinical application, and further studies are needed to uncover their potential as therapeutic targets.
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Affiliation(s)
- Jia-Li Shao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Li-Juan Wang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Ji Xiao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Jin-Feng Yang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
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Yu Q, Chen S, Li J, Tang H, Shi J, Guo W, Zhang S. Mitogen activated protein kinase phosphatase 5 alleviates liver ischemia-reperfusion injury by inhibiting TAK1/JNK/p38 pathway. Sci Rep 2023; 13:11110. [PMID: 37429895 PMCID: PMC10333288 DOI: 10.1038/s41598-023-37768-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/27/2023] [Indexed: 07/12/2023] Open
Abstract
Mitogen activated protein kinase phosphatase 5 (MKP5) is a member of the MKP family and has been implicated in diverse biological and pathological conditions. However, it is unknown what role MKP5 plays in liver ischemia/reperfusion (I/R) injury. In the present study, we used MKP5 global knockout (KO) and MKP5 overexpressing mice to establish a liver I/R injury model in vivo, and MKP5 knockdown or MKP5 overexpressing HepG2 cells to establish a hypoxia-reoxygenation (H/R) model in vitro. In this study we demonstrated that protein expression of MKP5 was significantly downregulated in liver tissue of mice after I/R injury, and HepG2 cells subjected to H/R injury. MKP5 KO or knockdown significantly increased liver injury, as demonstrated by elevated serum transaminases, hepatocyte necrosis, infiltrating inflammatory cells, secretion of pro-inflammatory cytokines, apoptosis, oxidative stress. Conversely, MKP5 overexpression significantly attenuated liver and cell injury. Furthermore, we showed that MKP5 exerted its protective effect by inhibiting c-Jun N-terminal kinase (JNK)/p38 activity, and its action was dependent on Transforming growth factor-β-activated kinase 1 (TAK1) activity. According to our results, MKP5 inhibited the TAK1/JNK/p38 pathway to protect liver from I/R injury. Our study identifies a novel target for the diagnosis and treatment of liver I/R injury.
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Affiliation(s)
- Qiwen Yu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
| | - Sanyang Chen
- Department of Emergency Surgery, the First Affiliated Hospital of Zhengzhou, Zhengzhou, Henan, China
| | - Jiye Li
- Department of Emergency Surgery, the First Affiliated Hospital of Zhengzhou, Zhengzhou, Henan, China
| | - Hongwei Tang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
| | - Jihua Shi
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, China.
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China.
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Zhu SF, Yuan W, Du YL, Wang BL. Research progress of lncRNA and miRNA in hepatic ischemia-reperfusion injury. Hepatobiliary Pancreat Dis Int 2023; 22:45-53. [PMID: 35934611 DOI: 10.1016/j.hbpd.2022.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 07/18/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (HIRI) is a common complication of liver surgeries, such as hepatectomy and liver transplantation. In recent years, several non-coding RNAs (ncRNAs) including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as factors involved in the pathological progression of HIRI. In this review, we summarized the latest research on lncRNAs, miRNAs and the lncRNA-miRNA regulatory networks in HIRI. DATA SOURCES The PubMed and Web of Science databases were searched for articles published up to December 2021 using the following keywords: "hepatic ischemia-reperfusion injury", "lncRNA", "long non-coding RNA", "miRNA" and "microRNA". The bibliography of the selected articles was manually screened to identify additional studies. RESULTS The mechanism of HIRI is complex, and involves multiple lncRNAs and miRNAs. The roles of lncRNAs such as AK139328, CCAT1, MALAT1, TUG1 and NEAT1 have been established in HIRI. In addition, numerous miRNAs are associated with apoptosis, autophagy, oxidative stress and cellular inflammation that accompany HIRI pathogenesis. Based on the literature, we conclude that four lncRNA-miRNA regulatory networks mediate the pathological progression of HIRI. Furthermore, the expression levels of some lncRNAs and miRNAs undergo significant changes during the progression of HIRI, and thus are potential prognostic markers and therapeutic targets. CONCLUSIONS Complex lncRNA-miRNA-mRNA networks regulate HIRI progression through mutual activation and antagonism. It is necessary to screen for more HIRI-associated lncRNAs and miRNAs in order to identify novel therapeutic targets.
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Affiliation(s)
- Shan-Fei Zhu
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Wei Yuan
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Yong-Liang Du
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Bai-Lin Wang
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China.
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Pretzsch E, Nieß H, Khaled NB, Bösch F, Guba M, Werner J, Angele M, Chaudry IH. Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes. Int J Mol Sci 2022; 23:12942. [PMID: 36361725 PMCID: PMC9657004 DOI: 10.3390/ijms232112942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/16/2022] [Accepted: 10/20/2022] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.
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Affiliation(s)
- Elise Pretzsch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Hanno Nieß
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Florian Bösch
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Markus Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Irshad H. Chaudry
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Xin W, Qin Y, Lei P, Zhang J, Yang X, Wang Z. From cerebral ischemia towards myocardial, renal, and hepatic ischemia: Exosomal miRNAs as a general concept of intercellular communication in ischemia-reperfusion injury. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 29:900-922. [PMID: 36159596 PMCID: PMC9464648 DOI: 10.1016/j.omtn.2022.08.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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PIAS1 Alleviates Hepatic Ischemia-Reperfusion Injury in Mice through a Mechanism Involving NFATc1 SUMOylation. DISEASE MARKERS 2022; 2022:4988539. [PMID: 36092961 PMCID: PMC9452975 DOI: 10.1155/2022/4988539] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 06/14/2022] [Indexed: 11/18/2022]
Abstract
Recently, attentions have come to the alleviatory effect of protein inhibitor of activated STAT1 (PIAS1) in hepatic ischemia-reperfusion injury (HIRI), but the underlying molecular mechanistic actions remain largely unknown, which were illustrated in the present study. Microarray-based analysis predicted a possible regulatory mechanism involving the PIAS1/NFATc1/HDAC1/IRF-1/p38 MAPK signaling axis in HIRI. Then, growth dynamics of hypoxia/reoxygenation- (H/R-) exposed hepatocytes and liver injury of HIRI-like mice were delineated after the alteration of the PIAS1 expression. We validated that PIAS1 downregulation occurred in H/R-exposed hepatocytes and HIRI-like mice, while the expression of NFATc1, HDAC1, and IRF-1 and phosphorylation levels of p38 were increased. PIAS1 inactivated p38 MAPK signaling by inhibiting HDAC1-mediated IRF-1 through NFATc1 SUMOylation, thereby repressing the inflammatory response and apoptosis of hepatocytes in vitro, and alleviated liver injury in vivo. Collectively, the NFATc1/HDAC1/IRF-1/p38 MAPK signaling axis is highlighted as a promising therapeutic target for potentiating hepatoprotective effects of PIAS1 against HIRI.
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12
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Ren W, Zhao F, Han Y, Liu Z, Zhai J, Jia K. Muscone improves hypoxia/reoxygenation (H/R)-induced neuronal injury by blocking HMGB1/TLR4/NF-κB pathway via modulating microRNA-142. PeerJ 2022; 10:e13523. [PMID: 35860039 PMCID: PMC9290999 DOI: 10.7717/peerj.13523] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 05/10/2022] [Indexed: 01/25/2023] Open
Abstract
Previous reports have indicated that natural muscone has neuroprotective effects against cerebral hypoxia injury; however, little is known in regards to its pharmacological mechanism. In this study, we tried to evaluate the neuroprotective effects and mechanisms of muscone against cerebral hypoxia injury using an in vitro model. The cerebral hypoxia injury cell model was produced by hypoxia/reoxygenation (H/R). The cell viability and apoptosis were measured using the cell counting Kit-8 and the Annexin V-FITC/PI Apoptosis Detection kit, respectively. To screen microRNAs regulated by muscone, we analyzed the gene expression datasets of GSE84216 retrieved from gene expression omnibus (GEO). Here, it was demonstrated that muscone treatment significantly alleviated the cell apoptosis, oxidative stress and inflammation in H/R-exposed neurons. Subsequently, through analyzing GSE84216 from the GEO database, miR-142-5p was markedly upregulated by treatment of muscone in this cell model of cerebral hypoxia injury. Further experiments revealed that downregulation of miR-142-5p eliminated the neuroprotective effects of muscone against H/R induced neuronal injury. Additionally, high mobility group box 1 (HMGB1), an important inflammatory factor, was identified as a direct target of miR-142-5p in neurons. Meanwhile, we further demonstrated that muscone could reduce the expression of HMGB1 by upregulating miR-142-5p expression, which subsequently resulted in the inactivation of TLR4/NF-κB pathway, finally leading to the improvement of cell injury in H/R-exposed neurons. Overall, we demonstrate for the first time that muscone treatment alleviates cerebral hypoxia injury in in vitro experiments through blocking activation of the TLR4/NF-κB signaling pathway by targeting HMGB1, suggesting that muscone may serve as a potential therapeutic drug for treating cerebral hypoxia injury.
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13
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Hong L, He M, Li S, Zhao J. Predicting for anti-(mutant) SARS-CoV-2 and anti-inflammation compounds of Lianhua Qingwen Capsules in treating COVID-19. Chin Med 2022; 17:84. [PMID: 35799189 PMCID: PMC9261255 DOI: 10.1186/s13020-022-00637-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 06/18/2022] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Lianhua Qingwen Capsules (LHQW) is a traditional Chinese medicine prescription commonly used to treat viral influenza in China. There has been sufficient evidence that LHQW could effectively treat COVID-19. Nevertheless, the potential anti-(mutant) SARS-CoV-2 and anti-inflammation compounds in LHQW are still vague. METHODS The compounds of LHQW and targets were collected from TCMSP, TCMID, Shanghai Institute of Organic Chemistry of CAS database, and relevant literature. Autodock Vina was used to carry out molecular docking. The pkCSM platform to predict the relevant parameters of compound absorption in vivo. The protein-protein interaction (PPI) network was constructed by the STRING database. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was carried out by Database for Annotation, Visualization, and Integrated Discovery (DAVID). The anti-(mutant) SARS-CoV-2 and anti-inflammation networks were constructed on the Cytoscape platform. RESULTS 280 compounds, 16 targets related to SARS-CoV-2, and 54 targets related to cytokine storm were obtained by screening. The key pathways Toll-like receptor signaling, NOD-like receptor signal pathway, and Jak-STAT signaling pathway, and the core targets IL6 were obtained by PPI network and KEGG pathway enrichment analysis. The network analysis predicted and discussed the 16 main anti-SARS-CoV-2 active compounds and 12 main anti-inflammation active compounds. Ochnaflavone and Hypericin are potential anti-mutant virus compounds in LHQW. CONCLUSIONS In summary, this study explored the potential anti-(mutant) SARS-CoV-2 and anti-inflammation compounds of LHQW against COVID-19, which can provide new ideas and valuable references for discovering active compounds in the treatment of COVID-19.
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Affiliation(s)
- Liang Hong
- grid.437123.00000 0004 1794 8068State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China ,grid.437123.00000 0004 1794 8068Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macau, China
| | - Min He
- grid.412982.40000 0000 8633 7608Department of Pharmaceutical Engineering, School of Chemical Engineering, Xiangtan University, Xiangtan, China
| | - Shaoping Li
- grid.437123.00000 0004 1794 8068State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China ,grid.437123.00000 0004 1794 8068Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macau, China
| | - Jing Zhao
- grid.437123.00000 0004 1794 8068State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China ,grid.437123.00000 0004 1794 8068Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macau, China
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14
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Chen Y, He Y, Zhao S, He X, Xue D, Xia Y. Hypoxic/Ischemic Inflammation, MicroRNAs and δ-Opioid Receptors: Hypoxia/Ischemia-Sensitive Versus-Insensitive Organs. Front Aging Neurosci 2022; 14:847374. [PMID: 35615595 PMCID: PMC9124822 DOI: 10.3389/fnagi.2022.847374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 03/21/2022] [Indexed: 11/15/2022] Open
Abstract
Hypoxia and ischemia cause inflammatory injury and critically participate in the pathogenesis of various diseases in various organs. However, the protective strategies against hypoxic and ischemic insults are very limited in clinical settings up to date. It is of utmost importance to improve our understanding of hypoxic/ischemic (H/I) inflammation and find novel therapies for better prevention/treatment of H/I injury. Recent studies provide strong evidence that the expression of microRNAs (miRNAs), which regulate gene expression and affect H/I inflammation through post-transcriptional mechanisms, are differentially altered in response to H/I stress, while δ-opioid receptors (DOR) play a protective role against H/I insults in different organs, including both H/I-sensitive organs (e.g., brain, kidney, and heart) and H/I-insensitive organs (e.g., liver and muscle). Indeed, many studies have demonstrated the crucial role of the DOR-mediated cyto-protection against H/I injury by several molecular pathways, including NLRP3 inflammasome modulated by miRNAs. In this review, we summarize our recent studies along with those of others worldwide, and compare the effects of DOR on H/I expression of miRNAs in H/I-sensitive and -insensitive organs. The alternation in miRNA expression profiles upon DOR activation and the potential impact on inflammatory injury in different organs under normoxic and hypoxic conditions are discussed at molecular and cellular levels. More in-depth investigations into this field may provide novel clues for new protective strategies against H/I inflammation in different types of organs.
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Affiliation(s)
- Yimeng Chen
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yichen He
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Shuchen Zhao
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiaozhou He
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Dong Xue
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
- *Correspondence: Dong Xue,
| | - Ying Xia
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
- Ying Xia,
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15
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Hua Y, Han A, Yu T, Hou Y, Ding Y, Nie H. Small Extracellular Vesicles Containing miR-34c Derived from Bone Marrow Mesenchymal Stem Cells Regulates Epithelial Sodium Channel via Targeting MARCKS. Int J Mol Sci 2022; 23:ijms23095196. [PMID: 35563590 PMCID: PMC9101277 DOI: 10.3390/ijms23095196] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/29/2022] [Accepted: 05/04/2022] [Indexed: 12/18/2022] Open
Abstract
Epithelial sodium channel (ENaC) is a pivotal regulator of alveolar fluid clearance in the airway epithelium and plays a key role in the treatment of acute lung injury (ALI), which is mainly composed of the three homologous subunits (α, β and γ). The mechanisms of microRNAs in small extracellular vesicles (sEVs) derived from mesenchymal stem cell (MSC-sEVs) on the regulation of lung ion transport are seldom reported. In this study, we aimed at investigating whether miR-34c had an effect on ENaC dysfunction induced by lipopolysaccharide and explored the underlying mechanism in this process. Primarily, the effect of miR-34c on lung edema and histopathology changes in an ALI mouse model was investigated. Then the uptake of PKH26-labeled sEVs was observed in recipient cells, and we observed that the overexpression of miR-34c in MSC-sEVs could upregulate the LPS-inhibited γ-ENaC expression. The dual luciferase reporter gene assay demonstrated that myristoylated alanine-rich C kinase substrate (MARCKS) was one of target genes of miR-34c, the protein expression of which was negatively correlated with miR-34c. Subsequently, either upregulating miR-34c or knocking down MARCKS could increase the protein expression of phospho-phosphatidylinositol 3-kinase (p-PI3K) and phospho-protein kinase B (p-AKT), implying a downstream regulation pathway was involved. All of the above suggest that miR-34c in MSC-sEVs can attenuate edematous lung injury via enhancing γ-ENaC expression, at least partially, through targeting MARCKS and activating the PI3K/AKT signaling pathway subsequently.
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16
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MicroRNAs: Novel Targets in Hepatic Ischemia–Reperfusion Injury. Biomedicines 2022; 10:biomedicines10040791. [PMID: 35453542 PMCID: PMC9028838 DOI: 10.3390/biomedicines10040791] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatic ischemia–reperfusion injury (IRI) is one of the main factors for early allograft dysfunction (EAD), which may lead to graft rejection, graft loss, or shortened graft life in liver transplantation. Hepatic IRI appears to be inevitable during the majority of liver procurement and transportation of donor organs, resulting in a cascade of biological changes. The activation of signaling pathways during IRI results in the up- and downregulation of genes and microRNAs (miRNAs). miRNAs are ~21 nucleotides in length and well-characterized for their role in gene regulations; they have recently been used for therapeutic approaches in addition to their role as biomarkers for many diseases. miRNAs that are associated with hepatic IRI in in vitro and in vivo animal models are comprehensively summarized in this review. In those studies, the manipulation of miRNAs has been shown for the inhibition of aggravated immune response, reduction of apoptosis, stimulation of tissue repair, and enhancement of cell recovery to attenuate liver damage. Therefore, the utilization of liver-specific miRNA holds great potential as a therapeutic agent to improve early allograft dysfunction, hepatic injury, and patient outcome.
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17
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Ramírez-Torres A, Gil J, Contreras S, Ramírez G, Valencia-González HA, Salazar-Bustamante E, Gómez-Caudillo L, García-Carranca A, Encarnación-Guevara S. Quantitative Proteomic Analysis of Cervical Cancer Tissues Identifies Proteins Associated With Cancer Progression. Cancer Genomics Proteomics 2022; 19:241-258. [PMID: 35181591 DOI: 10.21873/cgp.20317] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 12/09/2021] [Accepted: 01/07/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND/AIM To date, several proteomics studies in cervical cancer (CC) have focused mainly on squamous cervical cancer (SCC). Our study aimed to discover and clarify differences in SCC and CAD that may provide valuable information for the identification of proteins involved in tumor progression, in CC as a whole, or specific for SCC or CAD. MATERIALS AND METHODS Total protein extracts from 15 individual samples corresponding to 5 different CC tissue types were compared with a non-cancerous control group using bidimensional liquid chromatography-mass spectrometry (2D LC-MS/MS), isobaric tags for relative and absolute quantitation (ITRAQ), principal component analysis (PCA) and gene set enrichment analysis (GSEA). RESULTS A total of 622 statistically significant different proteins were detected. Exocytosis-related proteins were the most over-represented, accounting for 25% of the identified and quantified proteins. Based on the experimental results, reticulocalbin 3 (RCN3) and Ras-related protein Rab-14 (RAB14) were chosen for further downstream in vitro and vivo analyses. RCN3 was overexpressed in all CC tissues compared to the control and RAB14 was overexpressed in squamous cervical cancer (SCC) compared to invasive cervical adenocarcinoma (CAD). In the tumor xenograft experiment, RAB14 protein expression was positively correlated with increased tumor size. In addition, RCN3-expressing HeLa cells induced a discrete size increment compared to control, at day 47 after inoculation. CONCLUSION RAB14 and RCN3 are suggested as potential biomarkers and therapeutic targets in the treatment of CC.
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Affiliation(s)
- Alberto Ramírez-Torres
- Proteomics, Center for Genomic Sciences, The National Autonomous University of Mexico (UNAM), Cuernavaca, Mexico
| | - Jeovanis Gil
- Proteomics, Center for Genomic Sciences, The National Autonomous University of Mexico (UNAM), Cuernavaca, Mexico.,Division of Oncology, Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Lund, Sweden
| | - Sandra Contreras
- Proteomics, Center for Genomic Sciences, The National Autonomous University of Mexico (UNAM), Cuernavaca, Mexico
| | - Graciela Ramírez
- The National Institute of Cancerology (INCan), Mexico City, Mexico
| | | | - Emmanuel Salazar-Bustamante
- Proteomics, Center for Genomic Sciences, The National Autonomous University of Mexico (UNAM), Cuernavaca, Mexico
| | - Leopoldo Gómez-Caudillo
- Proteomics, Center for Genomic Sciences, The National Autonomous University of Mexico (UNAM), Cuernavaca, Mexico
| | | | - Sergio Encarnación-Guevara
- Proteomics, Center for Genomic Sciences, The National Autonomous University of Mexico (UNAM), Cuernavaca, Mexico;
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18
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Hu L, Yang K, Mai X, Wei J, Ma C. Depleted HDAC3 attenuates hyperuricemia-induced renal interstitial fibrosis via miR-19b-3p/SF3B3 axis. Cell Cycle 2022; 21:450-461. [PMID: 35025700 PMCID: PMC8942505 DOI: 10.1080/15384101.2021.1989899] [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] [Indexed: 11/03/2022] Open
Abstract
Dysfunctional histone deacetylases (HDACs) elicit unrestrained fibrosis and damage to organs. With regard to the link between HDACs and fibrosis, this research is practiced to decipher the concrete mechanism of HDAC3 in hyperuricemia (HN)-induced renal interstitial fibrosis (RIF) from microRNA-19b-3p/splicing factor 3b subunit 3 (miR-19b-3p/SF3B3) axis.The HN model was established on rats to induce RIF by oral administration of adenine and potassium oxalate. HN rats were injected with miR-19b-3p- or HDAC3-related vectors to figure out their effects on RIF through detecting 24-h urine protein, uric acid (UA), blood urea nitrogen (BUN) and serum creatinine (Scr) contents and α-smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1) and fibronectin (FN) contents in renal tissues and observing pathological damages and RIF index of renal tissues. HDAC3, miR-19b-3p and SF3B3 expression in renal tissues were tested, along with their interactions.Elevated HDAC3 and SF3B3 and reduced miR-19b-3p were displayed in renal tissues of HN rats. Suppressed HDAC3 or promoted miR-19b-3p relieved HN-induced RIF, as reflected by their inhibitory effects on 24 h urine protein, UA, BUN, Scr, α-SMA, TGF-β1, and FN contents and RIF index and their ameliorated effects on pathological damages of renal tissues. HDAC3 bound to the promoter of miR-19b-3p to regulate SF3B3. MiR-19b-3p depletion abrogated down-regulated HDAC3-induced effects on HN-induced RIF.It is delineated that depressed HDAC3 relives HN-induced RIF through restoring miR-19b-3p and knocking down SF3B3, replenishing the references for RIF curing.
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Affiliation(s)
- Langtao Hu
- Department of Nephrology, Hainan General Hospital, Haikou, China.,Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical College, Haikou, China
| | - Kai Yang
- Department of Nephrology, Hainan General Hospital, Haikou, China.,Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical College, Haikou, China
| | - Xing Mai
- Department of Nephrology, Hainan General Hospital, Haikou, China.,Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical College, Haikou, China
| | - Jiali Wei
- Department of Nephrology, Hainan General Hospital, Haikou, China.,Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical College, Haikou, China
| | - Chunyang Ma
- Department of Neurosurgery, First Affiliated Hospital of Hainan Medical College, Haikou, China
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19
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Wang SS, Zeng X, Wang YL, Dongzhi Z, Zhao YF, Chen YZ. Chinese Medicine Meets Conventional Medicine in Targeting COVID-19 Pathophysiology, Complications and Comorbidities. Chin J Integr Med 2022; 28:627-635. [PMID: 35583580 PMCID: PMC9116066 DOI: 10.1007/s11655-022-3573-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2021] [Indexed: 01/09/2023]
Abstract
OBJECTIVE To investigate how the National Health Commission of China (NHCC)-recommended Chinese medicines (CMs) modulate the major maladjustments of coronavirus disease 2019 (COVID-19), particularly the clinically observed complications and comorbidities. METHODS By focusing on the potent targets in common with the conventional medicines, we investigated the mechanisms of 11 NHCC-recommended CMs in the modulation of the major COVID-19 pathophysiology (hyperinflammations, viral replication), complications (pain, headache) and comorbidities (hypertension, obesity, diabetes). The constituent herbs of these CMs and their chemical ingredients were from the Traditional Chinese Medicine Information Database. The experimentally-determined targets and the activity values of the chemical ingredients of these CMs were from the Natural Product Activity and Species Source Database. The approved and clinical trial drugs against these targets were searched from the Therapeutic Target Database and DrugBank Database. Pathways of the targets was obtained from Kyoto Encyclopedia of Genes and Genomes and additional literature search. RESULTS Overall, 9 CMs modulated 6 targets discovered by the COVID-19 target discovery studies, 8 and 11 CMs modulated 8 and 6 targets of the approved or clinical trial drugs for the treatment of the major COVID-19 complications and comorbidities, respectively. CONCLUSION The coordinated actions of each NHCC-recommended CM against a few targets of the major COVID-19 pathophysiology, complications and comorbidities, partly have common mechanisms with the conventional medicines.
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Affiliation(s)
- Shan-shan Wang
- Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang Province, 315211 China
| | - Xian Zeng
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203 China
| | - Ya-li Wang
- Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Singapore, 117543 Singapore
| | | | - Yu-fen Zhao
- Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang Province, 315211 China ,Department of Chemical Biology, College of Chemistry and Chemical Engineering, and The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian Province, 361005 China ,Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, 102206 China
| | - Yu-zong Chen
- Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang Province, 315211 China ,Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Singapore, 117543 Singapore
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20
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Wei L, Su Y, Tan S, Zou Y, Tang Y, Kong G, Chen W. Retraction for Wei et al., Electroacupuncture stimulation at Yanglingquan acupoint ameliorates hepatic ischemia-reperfusion injury by down-regulating ET-1 to inhibit TAK1-JNK/p38 pathway. Am J Physiol Gastrointest Liver Physiol 2021; 321:G690. [PMID: 34346776 DOI: 10.1152/ajpgi.00012.2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Affiliation(s)
- Lai Wei
- Department of Anesthesiology, Hunan Provincial People's Hospital, Changsha, China
| | - Yinyin Su
- Department of Anesthesiology, Hunan Provincial People's Hospital, Changsha, China
| | - Siyou Tan
- Department of Anesthesiology, Hunan Provincial People's Hospital, Changsha, China
| | - Yi Zou
- Department of Anesthesiology, Hunan Provincial People's Hospital, Changsha, China
| | - Yixun Tang
- Department of Anesthesiology, Hunan Provincial People's Hospital, Changsha, China
| | - Gaoyin Kong
- Department of Anesthesiology, Hunan Provincial People's Hospital, Changsha, China
| | - Wenyan Chen
- Department of Anesthesiology, Hunan Provincial People's Hospital, Changsha, China
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21
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Fei Y, Shao J, Huang G, Wang L, Zou S, Sun H, Zheng C, Yang J. Effect of Edaravone on MicroRNA Expression in Exosomes after Hepatic Ischemia-reperfusion Injury. Curr Mol Pharmacol 2021; 15:870-882. [PMID: 34847855 DOI: 10.2174/1874467214666211130162152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/05/2021] [Accepted: 09/23/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND OBJECTIVE Hepatic ischemia-reperfusion injury (HIRI) results in serious complications after liver resection and transplantation. Edaravone (ED) has a protective effect on IRI. This study was designed to evaluate whether ED could protect the liver of rats from HIRI injury and explored its exosomal miRNA-related mechanism. METHODS The sham group, hepatic ischemia/reperfusion (IR group), and hepatic ischemia/reperfusion + edaravone (ED group) models were established. We determined the protective effect of ED by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), superoxide dismutase (SOD); enzyme-linked immunosorbent assay for tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β); hematoxylin-eosin staining and immunohistochemistry for histopathological changes. Exosomal miRNAs were subjected to second-generation sequencing to identify their differential expression. The results were analyzed using bioinformatics methods and validated using real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS HIRI rats showed higher levels of ALT, AST, oxidative stress, and inflammatory markers; ED attenuated these effects. The sequencing results showed 6 upregulated and 13 downregulated miRNAs in the IR vs. sham groups, 10 upregulated and 10 downregulated miRNAs in the ED vs. IR groups. PC-3p-190-42101 was screened as an overlapping differentially expressed miRNA, and RT-qPCR validation showed that its expression in HIRI rats was significantly decreased; ED prevented this downregulation. Moreover, the expression of PC-3P-190-42101 was significantly correlated with the level of inflammatory factors. CONCLUSION These findings indicate that ED can regulate the level of inflammatory factors by affecting the expression of miRNA PC-3p-190-42101 in plasma exosomes to protect the liver from IRI.
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Affiliation(s)
- Yanxia Fei
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Jiali Shao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Ge Huang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Lijuan Wang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Shuangfa Zou
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Huiping Sun
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Chumei Zheng
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Jinfeng Yang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
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22
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Wang W, Zhong GZ, Long KB, Liu Y, Liu YQ, Xu AL. Silencing miR-181b-5p upregulates PIAS1 to repress oxidative stress and inflammatory response in rats with alcoholic fatty liver disease through inhibiting PRMT1. Int Immunopharmacol 2021; 101:108151. [PMID: 34836796 DOI: 10.1016/j.intimp.2021.108151] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/01/2021] [Accepted: 09/08/2021] [Indexed: 02/08/2023]
Abstract
OBJECTIVE This study aimed to probe the function of microRNA-181b-5p (miR-181b-5p)/protein inhibitor of activated STAT1 (PIAS1)/protein arginine methyltransferase 1 (PRMT1) axis in the progression of alcoholic fatty liver disease (AFLD). METHODS A rat model of AFLD was established and treated with altered miR-181b-5p, PIAS1 or PRMT1 expression constructs to identify their effects on liver function, serum inflammation, liver tissue oxidative stress, hepatocyte apoptosis and pathological changes of liver tissue in rats using a series of assays. miR-181b-5p, PIAS1 and PRMT1 levels were detected, and the targeting relationship between miR-181b-5p and PIAS1 was confirmed. RESULTS MiR-181b-5p and PRMT1 were elevated while PIAS1 was reduced in AFLD rat liver tissues, miR-181b-5p inhibition, PIAS1 overexpression or PRMT1 inhibition improved liver function, attenuated inflammation, oxidative stress, pathological changes and hepatocyte apoptosis in AFLD rat liver tissues. The impacts of miR-181b-5p inhibition on AFLD rats were reversed by PIAS1 silencing. PIAS1 was confirmed as a target gene of miR-181b-5p, and miR-181b-5p regulated PRMT1 expression through binding to PIAS1. CONCLUSION Inhibiting miR-181b-5p can promote the expression of PIAS1, thereby inhibiting PRMT1 and ultimately improving AFLD.
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Affiliation(s)
- Wei Wang
- Gastroenterology Department, Hunan Aerospace Hospital, Changsha 410205, Hunan, China
| | - Guan-Zhen Zhong
- Gastroenterology Department, Hunan Aerospace Hospital, Changsha 410205, Hunan, China
| | - Kai-Bing Long
- Gastroenterology Department, Hunan Aerospace Hospital, Changsha 410205, Hunan, China
| | - Yang Liu
- Gastroenterology Department, Hunan Aerospace Hospital, Changsha 410205, Hunan, China
| | - Ya-Qian Liu
- Gastroenterology Department, Hunan Aerospace Hospital, Changsha 410205, Hunan, China
| | - Ai-Lei Xu
- Gastroenterology Department, Hunan Aerospace Hospital, Changsha 410205, Hunan, China.
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23
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Chen Z, Zhang W, Selmi C, Ridgway WM, Leung PS, Zhang F, Gershwin ME. The myristoylated alanine-rich C-kinase substrates (MARCKS): A membrane-anchored mediator of the cell function. Autoimmun Rev 2021; 20:102942. [PMID: 34509657 PMCID: PMC9746065 DOI: 10.1016/j.autrev.2021.102942] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 06/26/2021] [Indexed: 12/15/2022]
Abstract
The myristoylated alanine-rich C-kinase substrate (MARCKS) and the MARCKS-related protein (MARCKSL1) are ubiquitous, highly conserved membrane-associated proteins involved in the structural modulation of the actin cytoskeleton, chemotaxis, motility, cell adhesion, phagocytosis, and exocytosis. MARCKS includes an N-terminal myristoylated domain for membrane binding, a highly conserved MARCKS Homology 2 (MH2) domain, and an effector domain (which is the phosphorylation site). MARCKS can sequester phosphatidylinositol-4, 5-diphosphate (PIP2) at lipid rafts in the plasma membrane of quiescent cells, an action reversed by protein kinase C (PKC), ultimately modulating the immune function. Being expressed mostly in innate immune cells, MARCKS promotes the inflammation-driven migration and adhesion of cells and the secretion of cytokines such as tumor necrosis factor (TNF). From a clinical point of view, MARCKS is overexpressed in patients with schizophrenia and bipolar disorders, while the brain level of MARCKS phosphorylation is associated with Alzheimer's disease. Furthermore, MARCKS is associated with the development and progression of numerous types of cancers. Data in autoimmune diseases are limited to rheumatoid arthritis models in which a connection between MARCKS and the JAK-STAT pathway is mediated by miRNAs. We provide a comprehensive overview of the structure of MARCKS, its molecular characteristics and functions from a biological and pathogenetic standpoint, and will discuss the clinical implications of this pathway.
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Affiliation(s)
- Zhilei Chen
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA 95616, United States,Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Weici Zhang
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA 95616, United States,Corresponding authors. (W. Zhang), (F. Zhang)
| | - Carlo Selmi
- Humanitas Research Hospital - IRCCS, Rozzano, Milan, Italy
| | - William M. Ridgway
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA 95616, United States
| | - Patrick S.C. Leung
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA 95616, United States
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China,Corresponding authors. (W. Zhang), (F. Zhang)
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA 95616, United States
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Yu Q, Chen S, Tang H, Yang H, Zhang J, Shi X, Li J, Guo W, Zhang S. miR‑140‑5p alleviates mouse liver ischemia/reperfusion injury by targeting CAPN1. Mol Med Rep 2021; 24:675. [PMID: 34296301 PMCID: PMC8335737 DOI: 10.3892/mmr.2021.12314] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 07/05/2021] [Indexed: 12/21/2022] Open
Abstract
Ischemia/reperfusion (I/R)‑induced liver injury remains a primary concern in liver transplantation and hepatectomy. Previous studies have indicated that microRNAs (miRs) are involved in multiple pathophysiological processes, including liver I/R. miR‑140‑5p reportedly inhibits inflammatory responses and apoptosis in several diseases; however, the role of miR‑140‑5p in liver I/R remains unknown. The present study aimed to investigate the potential role and mechanism of miR‑140‑5p on liver I/R injury. Mouse liver I/R and mouse AML12 cell hypoxia/reoxygenation (H/R) models were established. miR‑140‑5p mimics, inhibitor or agonists were used to overexpress or inhibit miR‑140‑5p in vitro and in vivo. Reverse transcription‑quantitative polymerase chain reaction was used to detect miR‑140‑5p expression. Liver and cell injury were evaluated using several biochemical assays. The association between miR‑140‑5p and calpain‑1 (CAPN1) was confirmed using a dual‑luciferase reporter assay. The results revealed that miR‑140‑5p expression was decreased in the mouse model of liver I/R injury and AML12 cells subjected to H/R, while overexpressed miR‑140‑5p reduced liver injury in vivo and cell injury in vitro. In addition, CAPN1 was determined to be a target of miR‑140‑5p; overexpressed CAPN1 abrogated the effect of miR‑140‑5p on H/R‑induced cell injury. The present study indicated that miR‑140‑5p protected against liver I/R by targeting CAPN1, which may provide a novel therapeutic target for liver I/R injury.
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Affiliation(s)
- Qiwen Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Sanyang Chen
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Hongwei Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Han Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jiakai Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xiaoyi Shi
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jie Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Huang JQ, Li DM, Li JX, Lin JL, Tian X, Wang LJ, Chen XY, Fang X. 1,10/1,11-Cyclization catalyzed by diverged plant sesquiterpene synthases is dependent on a single residue. Org Biomol Chem 2021; 19:6650-6656. [PMID: 34264250 DOI: 10.1039/d1ob00827g] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The exquisite chemodiversity of terpenoids is the product of the large diverse terpene synthase (TPS) superfamily. Here, by using structural and phylogenetic analyses and site-directed mutagenesis, we identified a residue (Cys440 in Nicotiana tabacum 5-epi-aristolochene synthase) proximal to an ion-binding motif common to all TPSs and named the preNSE/DTE residue, which determines the product specificity of sesquiterpene synthases from different plant species. In sesquiterpene synthases catalyzing 1,10-cyclization (1,10-cyclases) of farnesyl diphosphate, mutation of the residue in both specific and promiscuous 1,10-cyclases from different lineages leads to the accumulation of monocyclic germacrene A-11-ol, which is "short-circuited" from complex cyclization cascades, suggesting a key role of this residue in generating the first common intermediate of 1,10-cyclization. Altering this residue in a specific 1,11-cyclase results in alternative 1,10-cyclization products. Moreover, the preNSE/DTE residue can be harnessed to engineer highly specific sesquiterpene synthases for an improved proportion of high-value terpenoids, such as patchoulol, a main constituent of several traditional Chinese medicines that could treat SARS-CoV-2.
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Affiliation(s)
- Jin-Quan Huang
- Yunnan University, Kunming, PR China and National Key Laboratory of Plant Molecular Genetics, Institute of Plant Physiology and Ecology/CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Dong-Mei Li
- Yunnan University, Kunming, PR China and State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, PR China.
| | - Jian-Xu Li
- National Key Laboratory of Plant Molecular Genetics, Institute of Plant Physiology and Ecology/CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Jia-Ling Lin
- National Key Laboratory of Plant Molecular Genetics, Institute of Plant Physiology and Ecology/CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, PR China and School of Life Science and Technology, ShanghaiTech University, Shanghai, PR China
| | - Xiu Tian
- National Key Laboratory of Plant Molecular Genetics, Institute of Plant Physiology and Ecology/CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Ling-Jian Wang
- National Key Laboratory of Plant Molecular Genetics, Institute of Plant Physiology and Ecology/CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Xiao-Ya Chen
- National Key Laboratory of Plant Molecular Genetics, Institute of Plant Physiology and Ecology/CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Xin Fang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, PR China.
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26
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Wang H, Guo L, Wang Y, Song S. Isoflurane upregulates microRNA-9-3p to protect rats from hepatic ischemia-reperfusion injury through inhibiting fibronectin type III domain containing 3B. Cell Cycle 2021; 20:1527-1539. [PMID: 34308776 PMCID: PMC8409784 DOI: 10.1080/15384101.2021.1947548] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 04/23/2021] [Accepted: 05/31/2021] [Indexed: 12/29/2022] Open
Abstract
Isoflurane has been studied in ischemia-reperfusion injury, while the regulatory mechanism by which isoflurane regulates microRNA(miR)-9-3p in hepatic ischemia/reperfusion injury (HIRI) via targeting fibronectin type III domain containing 3B (FNDC3B) remains seldom investigated. This study aims to determine the role of miR-9-3p in HIRI progression under the treatment of isoflurane. Rat HIRI models were established and treated with isoflurane. MiR-9-3p was altered to assess its role in inflammation, oxidative stress, transaminases, pathology, and hepatocyte apoptosis in HIRI rat liver tissues. Expression of miR-9-3p and FNDC3B in rat liver tissues was determined, and the targeting relationship between miR-9-3p and FNDC3B was confirmed using bioinformatic prediction and dual luciferase reporter gene assay. MiR-9-3p was downregulated, whereas FNDC3B was upregulated in HIRI rat liver tissues. Isoflurane treatment upregulated miR-9-3p and attenuated pathological changes, inflammation, oxidative stress, transaminases, and hepatocyte apoptosis in HIRI rat liver tissues. MiR-9-3p upregulation further strengthened the effect of isoflurane on HIRI, while miR-9-3p downregulation suppressed the therapeutic role of isoflurane. FNDC3B was confirmed as a target gene of miR-9-3p. Isoflurane upregulates miR-9-3p to protect rats from HIRI by inhibiting FNDC3VB. Our research may provide novel targets for HIRI treatment.
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Affiliation(s)
- Haiyan Wang
- Department of Anesthesiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Longlong Guo
- Department of Anesthesiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Yang Wang
- Department of Anesthesiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Shan Song
- Department of Anesthesiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
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Xu L, Ge F, Hu Y, Yu Y, Guo K, Miao C. Sevoflurane Postconditioning Attenuates Hepatic Ischemia-Reperfusion Injury by Limiting HMGB1/TLR4/NF-κB Pathway via Modulating microRNA-142 in vivo and in vitro. Front Pharmacol 2021; 12:646307. [PMID: 33935744 PMCID: PMC8085516 DOI: 10.3389/fphar.2021.646307] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Preconditioning of sevoflurane (Sevo) has been demonstrated to protect the liver from ischemia/reperfusion (I/R) injury. However, it is unknown whether it has hepatoprotective when given at the onset of reperfusion (postconditioning), a protocol with more clinical impact. The present study aimed to explore the hepatoprotective effects of Sevo postconditioning against hepatic IR injury in vivo and in vitro and the possible mechanisms. Using a mouse model of hepatic I/R, Sevo postconditioning significantly improved hepatic injury after reperfusion, as demonstrated by reduced AST, ALT, and LDH serum levels and reduced histologic damage in liver tissues. Furthermore, Sevo postconditioning could suppress the apoptosis, inhibit oxidative stress and inflammatory response in liver tissue of HIRI mice, as well as improve the survival rate of HIRI mice. Through analyzing GSE72314 from the gene expression omnibus (GEO) database, it was demonstrated that microRNA (miR)-142 is downregulated by HIRI, which was reversed by Sevo treatment. Further investigation showed that agomiR-142 injection could enhance the hepatoprotective effects of Sevo postconditioning on I/R injury, while antagomiR-142 reversed these effects in mice. Notably, high mobility group box 1 (HMGB1), an important inflammatory factor, was directly targeted by miR-142 in hepatic cells, and we further found that Sevo could inhibit the expression of HMGB1 through up-regulating miR-142 expression in HIRI mice model. In addition, we found that I/R injury induced the activation of TLR4/NF-κB inflammatory pathway was partially suppressed by Sevo postconditioning, and miR-142 mediated the regulatory role of Sevo postconditioning. In line with the in vivo results, Sevo treatment improved the cell viability, inhibited cell apoptosis, oxidative stress and inflammatory response in vitro HIRI model, while these effects were reversed by antagomiR-142 transfection. Collectively, our findings demonstrated that Sevo postconditioning counteracts the downregulation of miR-142 provoked by I/R, in turn decreased the expression of HMGB1, blocking TLR4/NF-κB pathway activation, thus improving hepatic I/R injury. Our data suggest that Sevo may be a valuable alternative anaesthetic agent in liver transplantation and major liver surgeries.
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Affiliation(s)
- Liying Xu
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Feng Ge
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Yan Hu
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Ying Yu
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Kefang Guo
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Changhong Miao
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai, China
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28
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Li HW, Ying P, Cai QQ, Yang ZH, Wu XL. Exogenous melatonin alleviates hemorrhagic shock‑induced hepatic ischemic injury in rats by inhibiting the NF‑κB/IκBα signaling pathway. Mol Med Rep 2021; 23:341. [PMID: 33760198 PMCID: PMC7974417 DOI: 10.3892/mmr.2021.11980] [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] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 10/27/2020] [Indexed: 01/24/2023] Open
Abstract
Melatonin (MT) is an indoleamine hormone that can counteract ischemia-induced organ injury through its antioxidant effects. The aim of the present study was to investigate the protective effects of exogenous MT against hemorrhagic shock (HS)-induced hepatic ischemic injury in rats, and the role of the nuclear factor (NF)-κB signaling pathway in this process. A rat model of HS-induced hepatic ischemic injury was established. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), glutamate dehydrogenase (GDH), tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-6 and IL-1β were measured every 6 h, and the 24-h survival rate of the rats was analyzed. All surviving rats were sacrificed after 24 h. Pathological changes in the liver and the hepatocyte apoptosis rate were observed by hematoxylin and eosin staining and TUNEL assay, respectively, and the expression levels of NF-κB p65 and NF-κB inhibitor α (IκBα) were analyzed by reverse transcription-quantitative PCR analysis and western blotting. The results demonstrated that the serum levels of ALT, AST, LDH, GDH, TNF-α, IFN-γ, IL-6 and IL-1β gradually increased after HS compared with those in rats subjected to a sham procedure, but this increase was attenuated by MT. Furthermore, the survival rate of the MT group was significantly higher compared with that of the HS group. The degree of pathological hepatic injury, the hepatocyte apoptosis rate, and the hepatic levels of TNF-α, IFN-γ, IL-6 and IL-1β were significantly decreased in the MT group compared with the HS group. In addition, the mRNA expression of NF-κB p65 was significantly decreased and the mRNA expression of IκBα was significantly increased in the MT group compared with the sham group. Furthermore, the NF-κB p65 protein levels in the MT group were significantly increased in the cytosol but decreased in the nucleus, and the IκBα protein levels were increased while those of phosphorylated IκBα were decreased compared with those in the HS group. Therefore, it may be inferred that exogenous MT alleviates HS-induced hepatic ischemic injury in rats via the inhibition of NF-κB activation and IκBα phosphorylation.
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Affiliation(s)
- Hai-Wei Li
- Department of Emergency, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, P.R. China
| | - Pan Ying
- Department of Emergency, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, P.R. China
| | - Qi-Qi Cai
- Department of Emergency, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, P.R. China
| | - Zhi-Hui Yang
- Department of Emergency, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, P.R. China
| | - Xian-Long Wu
- Department of Emergency, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, P.R. China
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29
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Bai Y, Tao X. Comparison of COVID-19 and influenza characteristics. J Zhejiang Univ Sci B 2021; 22:87-98. [PMID: 33615750 PMCID: PMC7885750 DOI: 10.1631/jzus.b2000479] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023]
Abstract
The emergence of coronavirus disease 2019 (COVID-19) not only poses a serious threat to the health of people worldwide but also affects the global economy. The outbreak of COVID-19 began in December 2019, at the same time as the influenza season. However, as the treatments and prognoses of COVID-19 and influenza are different, it is important to accurately differentiate these two different respiratory tract infections on the basis of their respective early-stage characteristics. We reviewed official documents and news released by the National Health Commission of the People's Republic of China, the Chinese Center for Disease Control and Prevention (China CDC), the United States CDC, and the World Health Organization (WHO), and we also searched the PubMed, Web of Science, Excerpta Medica database (Embase), China National Knowledge Infrastructure (CNKI), Wanfang, preprinted bioRxiv and medRxiv databases for documents and guidelines from earliest available date up until October 3rd, 2020. We obtained the latest information about COVID-19 and influenza and summarized and compared their biological characteristics, epidemiology, clinical manifestations, pathological mechanisms, treatments, and prognostic factors. We show that although COVID-19 and influenza are different in many ways, there are numerous similarities; thus, in addition to using nucleic acid-based polymerase chain reaction (PCR) and antibody-based approaches, clinicians and epidemiologists should distinguish between the two using their respective characteristics in early stages. We should utilize experiences from other epidemics to provide additional guidance for the treatment and prevention of COVID-19.
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Affiliation(s)
- Yu Bai
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaonan Tao
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Abstract
Covid-19 pandemic has caused hundreds of thousands deaths and millions of infections and continued spreading violently. Although researchers are racing to find or develop effective drugs or vaccines, no drugs from modern medical system have been proven effective and the high mutant rates of the virus may lead it resistant to whatever drugs or vaccines developed following modern drug development procedure. Current evidence has demonstrated impressive healing effects of several Chinese medicines (CMs) for Covid-19, which urges us to reflect on the role of CM in the era of modern medicine. Undoubtedly, CM could be promising resources for developing drug candidates for the treatment of Covid-19 in a way similar to the development of artemisinin. But the theory that builds CM, like the emphasis of driving away exogenous pathogen (virus, etc.) by restoring self-healing capacity rather than killing the pathogen directly from the inside and the 'black-box' mode of diagnosing and treating patients, is as important, yet often ignored, an treasure as CM herbs and should be incorporated into modern medicine for future advancement and innovation of medical science.
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31
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Sabet Sarvestani F, Azarpira N, Al-Abdullah IH, Tamaddon AM. microRNAs in liver and kidney ischemia reperfusion injury: insight to improve transplantation outcome. Biomed Pharmacother 2020; 133:110944. [PMID: 33227704 DOI: 10.1016/j.biopha.2020.110944] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/03/2020] [Accepted: 10/25/2020] [Indexed: 12/26/2022] Open
Abstract
Ischemia reperfusion injury (IRI) is a condition that occurs wherever blood flow and oxygen is reduced or absent, such as trauma, vascular disease, stroke, and solid organ transplantation. This condition can lead to tissue damage, especially during organ transplantation. Under such circumstances, some signaling pathways are activated, leading to up- or down- regulation of several genes such as microRNAs (miRNAs) that might attenuate or ameliorate this status. Therefore, by manipulating miRNAs level, they can be used as a biomarker for early diagnosis of IRI or suggestive to be therapeutic agents in clinical situation in future.
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Affiliation(s)
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Ismail H Al-Abdullah
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, USA.
| | - Ali-Mohammad Tamaddon
- Department of Pharmaceutics and Center for Nanotechnology in Drug Delivery, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Huynh T, Wang H, Luan B. Structure-based lead optimization of herbal medicine rutin for inhibiting SARS-CoV-2's main protease. Phys Chem Chem Phys 2020; 22:25335-25343. [PMID: 33140777 DOI: 10.1039/d0cp03867a] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific treatments. To fight COVID-19, various traditional antiviral medicines have been prescribed in China to infected patients with mild to moderate symptoms and received unexpected success in controlling the disease. However, the molecular mechanisms of how these herbal medicines interact with the SARS-CoV-2 virus that causes COVID-19 have remained elusive. It is well known that the main protease (Mpro) of SARS-CoV-2 plays an important role in maturation of many viral proteins such as the RNA-dependent RNA polymerase. Here, we explore the underlying molecular mechanisms of the computationally determined top candidate, namely, rutin which is a key component in many traditional antiviral medicines such as Lianhuaqinwen and Shuanghuanlian, for inhibiting the viral target-Mpro. Using in silico methods (docking and molecular dynamics simulations), we revealed the dynamics and energetics of rutin when interacting with the Mpro of SARS-CoV-2, suggesting that the highly hydrophilic rutin molecule can be bound inside the Mpro's pocket (active site) and possibly inhibit its biological functions. In addition, we optimized the structure of rutin and designed two more hydrophobic analogs, M1 and M2, which satisfy the rule of five for western medicines and demonstrated that they (M2 in particular) possess much stronger binding affinities to the SARS-COV-2s Mpro than rutin, due to the enhanced hydrophobic interaction as well as more hydrogen bonds. Therefore, our results provide invaluable insights into the mechanism of a ligand's binding inside the Mpro and shed light on future structure-based designs of high-potent inhibitors for SARS-CoV-2 Mpro.
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Affiliation(s)
- Tien Huynh
- Computational Biological Center, IBM Thomas J. Watson Research, Yorktown Heights, New York 10598, USA.
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33
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Luo H, Zhao M, Tan D, Liu C, Yang L, Qiu L, Gao Y, Yu H. Anti-COVID-19 drug screening: Frontier concepts and core technologies. Chin Med 2020; 15:115. [PMID: 33133232 PMCID: PMC7592451 DOI: 10.1186/s13020-020-00393-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 10/15/2020] [Indexed: 02/08/2023] Open
Abstract
The outbreak of COVID-19 has recently evolved into a global pandemic. Up to July 2020, almost every country has confirmed COVID-19 cases reported worldwide. Many leading experts have predicted that the epidemic will persist for relatively a long period of time. Thus far, there have been no remedies proven effective against the disease. As the nation where COVID-19 broke out first, China has adopted a combination of traditional Chinese medicine and western medicine to fight against the disease, and has achieved significant clinical result. Up to now, the COVID-19 pandemic has been effectively controlled in China. However, the rest of the world (except for a limited number of countries and regions) is still in deep water. This paper thoroughly summarizes interdisciplinary notions and techniques, including disease model, biochip, network pharmacology, and molecular docking technology, etc., providing a reference for researchers in the screening of drugs for COVID-19 prevention and treatment. These methodologies may facilitate researchers to screen out more potential drugs for treating COVID-19 pneumonia and to tackle this global crisis.
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Affiliation(s)
- Hua Luo
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Room 8008, Building N22, Avenida da Universidade, Taipa, Macao SAR China
| | - Mingming Zhao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Room 8008, Building N22, Avenida da Universidade, Taipa, Macao SAR China
| | - Dechao Tan
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Room 8008, Building N22, Avenida da Universidade, Taipa, Macao SAR China
| | - Chang Liu
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Room 8008, Building N22, Avenida da Universidade, Taipa, Macao SAR China
| | - Lin Yang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Room 8008, Building N22, Avenida da Universidade, Taipa, Macao SAR China
| | - Ling Qiu
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Room 8008, Building N22, Avenida da Universidade, Taipa, Macao SAR China
| | - Yan Gao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Room 8008, Building N22, Avenida da Universidade, Taipa, Macao SAR China
| | - Hua Yu
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Room 8008, Building N22, Avenida da Universidade, Taipa, Macao SAR China
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A Potential Chinese Medicine Granule Suppressing ARDS of COVID-19: Keguan-1. Chin J Integr Med 2020; 26:803-804. [PMID: 33017033 PMCID: PMC7533665 DOI: 10.1007/s11655-020-3437-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2020] [Indexed: 01/08/2023]
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Affiliation(s)
- Kaixian Chen
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Hongzhuan Chen
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
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36
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Li Q, Wang H, Li X, Zheng Y, Wei Y, Zhang P, Ding Q, Lin J, Tang S, Zhao Y, Zhao L, Tong X. The role played by traditional Chinese medicine in preventing and treating COVID-19 in China. Front Med 2020; 14:681-688. [PMID: 32651936 PMCID: PMC7348116 DOI: 10.1007/s11684-020-0801-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 06/04/2020] [Indexed: 01/01/2023]
Abstract
Traditional Chinese medicine (TCM), an ancient system of alternative medicine, played an active role in the prevention and control of COVID-19 in China. It improved the clinical symptoms of patients, reduced the mortality rate, improved the recovery rate, and effectively relieved the operating pressure on the national medical system during critical conditions. In light of the current global pandemic, TCM-related measures might open up a new channel in the control of COVID-19 in other countries and regions. Here, we summarize the TCM-related measures that were widely used in China, including TCM guidelines, the Wuchang pattern, mobile cabin hospitals, integrated treatment of TCM and modern medicine for critical patients, and non-medicine therapy for convalescent patients, and describe how TCM effectively treated patients afflicted with the COVID-19. Effective TCM therapies could, therefore, be recommended and practiced based on the existing medical evidence from increased scientific studies.
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Affiliation(s)
- Qingwei Li
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China
| | - Han Wang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China.,Academic Inheritance Workstation of Academician Tong Xiaolin of Shenzhen Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, 518034, China
| | - Xiuyang Li
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China
| | - Yujiao Zheng
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China.,Beijing University of Chinese Medicine, Beijing, 100019, China
| | - Yu Wei
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China.,Beijing University of Chinese Medicine, Beijing, 100019, China
| | - Pei Zhang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China
| | - Qiyou Ding
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China.,Beijing University of Chinese Medicine, Beijing, 100019, China
| | - Jiaran Lin
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China.,Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Shuang Tang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China.,Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Yikun Zhao
- Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Linhua Zhao
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China.
| | - Xiaolin Tong
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100056, China.
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