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Pan T, Wu F, Zhang J, Xiang B, Huang K, Chen Y, Jin X. The molecular structure of SHISA5 protein and its novel role in primary biliary cholangitis: From single-cell RNA sequencing to biomarkers. Int J Biol Macromol 2025; 296:139775. [PMID: 39800023 DOI: 10.1016/j.ijbiomac.2025.139775] [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: 11/20/2024] [Revised: 12/24/2024] [Accepted: 01/09/2025] [Indexed: 01/15/2025]
Abstract
The study collected liver tissue samples from PBC patients and healthy controls and performed transcriptomic analysis of the cells in the samples using single-cell RNA sequencing. The expression characteristics of SHISA5 in PBC were revealed by comparing the difference of SHISA5 protein in the two groups of samples. The structure of SHISA5 protein was predicted and its possible biological function was analysed by bioinformatics method. The results showed that the expression of SHISA5 protein in liver tissue of PBC patients was significantly higher than that of healthy controls. Single-cell RNA sequencing data showed that SHISA5 was mainly expressed in hepatocytes and bile duct cells, and its expression level was positively correlated with the disease activity of PBC. Through structural prediction, we found that the SHISA5 protein molecule has a unique transmembrane domain and may be involved in cell signaling and intercellular interactions. Further functional analysis revealed that SHISA5 may participate in the pathological process of PBC by regulating the differentiation and function of bile duct cells.
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Affiliation(s)
- Tongtong Pan
- Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Faling Wu
- Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Jiarong Zhang
- Department of Infection Control, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Bingyu Xiang
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Kate Huang
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Yongping Chen
- Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
| | - Xiaoya Jin
- Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; Department of Infection Control, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
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Zhai P, Sung EA, Shiheido-Watanabe Y, Takayama K, Tian Y, Sadoshima J. Suppression of autophagy induces senescence in the heart. J Mol Cell Cardiol 2024; 195:83-96. [PMID: 39117176 DOI: 10.1016/j.yjmcc.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 07/25/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
Aging is a critical risk factor for heart disease, including ischemic heart disease and heart failure. Cellular senescence, characterized by DNA damage, resistance to apoptosis and the senescence-associated secretory phenotype (SASP), occurs in many cell types, including cardiomyocytes. Senescence precipitates the aging process in surrounding cells and the organ through paracrine mechanisms. Generalized autophagy, which degrades cytosolic materials in a non-selective manner, is decreased during aging in the heart. This decrease causes deterioration of cellular quality control mechanisms, facilitates aging and negatively affects lifespan in animals, including mice. Although suppression of generalized autophagy could promote senescence, it remains unclear whether the suppression of autophagy directly stimulates senescence in cardiomyocytes, which, in turn, promotes myocardial dysfunction in the heart. We addressed this question using mouse models with a loss of autophagy function. Suppression of general autophagy in cardiac-specific Atg7 knockout (Atg7cKO) mice caused accumulation of senescent cardiomyocytes. Induction of senescence via downregulation of Atg7 was also observed in chimeric Atg7 cardiac-specific KO mice and cultured cardiomyocytes in vitro, suggesting that the effect of autophagy suppression upon induction of senescence is cell autonomous. ABT-263, a senolytic agent, reduced the number of senescent myocytes and improved cardiac function in Atg7cKO mice. Suppression of autophagy and induction of senescence were also observed in doxorubicin-treated hearts, where reactivation of autophagy alleviated senescence in cardiomyocytes and cardiac dysfunction. These results suggest that suppression of general autophagy directly induces senescence in cardiomyocytes, which in turn promotes cardiac dysfunction.
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Affiliation(s)
- Peiyong Zhai
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103
| | - Eun-Ah Sung
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103
| | - Yuka Shiheido-Watanabe
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103
| | - Koichiro Takayama
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103
| | - Yimin Tian
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103.
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Chatterjee N, Sharma R, Kale PR, Trehanpati N, Ramakrishna G. Is the liver resilient to the process of ageing? Ann Hepatol 2024; 30:101580. [PMID: 39276981 DOI: 10.1016/j.aohep.2024.101580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 09/17/2024]
Abstract
The liver's unique regenerative capacity, immunotolerant feature, and polyploidy status distinguish it as a metabolic organ unlike any other in the body. Despite aging, the liver generally exhibits fewer pathological abnormalities than other organs (such as the kidney), maintaining its functions near-normal balanced manner. Subtle changes in the liver, including reduced blood flow, detoxification alterations, pseudo-capillarization, and lipofuscin deposition, may occur with chronological age. Research indicates that carefully selected liver grafts from octogenarian donors can perform well post-transplant, emphasizing instances where age doesn't necessarily compromise liver function. Notably, a recent report suggests that the liver is a youthful organ, with hepatocytes averaging an age of only 3 years. Despite the liver's impressive regenerative capabilities and cellular reserve, a lingering question persists: how does the liver maintain its youthful characteristic amidst the chronological aging of the entire organism? The various adaptive mechanism possibly include:(a) cellular hypertrophy to maintain physiological capacity even before proliferation initiates, (b) the "ploidy conveyor" as a genetic adaptation to endure aging-related stress, (c) sustained telomere length indicative of youthfulness (d) active extracellular matrix remodelling for normal cellular functioning, (e) Mitochondria-Endoplasmic Reticulum based metabolic adaptation and (c) cellular plasticity as fitness mechanisms for healthy aging. However, it is crucial to note that aged livers may have compromised regenerative capacity and chronic liver disease is often associated with declining function due to premature hepatocyte senescence. This review delves into varied cellular adaptations sustaining liver homeostasis with chronological aging and briefly explores the role of accelerated hepatocyte aging as a precursor to chronic liver disease.
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Affiliation(s)
- Nirupama Chatterjee
- Artemis Education and Research Foundation, Artemis Health Institute, Sector 51 Gurugram, India
| | - Rishabh Sharma
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana Amity Education Valley, Panchgaon, Manesar Gurugram, HR 122413, India
| | - Pratibha R Kale
- Department of Clinical Microbiology, Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India.
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Zhai P, Sung EA, Shiheido-Watanabe Y, Takayama K, Tian Y, Sadoshima J. Suppression of autophagy induces senescence in the heart. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.26.595978. [PMID: 38854107 PMCID: PMC11160656 DOI: 10.1101/2024.05.26.595978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Aging is a critical risk factor for heart disease, including ischemic heart disease and heart failure. Cellular senescence, characterized by DNA damage, resistance to apoptosis and the senescence-associated secretory phenotype (SASP), occurs in many cell types, including cardiomyocytes. Senescence precipitates the aging process in surrounding cells and the organ through paracrine mechanisms. Generalized autophagy, which degrades cytosolic materials in a non-selective manner, is decreased during aging in the heart. This decrease causes deterioration of cellular quality control mechanisms, facilitates aging and negatively affects lifespan in animals, including mice. Although suppression of generalized autophagy could promote senescence, it remains unclear whether the suppression of autophagy directly stimulates senescence in cardiomyocytes, which, in turn, promotes myocardial dysfunction in the heart. We addressed this question using mouse models with a loss of autophagy function. Suppression of general autophagy in cardiac-specific Atg7 knockout ( Atg7 cKO) mice caused accumulation of senescent cardiomyocytes. Induction of senescence via downregulation of Atg7 was also observed in chimeric Atg7 cardiac-specific KO mice and cultured cardiomyocytes in vitro , suggesting that the effect of autophagy suppression upon induction of senescence is cell autonomous. ABT-263, a senolytic agent, reduced the number of senescent myocytes and improved cardiac function in Atg7 cKO mice. Suppression of autophagy and induction of senescence were also observed in doxorubicin-treated hearts, where activation of autophagy alleviated senescence in cardiomyocytes and cardiac dysfunction. These results suggest that suppression of general autophagy directly induces senescence in cardiomyocytes, which in turn promotes cardiac dysfunction.
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Hrncir HR, Hantelys F, Gracz AD. Panic at the Bile Duct: How Intrahepatic Cholangiocytes Respond to Stress and Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1440-1454. [PMID: 36870530 PMCID: PMC10548281 DOI: 10.1016/j.ajpath.2023.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 03/06/2023]
Abstract
In the liver, biliary epithelial cells (BECs) line intrahepatic bile ducts (IHBDs) and are primarily responsible for modifying and transporting hepatocyte-produced bile to the digestive tract. BECs comprise only 3% to 5% of the liver by cell number but are critical for maintaining choleresis through homeostasis and disease. To this end, BECs drive an extensive morphologic remodeling of the IHBD network termed ductular reaction (DR) in response to direct injury or injury to the hepatic parenchyma. BECs are also the target of a broad and heterogenous class of diseases termed cholangiopathies, which can present with phenotypes ranging from defective IHBD development in pediatric patients to progressive periductal fibrosis and cancer. DR is observed in many cholangiopathies, highlighting overlapping similarities between cell- and tissue-level responses by BECs across a spectrum of injury and disease. The following core set of cell biological BEC responses to stress and injury may moderate, initiate, or exacerbate liver pathophysiology in a context-dependent manner: cell death, proliferation, transdifferentiation, senescence, and acquisition of neuroendocrine phenotype. By reviewing how IHBDs respond to stress, this review seeks to highlight fundamental processes with potentially adaptive or maladaptive consequences. A deeper understanding of how these common responses contribute to DR and cholangiopathies may identify novel therapeutic targets in liver disease.
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Affiliation(s)
- Hannah R Hrncir
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia
| | - Fransky Hantelys
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia
| | - Adam D Gracz
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia.
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Shreya S, Grosset CF, Jain BP. Unfolded Protein Response Signaling in Liver Disorders: A 2023 Updated Review. Int J Mol Sci 2023; 24:14066. [PMID: 37762367 PMCID: PMC10531763 DOI: 10.3390/ijms241814066] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/04/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Endoplasmic reticulum (ER) is the site for synthesis and folding of secreted and transmembrane proteins. Disturbance in the functioning of ER leads to the accumulation of unfolded and misfolded proteins, which finally activate the unfolded protein response (UPR) signaling. The three branches of UPR-IRE1 (Inositol requiring enzyme 1), PERK (Protein kinase RNA-activated (PKR)-like ER kinase), and ATF6 (Activating transcription factor 6)-modulate the gene expression pattern through increased expression of chaperones and restore ER homeostasis by enhancing ER protein folding capacity. The liver is a central organ which performs a variety of functions which help in maintaining the overall well-being of our body. The liver plays many roles in cellular physiology, blood homeostasis, and detoxification, and is the main site at which protein synthesis occurs. Disturbance in ER homeostasis is triggered by calcium level imbalance, change in redox status, viral infection, and so on. ER dysfunction and subsequent UPR signaling participate in various hepatic disorders like metabolic (dysfunction) associated fatty liver disease, liver cancer, viral hepatitis, and cholestasis. The exact role of ER stress and UPR signaling in various liver diseases is not fully understood and needs further investigation. Targeting UPR signaling with drugs is the subject of intensive research for therapeutic use in liver diseases. The present review summarizes the role of UPR signaling in liver disorders and describes why UPR regulators are promising therapeutic targets.
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Affiliation(s)
- Smriti Shreya
- Gene Expression and Signaling Lab, Department of Zoology, Mahatma Gandhi Central University, Motihari 845401, Bihar, India;
| | - Christophe F. Grosset
- MIRCADE Team, U1312, Bordeaux Institute in Oncology, BRIC, Université de Bordeaux, 146 Rue Léo Saignat, F-33000 Bordeaux, France
| | - Buddhi Prakash Jain
- Gene Expression and Signaling Lab, Department of Zoology, Mahatma Gandhi Central University, Motihari 845401, Bihar, India;
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An involvement of Hippo-yes-associated protein pathway in biliary epithelial senescence in primary biliary cholangitis. Clin Res Hepatol Gastroenterol 2023; 47:102106. [PMID: 36849079 DOI: 10.1016/j.clinre.2023.102106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/03/2023] [Accepted: 02/24/2023] [Indexed: 03/01/2023]
Abstract
BACKGROUND & AIMS Accumulating evidence suggest that Hippo-yes-associated protein (YAP) pathway plays important roles in development and repair after injuries in biliary system. We disclosed that senescent biliary epithelial cells (BECs) participate in the pathogenesis of primary biliary cholangitis (PBC). We hypothesized that dysregulation of Hippo-YAP pathway may be associated with biliary epithelial senescence in pathogenesis of PBC. APPROACH & RESULTS Cellular senescence was induced in cultured BECs by treatment with serum depletion or glycochenodeoxycholic acid. The expression and activity of YAP1 were significantly decreased in senescent BECs (p<0.01). Cellular senescence and apoptosis were significantly increased (p<0.01) and a proliferation activity and a 3D-cyst formation activity were significantly decreased (p<0.01) by a knockdown of YAP1 in BECs. The expression of YAP1 were immunohistochemically determined in livers taken from the patients with PBC (n = 79) and 79 control diseased and normal livers and its association with senescent markers p16INK4a and p21WAF1/Cip1 was analyzed. The nuclear expression of YAP1, which indicates activation of YAP1, was significantly decreased in BECs in small bile ducts involved in cholangitis and ductular reactions in PBC, compared to control livers (p<0.01). The decreased expression of YAP1 was seen in senescent BECs showing expression of p16INK4a and p21WAF1/Cip1 in bile duct lesions. CONCLUSION Dysregulation of Hippo-YAP1 pathway may be involved in the pathogenesis of PBC in association with biliary epithelial senescence.
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Park JW, Kim JH, Kim SE, Jung JH, Jang MK, Park SH, Lee MS, Kim HS, Suk KT, Kim DJ. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics. Biomedicines 2022; 10:1288. [PMID: 35740310 PMCID: PMC9220082 DOI: 10.3390/biomedicines10061288] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.
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Affiliation(s)
- Ji-Won Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jung-Hee Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jang Han Jung
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Myoung-Kuk Jang
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sang-Hoon Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Myung-Seok Lee
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Hyoung-Su Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
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Meadows V, Baiocchi L, Kundu D, Sato K, Fuentes Y, Wu C, Chakraborty S, Glaser S, Alpini G, Kennedy L, Francis H. Biliary Epithelial Senescence in Liver Disease: There Will Be SASP. Front Mol Biosci 2021; 8:803098. [PMID: 34993234 PMCID: PMC8724525 DOI: 10.3389/fmolb.2021.803098] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis. Liver size and function change with aging, and presumably with increasing cellular senescence, so it is important to understand the mechanisms by which cellular senescence affects the functional nature of the liver in health and disease. As well, cells in a SASP state secrete a multitude of inflammatory and pro-fibrogenic factors that modulate the microenvironment. Cellular SASP and the associated, secreted factors have been implicated in the progression of liver diseases, such as cholestatic injury that target the biliary epithelial cells (i.e., cholangiocytes) lining the bile ducts. Indeed, cholangiocyte senescence/SASP is proposed to be a driver of disease phenotypes in a variety of liver injuries. Within this review, we will discuss the impact of cholangiocyte senescence and SASP in the pathogenesis of cholestatic disorders.
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Affiliation(s)
- Vik Meadows
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
| | | | - Debjyoti Kundu
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
| | - Keisaku Sato
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
| | - Yessenia Fuentes
- Clinical and Translational Sciences Institute, STEM GEHCS Program, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, TX, United States
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, United States
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, United States
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
| | - Lindsey Kennedy
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
| | - Heather Francis
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
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Tuttle CS, Luesken SW, Waaijer ME, Maier AB. Senescence in tissue samples of humans with age-related diseases: A systematic review. Ageing Res Rev 2021; 68:101334. [PMID: 33819674 DOI: 10.1016/j.arr.2021.101334] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 03/03/2021] [Accepted: 03/20/2021] [Indexed: 12/31/2022]
Abstract
BACKGROUND Higher numbers of senescent cells have been implicated in age-related disease pathologies. However, whether different diseases have different senescent phenotypes is unknown. Here we provide a systematic overview of the current available evidence of senescent cells in age-related diseases pathologies in humans and the markers currently used to detect senescence levels in humans. METHODS PubMed, Web of Science and EMBASE were systematically searched from inception to the 29th of September 2019, using keywords related to 'senescence', 'age-related diseases' and 'biopsies'. RESULTS In total 12,590 articles were retrieved of which 103 articles were included in this review. The role of senescence in age-related disease has been assessed in 9 different human organ system and 27 different age-related diseases of which heart (27/103) and the respiratory systems (18/103) are the most investigated. Overall, 27 different markers of senescence have been used to determine cellular senescence and the cell cycle regulator p16ink4a is most often used (23/27 age-related pathologies). CONCLUSION This review demonstrates that a higher expression of senescence markers are observed within disease pathologies. However, not all markers to detect senescence have been assessed in all tissue types.
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Chakrabarty A, Chakraborty S, Bhattacharya R, Chowdhury G. Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies. Front Oncol 2021; 11:674354. [PMID: 34249714 PMCID: PMC8264500 DOI: 10.3389/fonc.2021.674354] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/01/2021] [Indexed: 01/10/2023] Open
Abstract
Triple negative breast cancer (TNBC) is classically treated with combination chemotherapies. Although, initially responsive to chemotherapies, TNBC patients frequently develop drug-resistant, metastatic disease. Chemotherapy resistance can develop through many mechanisms, including induction of a transient growth-arrested state, known as the therapy-induced senescence (TIS). In this paper, we will focus on chemoresistance in TNBC due to TIS. One of the key characteristics of senescent cells is a complex secretory phenotype, known as the senescence-associated secretory proteome (SASP), which by prompting immune-mediated clearance of senescent cells maintains tissue homeostasis and suppresses tumorigenesis. However, in cancer, particularly with TIS, senescent cells themselves as well as SASP promote cellular reprograming into a stem-like state responsible for the emergence of drug-resistant, aggressive clones. In addition to chemotherapies, outcomes of recently approved immune and DNA damage-response (DDR)-directed therapies are also affected by TIS, implying that this a common strategy used by cancer cells for evading treatment. Although there has been an explosion of scientific research for manipulating TIS for prevention of drug resistance, much of it is still at the pre-clinical stage. From an evolutionary perspective, cancer is driven by natural selection, wherein the fittest tumor cells survive and proliferate while the tumor microenvironment influences tumor cell fitness. As TIS seems to be preferred for increasing the fitness of drug-challenged cancer cells, we will propose a few tactics to control it by using the principles of evolutionary biology. We hope that with appropriate therapeutic intervention, this detrimental cellular fate could be diverted in favor of TNBC patients.
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12
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Talukdar S, Das SK, Emdad L, Fisher PB. Autophagy and senescence: Insights from normal and cancer stem cells. Adv Cancer Res 2021; 150:147-208. [PMID: 33858596 DOI: 10.1016/bs.acr.2021.01.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Autophagy is a fundamental cellular process, which allows cells to adapt to metabolic stress through the degradation and recycling of intracellular components to generate macromolecular precursors and produce energy. Autophagy is also critical in maintaining cellular/tissue homeostasis, as well preserving immunity and preventing human disease. Deregulation of autophagic processes is associated with cancer, neurodegeneration, muscle and heart disease, infectious diseases and aging. Research on a variety of stem cell types establish that autophagy plays critical roles in normal and cancer stem cell quiescence, activation, differentiation, and self-renewal. Considering its critical function in regulating the metabolic state of stem cells, autophagy plays a dual role in the regulation of normal and cancer stem cell senescence, and cellular responses to various therapeutic strategies. The relationships between autophagy, senescence, dormancy and apoptosis frequently focus on responses to various forms of stress. These are interrelated processes that profoundly affect normal and abnormal human physiology that require further elucidation in cancer stem cells. This review provides a current perspective on autophagy and senescence in both normal and cancer stem cells.
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Affiliation(s)
- Sarmistha Talukdar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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13
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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14
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Ferreira-Gonzalez S, Rodrigo-Torres D, Gadd VL, Forbes SJ. Cellular Senescence in Liver Disease and Regeneration. Semin Liver Dis 2021; 41:50-66. [PMID: 33764485 DOI: 10.1055/s-0040-1722262] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Cellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.
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Affiliation(s)
| | - Daniel Rodrigo-Torres
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Victoria L Gadd
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Stuart J Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
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15
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Panzitt K, Fickert P, Wagner M. Regulation of autophagy by bile acids and in cholestasis - CholestoPHAGY or CholeSTOPagy. Biochim Biophys Acta Mol Basis Dis 2020; 1867:166017. [PMID: 33242590 DOI: 10.1016/j.bbadis.2020.166017] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/13/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022]
Abstract
Autophagy is a lysosomal degradation pathway in which the cell self-digests its own components to provide nutrients in harsh environmental conditions. It also represents an opportunity to rid the cell of superfluous and damaged organelles, misfolded proteins or invaded microorganisms. Liver autophagy contributes to basic hepatic functions such as lipid, glycogen and protein turnover. Deregulated hepatic autophagy has been linked to many liver diseases including alpha-1-antitrypsin deficiency, alcoholic and non-alcoholic fatty liver diseases, hepatitis B and C infections, liver fibrosis as well as liver cancer. Recently, bile acids and the bile acid receptor FXR have been implicated in the regulation of hepatic autophagy, which implies a role of autophagy also for cholestatic liver diseases. This review summarizes the current evidence of bile acid mediated effects on autophagy and how this affects cholestatic liver diseases. Although detailed studies are lacking, we suggest a concept that the activity of autophagy in cholestasis depends on the disease stage, where autophagy may be induced at early stages ("cholestophagy") but may be impaired in prolonged cholestatic states ("cholestopagy").
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Affiliation(s)
- Katrin Panzitt
- Research Unit for Translational Nuclear Receptor Research, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Peter Fickert
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Martin Wagner
- Research Unit for Translational Nuclear Receptor Research, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
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16
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Alamandine attenuates hepatic fibrosis by regulating autophagy induced by NOX4-dependent ROS. Clin Sci (Lond) 2020; 134:853-869. [PMID: 32227122 DOI: 10.1042/cs20191235] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/10/2020] [Accepted: 03/27/2020] [Indexed: 12/20/2022]
Abstract
Angiotensin II (Ang II) has been reported to aggravate hepatic fibrosis by inducing NADPH oxidase (NOX)-dependent oxidative stress. Alamandine (ALA) protects against fibrosis by counteracting Ang II via the MAS-related G-protein coupled (MrgD) receptor, though the effects of alamandine on hepatic fibrosis remain unknown. Autophagy activated by reactive oxygen species (ROS) is a novel mechanism of hepatic fibrosis. However, whether autophagy is involved in the regulation of Ang II-induced hepatic fibrosis still requires investigation. We explored the effect of alamandine on hepatic fibrosis via regulation of autophagy by redox balance modulation. In vivo, alamandine reduced CCl4-induced hepatic fibrosis, hydrogen peroxide (H2O2) content, protein levels of NOX4 and autophagy impairment. In vitro, Ang II treatment elevated NOX4 protein expression and ROS production along with up-regulation of the angiotensin converting enzyme (ACE)/Ang II/Ang II type 1 receptor (AT1R) axis. These changes resulted in the accumulation of impaired autophagosomes in hepatic stellate cells (HSCs). Treatment with NOX4 inhibitor VAS2870, ROS scavenger N-acetylcysteine (NAC), and NOX4 small interfering RNA (siRNA) inhibited Ang II-induced autophagy and collagen synthesis. Alamandine shifted the balance of renin-angiotensin system (RAS) toward the angiotensin converting enzyme 2 (ACE2)/alamandine/MrgD axis, and inhibited both Ang II-induced ROS and autophagy activation, leading to attenuation of HSCs migration or collagen synthesis. In summary, alamandine attenuated liver fibrosis by regulating autophagy induced by NOX4-dependent ROS.
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17
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Complex Cell Type-Specific Roles of Autophagy in Liver Fibrosis and Cirrhosis. Pathogens 2020; 9:pathogens9030225. [PMID: 32197543 PMCID: PMC7157207 DOI: 10.3390/pathogens9030225] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/14/2020] [Accepted: 03/17/2020] [Indexed: 02/06/2023] Open
Abstract
The lysosomal degradation pathway, or autophagy, plays a fundamental role in cellular, tissue, and organismal homeostasis. A correlation between dysregulated autophagy and liver fibrosis (including end-stage disease, cirrhosis) is well-established. However, both the up and downregulation of autophagy have been implicated in fibrogenesis. For example, the inhibition of autophagy in hepatocytes and macrophages can enhance liver fibrosis, whereas autophagic activity in hepatic stellate cells and reactive ductular cells is permissive towards fibrogenesis. In this review, the contributions of specific cell types to liver fibrosis as well as the mechanisms underlying the effects of autophagy are summarized. In view of the functional effects of multiple cell types on the complex process of hepatic fibrogenesis, integrated approaches that consider the role of autophagy in each liver cell type should be a focus of future research.
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18
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Greenberg SA. Inclusion body myositis: clinical features and pathogenesis. Nat Rev Rheumatol 2020; 15:257-272. [PMID: 30837708 DOI: 10.1038/s41584-019-0186-x] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Inclusion body myositis (IBM) is often viewed as an enigmatic disease with uncertain pathogenic mechanisms and confusion around diagnosis, classification and prospects for treatment. Its clinical features (finger flexor and quadriceps weakness) and pathological features (invasion of myofibres by cytotoxic T cells) are unique among muscle diseases. Although IBM T cell autoimmunity has long been recognized, enormous attention has been focused for decades on several biomarkers of myofibre protein aggregates, which are present in <1% of myofibres in patients with IBM. This focus has given rise, together with the relative treatment refractoriness of IBM, to a competing view that IBM is not an autoimmune disease. Findings from the past decade that implicate autoimmunity in IBM include the identification of a circulating autoantibody (anti-cN1A); the absence of any statistically significant genetic risk factor other than the common autoimmune disease 8.1 MHC haplotype in whole-genome sequencing studies; the presence of a marked cytotoxic T cell signature in gene expression studies; and the identification in muscle and blood of large populations of clonal highly differentiated cytotoxic CD8+ T cells that are resistant to many immunotherapies. Mounting evidence that IBM is an autoimmune T cell-mediated disease provides hope that future therapies directed towards depleting these cells could be effective.
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Affiliation(s)
- Steven A Greenberg
- Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. .,Children's Hospital Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA. .,Harvard Medical School, Boston, MA, USA.
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19
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Ye HL, Zhang JW, Chen XZ, Wu PB, Chen L, Zhang G. Ursodeoxycholic acid alleviates experimental liver fibrosis involving inhibition of autophagy. Life Sci 2019; 242:117175. [PMID: 31843528 DOI: 10.1016/j.lfs.2019.117175] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/04/2019] [Accepted: 12/12/2019] [Indexed: 12/12/2022]
Abstract
AIMS Ursodeoxycholic acid (UDCA) has been widely used in the treatment of primary biliary cholangitis (PBC) with chronic liver fibrosis, but its detailed mechanism remains unclear. This study was aimed to determine whether autophagic signaling is involved in the therapeutic effect of UDCA on liver fibrosis. METHODS By using hepatic stellate cell (HSC) line LX2 and CCl4-induced fibrotic rat model, autophagy signaling was investigated by western blotting and mRFP-EGFP-LC3 tandem fluorescent tagged plasmid (ptfLC3) transfection technique. Anti-fibrotic profile was determined by western blotting, qRT-PCR, MTT assay, trypan blue, hydroxyproline assay and Masson staining. KEY FINDINGS TGFβ1 treatment decreased P62 accumulation and increased both autophagosomes and autolysosomes in LX2 cells, thereby elevated autophagic flux. Hydroxychloroquine (HCQ), antagonist of autophagy, was found to dramatically inhibit COL1A2 mRNA expression and cell proliferation in a dose-dependent manner. This coincides with the effect of UDCA intervention on collagen aggradation and cell viability. Meanwhile, UDCA inhibited TGFβ1-induced autophagy flux. And rapamycin, agonist of autophagy, was found to impair the anti-fibrotic effect of UDCA. Moreover, study in vivo showed that UDCA alone or in combination with HCQ restored the CCl4-induced liver fibrosis in rodent models with autophagy inhibited profile. SIGNIFICANCE Taken together, our study revealed that UDCA displays anti-fibrotic role by protecting HSC against production of collagen and inhibiting cellular viability involving autophagy inhibition and provide a new insight into the pharmacological basis of UDCA treatment for hepatic fibrosis.
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Affiliation(s)
- Hui-Lan Ye
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, PR China; Department of Internal Medicine, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, Guangxi, PR China
| | - Ji-Wang Zhang
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, PR China
| | - Xing-Zhou Chen
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, PR China
| | - Peng-Bo Wu
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, PR China; Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China
| | - Li Chen
- New Drug Research & Development Center, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, PR China
| | - Guo Zhang
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, PR China.
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20
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Rajendran P, Alzahrani AM, Hanieh HN, Kumar SA, Ben Ammar R, Rengarajan T, Alhoot MA. Autophagy and senescence: A new insight in selected human diseases. J Cell Physiol 2019; 234:21485-21492. [PMID: 31144309 DOI: 10.1002/jcp.28895] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/14/2019] [Accepted: 05/14/2019] [Indexed: 12/28/2022]
Abstract
Senescence and autophagy play important roles in homeostasis. Cellular senescence and autophagy commonly cause several degenerative processes, including oxidative stress, DNA damage, telomere shortening, and oncogenic stress; hence, both events are known to be interrelated. Autophagy is well known for its disruptive effect on human diseases, and it is currently proposed to have a direct effect on triggering senescence and quiescence. However, it is yet to be proven whether autophagy has a positive or negative impact on senescence. It is known that elevated levels of autophagy induce cell death, whereas inadequate autophagy can trigger cellular senescence. Both have important roles in human diseases such as aging, renal degeneration, neurodegenerative disorders, and cancer. Therefore, this review aims to highlight the relevance of senescence and autophagy in selected human ailments through a summary of recent findings on the connection and effects of autophagy and senescence in these diseases.
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Affiliation(s)
- Peramaiyan Rajendran
- Department of Biological Sciences, College of Science, King Faisal University, Hofouf, Saudi Arabia
| | - Abdullah M Alzahrani
- Department of Biological Sciences, College of Science, King Faisal University, Hofouf, Saudi Arabia
| | - Hamza N Hanieh
- Department of Biological Sciences, College of Science, Al-Hussein Bin Talal University, Ma'an, Jordan.,Department of Medical Analysis, Aisha Bint Al Hussein College for Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma'an, Jordan
| | - Sekar Ashok Kumar
- Faculty of Technology, Center of Biotechnology, Anna University, Chennai, India
| | - Rebai Ben Ammar
- Department of Biological Sciences, College of Science, King Faisal University, Hofouf, Saudi Arabia.,Laboratory of Aromatic and Medicinal Plants, Center of Biotechnology, Hammam-Lif, Tunisia
| | | | - Mohammed A Alhoot
- Department of Medical Microbiology Unit, International Medical School (IMS), Management & Science University (MSU), Shah Alam, Malaysia
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21
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Tang YM, Yu HY. Progress in research of mechanism of biliary epithelial cell injury in primary biliary cholangitis. Shijie Huaren Xiaohua Zazhi 2019; 27:36-42. [DOI: 10.11569/wcjd.v27.i1.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by chronic biliary cholestasis and progressive intrahepatic and small bile duct non- suppurative inflammation with early infiltration of inflammatory cells around biliary epithelial cells (BECs). BECs lining the bile duct express multiple receptors for pathogen-associated molecular patterns and can activate intracellular signaling pathways and participate in immune regulation. The etiology and pathogenesis of PBC are not fully understood yet, but the key step found in its pathogenesis is the targeted destruction of biliary cells. Since bile duct epithelial cells participate in a series of intrahepatic immune regulation processes, bile duct epithelial cell injury is an important mechanism involved in the development of intrahepatic inflammation in PBC. Therefore, understanding the mechanism of BEC injury can help us find some new targets for the treatment of PBC. This article briefly reviews the progress in the research of mechanism of biliary epithelial cell injury in PBC.
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Affiliation(s)
- Ying-Mei Tang
- Department of Gastroenterology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Hai-Yan Yu
- Department of Gastroenterology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
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22
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Wang J, Qi Q, Zhou W, Feng Z, Huang B, Chen A, Zhang D, Li W, Zhang Q, Jiang Z, Bjerkvig R, Prestegarden L, Thorsen F, Wang X, Li X, Wang J. Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy. Autophagy 2018; 14:2007-2022. [PMID: 30025493 PMCID: PMC6152528 DOI: 10.1080/15548627.2018.1501133] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 06/18/2018] [Accepted: 07/10/2018] [Indexed: 12/12/2022] Open
Abstract
Flavokawain B (FKB), a natural kava chalcone, displays potent antitumor activity in various types of cancer. The mechanism of action, however, remains unclear. Here, we evaluated the efficacy of FKB in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its inhibitory effects in cancer. Approximately 60% of GBM cells became senescent after treatment with FKB as assessed in the senescence-associated (SA)-GLB1/SA-β-galactosidase assay. The cellular process of autophagy potentially contributed to the establishment of senescence. Transmission electron microscopy revealed the formation of autophagic vesicles under FKB treatment, and MAP1LC3B (microtubule associated protein 1 light chain 3 beta)-II was increased. Transfection of ATG5 or ATG7 small interfering RNAs (siRNAs) inhibited FKB-induced autophagy in U251 cells. Western blot revealed that molecular components of the endoplasmic reticulum stress pathway were activated, including ATF4 (activating transcription factor 4) and DDIT3 (DNA damage inducible transcript 3), while levels of TRIB3 (tribbles pseudokinase 3) increased. In addition, based on the phosphorylation status, the AKT-MTOR-RPS6KB1 pathway was inhibited, which induced autophagy in GBM cells. Inhibition of autophagy by autophagy inhibitors 3-methyladenine and chloroquine or knockdown of ATG5 or ATG7 caused FKB-treated U251 cells to switch from senescence to apoptosis. Finally, knockdown of ATG5 or treatment with chloroquine in combination with FKB, significantly inhibited tumor growth in vivo. Our results demonstrated that FKB induced protective autophagy through the ATF4-DDIT3-TRIB3-AKT-MTOR-RPS6KB1 signaling pathway in GBM cells, indicating that the combination treatment of FKB with autophagy inhibitors may potentially be an effective therapeutic strategy for GBM. ABBREVIATIONS 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; AKT: AKT serine/threonine kinase; ATF4: activating transcription factor 4; ATG: autophagy related; CASP3: caspase 3; CCK-8: cell counting kit-8; CDKN1A: cyclin-dependent kinase inhibitor 1A; CQ: chloroquine; DDIT3: DNA damage inducible transcript 3; DMEM: Dulbecco's modified Eagle's medium; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; FKB: flavokawain B; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBM: glioblastoma multiforme; GFP: green fluorescent protein; HSPA5: heat shock protein family A (Hsp70) member 5; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PARP1: poly(ADP-ribose) polymerase; 1RPS6KB1: ribosomal protein S6 kinase B1; SA-GLB1: senescence-associated galactosidase beta 1; siRNA: short interfering RNA; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TRIB3: tribbles pseudokinase 3; TUNEL: deoxynucleotidyl transferase-mediated dUTP nick-end labeling.
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Affiliation(s)
- Jiwei Wang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Qichao Qi
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Wenjing Zhou
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Zichao Feng
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Bin Huang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Anjing Chen
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Di Zhang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Wenjie Li
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Qing Zhang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Zheng Jiang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Rolf Bjerkvig
- Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Lars Prestegarden
- Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Frits Thorsen
- Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway
- The Molecular Imaging Center, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Xinyu Wang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Xingang Li
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
| | - Jian Wang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Jinan, Shandong, P.R. China
- Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway
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23
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Sun Y, Zheng Y, Wang C, Liu Y. Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells. Cell Death Dis 2018; 9:753. [PMID: 29988039 PMCID: PMC6037763 DOI: 10.1038/s41419-018-0794-4] [Citation(s) in RCA: 398] [Impact Index Per Article: 56.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 06/09/2018] [Accepted: 06/14/2018] [Indexed: 12/28/2022]
Abstract
Glutathione (GSH) protects against oxidative damage in many tissues, including retinal pigment epithelium (RPE). Oxidative stress-mediated senescence and death of RPE and subsequent death of photoreceptors have been observed in age-related macular degeneration (AMD). Although the consequences of GSH depletion have been described previously, questions remain regarding the molecular mechanisms. We herein examined the downstream effects of GSH depletion on stress-induced premature senescence (SIPS) and cell death in human RPE cells. Briefly, cultured ARPE-19 cells were depleted of GSH using: (1) incubation in cystine (Cys2)-free culture medium; (2) treatment with buthionine sulphoximine (BSO, 1000 µM) to block de novo GSH synthesis for 24-48 h; or (3) treatment with erastin (10 µM for 12-24 h) to inhibit Cys2/glutamate antiporter (system xc-). These treatments decreased cell viability and increased both soluble and lipid reactive oxygen species (ROS) generation but did not affect mitochondrial ROS or mitochondrial mass. Western blot analysis revealed decreased expression of ferroptotic modulator glutathione peroxidase 4 (GPX4). Increased autophagy was apparent, as reflected by increased LC3 expression, autophagic vacuoles, and autophagic flux. In addition, GSH depletion induced SIPS, as evidenced by increased percentage of the senescence-associated β-galactosidase-positive cells, increased senescence-associated heterochromatin foci (SAHF), as well as cell cycle arrest at the G1 phase. GSH depletion-dependent cell death was prevented by selective ferroptosis inhibitors (8 μM Fer-1 and 600 nM Lip-1), iron chelator DFO (80 μM), as well as autophagic inhibitors Baf-A1 (75 nM) and 3-MA (10 mM). Inhibiting autophagy with Baf-A1 (75 nM) or 3-MA (10 mM) promoted SIPS. In contrast, inducing autophagy with rapamycin (100 nM) attenuated SIPS. Our findings suggest that GSH depletion induces ferroptosis, autophagy, and SIPS. In addition, we found that autophagy is activated in the process of ferroptosis and reduces SIPS, suggesting an essential role of autophagy in ferroptosis and SIPS.
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Affiliation(s)
- Yun Sun
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yingfeng Zheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chunxiao Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yizhi Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
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24
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Zhu Y, Wang Q, Tang X, Yao G, Sun L. Mesenchymal stem cells enhance autophagy of human intrahepatic biliary epithelial cells in vitro. Cell Biochem Funct 2018; 36:280-287. [PMID: 29974509 DOI: 10.1002/cbf.3340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 03/28/2018] [Accepted: 05/29/2018] [Indexed: 12/15/2022]
Abstract
Dysfunctional autophagy in intrahepatic biliary epithelial cells (IBECs) is the main mechanism underlying the pathogenesis of bile duct lesions in primary biliary cholangitis. Autophagy may be a key pathogenesis for aetiology of primary biliary cholangitis. Immunoblotting and immunofluorescence analyses were used for the evaluation of autophagy in human intrahepatic biliary epithelial cells (HiBECs) at various time points. Glycochenodeoxycholate (GCDC) induced autophagy in HiBECs; the ratio of microtubule-associated protein light chain 3-II/microtubule-associated protein light chain 3-I (LC3-II/LC3-I) expression markedly increased at 48 hours, and then declined. However, compared with cells treated with GCDC alone, the expression of LC3-II increased and the clearance of autophagosome enhanced in GCDC-treated cells cocultured with mesenchymal stem cells (MSCs). Furthermore, the level of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) decreased in HiBECs cocultured with MSCs relative to those cultured without MSCs. Following STAT3 silencing, decreased expression of phosphorylated eukaryotic initiation factor 2α was consistently observed. The present data suggest that mesenchymal stem cells may enhance autophagic flux of HiBECs through the inhibition of STAT3 activity. SIGNIFICANCE PARAGRAPH The present findings constitute the first report that human umbilical cord-derived MSCs enhance autophagic flux in HiBECs through a STAT3-dependent way: MSCs enhance the autophagic flux by increasing the formation of autophagosome and autolysosome in GCDC-treated HiBECs. MSCs decrease the STAT3 activity and the expression of eIF2α in GCDC-treated HiBECs; in addition, MSCs increase the expression of PKR. With STAT3 silencing, MSCs enhance neither the levels of LC3II nor the expression of PKR in GCDC-treated HiBECs.
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Affiliation(s)
- Yun Zhu
- Department of Rheumatology and Immunology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, China.,Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Qian Wang
- Department of Rheumatology and Immunology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaojun Tang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Genhong Yao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Lingyun Sun
- Department of Rheumatology and Immunology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, China.,Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
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25
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An impaired biliary bicarbonate umbrella may be involved in dysregulated autophagy in primary biliary cholangitis. J Transl Med 2018; 98:745-754. [PMID: 29540861 DOI: 10.1038/s41374-018-0045-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 01/06/2018] [Accepted: 01/19/2018] [Indexed: 12/12/2022] Open
Abstract
Dysregulated autophagy may be a central player in trehe pathogenesis of primary biliary cholangitis (PBC) by inducing autoimmune processes via abnormal expression of mitochondrial antigens such as pyruvate dehydrogenase complex, E2 component (PDC-E2) and also by inducing cellular senescence in biliary epithelial cells (BECs) in bile duct lesions in PBC. We examined the association of an impaired "biliary bicarbonate umbrella" due to dysfunction of anion exchanger 2 (AE2) with dysregulated autophagy and cellular senescence in PBC. The expression of AE2 was examined in cultured BECs treated with bile acids such as glycochenodeoxycholic acid (GCDC) and tauro-ursodeoxycholic acid (TUDCA), various cytokines (IL-4, IL-13, IFNγ, TNFα, TGFβ), and serum deprivation. The effect of AE2 knockdown using siRNA on autophagy, cell surface expression of PDC-E2, and cellular senescence was also examined. The expression of AE2 and its association with autophagy-related markers and senescent markers p16INK4a and p21WAF1/Cip1 were immunohistochemically determined in livers taken from the patients with PBC (n = 50) and 69 control diseased and normal livers. The expression of AE2 was significantly induced in the cultured BECs shortly treated with GCDC and other stresses, whereas it was significantly decreased in senescent BECs induced by GCDC and other stresses (p < 0.05). Dysregulated autophagy, cell surface expression of PDC-E2, and cellular senescence were significantly increased by knockdown of AE2 (p < 0.05). The expression of AE2 was significantly decreased in cholangitis in PBC, compared to control livers (p < 0.05). The decreased expression of AE2 was correlated with dysregulated autophagy, abnormal expression of PDC-E2, and cellular senescence in bile duct lesions in PBC. In conclusion, an impaired biliary bicarbonate umbrella may be involved in the pathogenesis of PBC by inducing dysregulated autophagy.
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Luo X, Wang D, Zhu X, Wang G, You Y, Ning Z, Li Y, Jin S, Huang Y, Hu Y, Chen T, Meng Y, Li X. Autophagic degradation of caveolin-1 promotes liver sinusoidal endothelial cells defenestration. Cell Death Dis 2018; 9:576. [PMID: 29760379 PMCID: PMC5951836 DOI: 10.1038/s41419-018-0567-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 03/25/2018] [Accepted: 04/04/2018] [Indexed: 02/07/2023]
Abstract
Autophagy, interacting with actin cytoskeleton and the NO-dependent pathway, may affect the phenotype and function of endothelial cells. Moreover, caveolin-1 (Cav-1), as a structure protein in liver sinusoidal endothelial cells (LSECs), is closely related to autophagy. Hence, we aim to explore the role of autophagic degradation of Cav-1 in LSECs defenestration. In vivo, we found the increase of autophagy in liver sinusoidal endothelium in human fibrotic liver. Furthermore, autophagy, degradation of Cav-1, and actin filament (F-actin) remodeling were triggered during the process of CCl4-induced LSECs defenestration; in contrast, autophagy inhibitor 3MA diminished the degradation of Cav-1 to maintain fenestrae and relieve CCl4-induced fibrosis. In vitro, during LSECs defenestration, the NO-dependent pathway was down-regulated through the reduction of the PI3K–AKT–MTOR pathway and initiation of autophagic degradation of Cav-1; while, these effects were aggravated by starvation. However, VEGF inhibited autophagic degradation of Cav-1 and F-actin remodeling to maintain LSECs fenestrae via activating the PI3K–AKT–MTOR pathway. Additionally, inhibiting autophagy, such as 3MA, bafilomycin, or ATG5-siRNA, could attenuate the depletion of Cav-1 and F-actin remodeling to maintain LSECs fenestrae and improve the NO-dependent pathway; in turn, eNOS-siRNA and L-NAME, for blocking the NO-dependent pathway, could elevate autophagic degradation of Cav-1 to aggravate defenestration. Finally, overexpressed Cav-1 rescued rapamycin-induced autophagic degradation of Cav-1 to maintain LSECs fenestrae; whereas knockdown of Cav-1 facilitated defenestration due to the activation of the AMPK-dependent autophagy. Consequently, autophagic degradation of Cav-1 promotes LSECs defenestration via inhibiting the NO-dependent pathway and F-actin remodeling.
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Affiliation(s)
- Xiaoying Luo
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dan Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xintao Zhu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guozhen Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuehua You
- Department of Stomatology, People's hospital of Longhua, Shenzhen, Guangdong, China
| | - Zuowei Ning
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Siyi Jin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yun Huang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ye Hu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tingting Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ying Meng
- Department of Respiratory Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Xu Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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27
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Seno K, Tanikawa N, Takahashi H, Ohkuchi A, Suzuki H, Matsubara S, Iwata H, Kuwayama T, Shirasuna K. Oxygen concentration modulates cellular senescence and autophagy in human trophoblast cells. Am J Reprod Immunol 2018; 79:e12826. [PMID: 29446169 DOI: 10.1111/aji.12826] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Accepted: 01/23/2018] [Indexed: 12/28/2022] Open
Abstract
PROBLEM We investigated the effect of oxygen concentrations on cellular senescence and autophagy and examined the role of autophagy in human trophoblast cells. METHOD OF STUDY Human first-trimester trophoblast cells (Sw.71) were incubated under 21%, 5%, or 1% O2 concentrations for 24 hours. We examined the extent of senescence caused using senescence-associated β-galactosidase (SA-β-Gal) and senescence-associated secretory phenotype (SASP) as markers. Moreover, we examined the role of autophagy in causing cellular senescence using an autophagy inhibitor (3-methyladenine, 3MA). RESULTS Physiological normoxia (5% O2 ) decreased SA-β-Gal-positive cells and SASP including interleukin-6 (IL-6) and IL-8 compared with cultured cells in 21% O2 . Pathophysiological hypoxia (1% O2 ) caused cytotoxicity, including extracellular release of ATP and lactate dehydrogenase, and decreased senescence phenotypes. 3MA-treated trophoblast cells significantly suppressed senescence markers (SA-β-Gal-positive cells and SASP secretion) in O2 -independent manner. CONCLUSION We conclude that O2 concentration modulates cellular senescence phenotypes regulating autophagy in the human trophoblast cells. Moreover, inhibiting autophagy suppresses cellular senescence, suggesting that autophagy contributes to oxygen stress-induced cellular senescence.
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Affiliation(s)
- Kotomi Seno
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, Kanagawa, Japan
| | - Nao Tanikawa
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, Kanagawa, Japan
| | - Hironori Takahashi
- Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Akihide Ohkuchi
- Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Hirotada Suzuki
- Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Shigeki Matsubara
- Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Hisataka Iwata
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, Kanagawa, Japan
| | - Takehito Kuwayama
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, Kanagawa, Japan
| | - Koumei Shirasuna
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, Kanagawa, Japan
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28
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Moreno-Blas D, Gorostieta-Salas E, Castro-Obregón S. Connecting chaperone-mediated autophagy dysfunction to cellular senescence. Ageing Res Rev 2018; 41:34-41. [PMID: 29113832 DOI: 10.1016/j.arr.2017.11.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 10/26/2017] [Accepted: 11/03/2017] [Indexed: 12/20/2022]
Abstract
Chaperone-mediated autophagy (CMA) is one of the main pathways of the lysosome-autophagy proteolytic system. It regulates different cellular process through the selective degradation of cytosolic proteins. In ageing, the function of CMA is impaired causing an inefficient stress response and the accumulation of damaged, oxidized or misfolded proteins, which is associated with numerous age-related diseases. Deficient protein degradation alters cellular proteostasis and activates signaling pathways that culminate in the induction of cellular senescence, whose accumulation is a typical feature of ageing. However, the relationship between CMA activity and cellular senescence has been poorly studied. Here, we review and integrate evidence showing that CMA dysfunction correlates with the acquisition of many hallmarks of cellular senescence and propose that loss of CMA function during aging promotes cellular senescence.
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Affiliation(s)
- Daniel Moreno-Blas
- Department of Neurodevelopment and Physiology, Institute of Cellular Physiology, National Autonomous University of México (UNAM), Mexico City, Mexico.
| | - Elisa Gorostieta-Salas
- Department of Neurodevelopment and Physiology, Institute of Cellular Physiology, National Autonomous University of México (UNAM), Mexico City, Mexico.
| | - Susana Castro-Obregón
- Department of Neurodevelopment and Physiology, Institute of Cellular Physiology, National Autonomous University of México (UNAM), Mexico City, Mexico.
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29
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Abbadie C, Pluquet O, Pourtier A. Epithelial cell senescence: an adaptive response to pre-carcinogenic stresses? Cell Mol Life Sci 2017; 74:4471-4509. [PMID: 28707011 PMCID: PMC11107641 DOI: 10.1007/s00018-017-2587-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 06/27/2017] [Accepted: 07/06/2017] [Indexed: 01/01/2023]
Abstract
Senescence is a cell state occurring in vitro and in vivo after successive replication cycles and/or upon exposition to various stressors. It is characterized by a strong cell cycle arrest associated with several molecular, metabolic and morphologic changes. The accumulation of senescent cells in tissues and organs with time plays a role in organismal aging and in several age-associated disorders and pathologies. Moreover, several therapeutic interventions are able to prematurely induce senescence. It is, therefore, tremendously important to characterize in-depth, the mechanisms by which senescence is induced, as well as the precise properties of senescent cells. For historical reasons, senescence is often studied with fibroblast models. Other cell types, however, much more relevant regarding the structure and function of vital organs and/or regarding pathologies, are regrettably often neglected. In this article, we will clarify what is known on senescence of epithelial cells and highlight what distinguishes it from, and what makes it like, replicative senescence of fibroblasts taken as a standard.
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Affiliation(s)
- Corinne Abbadie
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161-M3T-Mechanisms of Tumorigenesis and Targeted Therapies, 59000, Lille, France.
| | - Olivier Pluquet
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161-M3T-Mechanisms of Tumorigenesis and Targeted Therapies, 59000, Lille, France
| | - Albin Pourtier
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161-M3T-Mechanisms of Tumorigenesis and Targeted Therapies, 59000, Lille, France
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30
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Ronca V, Carbone M, Bernuzzi F, Malinverno F, Mousa HS, Gershwin ME, Invernizzi P. From pathogenesis to novel therapies in the treatment of primary biliary cholangitis. Expert Rev Clin Immunol 2017; 13:1121-1131. [DOI: 10.1080/1744666x.2017.1391093] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Vincenzo Ronca
- Department of Medicine, S. Paolo Hospital, University of Milan, Milan, Italy
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Marco Carbone
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Francesca Bernuzzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Federica Malinverno
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Hani S. Mousa
- School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, CB2 0AH, United Kingdom
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Pietro Invernizzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
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31
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Fickert P, Wagner M. Biliary bile acids in hepatobiliary injury - What is the link? J Hepatol 2017; 67:619-631. [PMID: 28712691 DOI: 10.1016/j.jhep.2017.04.026] [Citation(s) in RCA: 142] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Revised: 04/14/2017] [Accepted: 04/28/2017] [Indexed: 02/08/2023]
Abstract
The main trigger for liver injury in acquired cholestatic liver disease remains unclear. However, the accumulation of bile acids (BAs) undoubtedly plays a role. Recent progress in deciphering the pathomechanisms of inborn cholestatic liver diseases, decoding mechanisms of BA-induced cell death, and generating modern BA-derived drugs has improved the understanding of the regulation of BA synthesis and transport. Now is the appropriate time to reassess current knowledge about the specific role of BAs in hepatobiliary injury.
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Affiliation(s)
- Peter Fickert
- Department of Gastroenterology and Hepatology, Medical University Graz, Austria.
| | - Martin Wagner
- Department of Gastroenterology and Hepatology, Medical University Graz, Austria
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32
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Li JJ, Ma FX, Wang YW, Chen F, Lu SH, Chi Y, Du WJ, Song BQ, Hu LD, Chen H, Han ZC. Knockdown of IL-8 Provoked Premature Senescence of Placenta-Derived Mesenchymal Stem Cells. Stem Cells Dev 2017; 26:912-931. [PMID: 28418782 DOI: 10.1089/scd.2016.0324] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have shown promise for use in cell therapy, and due to their tumor tropism can serve as vehicles for delivering therapeutic agents to tumor sites. Because interleukin-8 (IL-8) is known to mediate the protumor effect of MSCs, elimination of IL-8 secretion by MSCs may enhance their safety for use in cancer gene therapy. However, little is known concerning the effect of endogenously secreted IL-8 on MSCs. We performed studies using placenta-derived MSCs (PMSCs) to determine whether knockdown of IL-8 would influence their biological activity. We first verified that IL-8 and its membrane receptor CXCR2, but not CXCR1, were highly expressed in PMSCs. We then employed lentivirus-mediated small hairpin RNA interference to generate stable IL-8-silenced PMSCs, which displayed a variety of characteristic senescent phenotypes. We observed that at day 9 post-transfection, IL-8-silenced PMSCs had become larger and displayed a more flattened appearance when compared with their controls. Moreover, their proliferation, colony forming unit-fibroblast formation, adipogenic and osteogenic differentiation, and immunosuppressive potentials were significantly impaired. Enhanced senescence-associated β-galactosidase (SA-β-gal) activity and specific global gene expression profiles confirmed that IL-8 silencing evoked the senescence process in PMSCs. Increased levels of p-Akt and decreased levels of FOXO3a protein expression suggested that reactive oxygen species played a role in the initiation and maintenance of senescence in IL-8-silenced PMSCs. Notably, the majority of CXCR2 ligands were downregulated in presenescent IL-8-silenced PMSCs but upregulated in senescent cells, indicating an antagonistic pleiotropy of the IL-8/CXCR2 signaling pathway in PMSCs. This effect may promote the proliferation of young cells and accelerate senescence of old cells.
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Affiliation(s)
- Juan-Juan Li
- 1 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases , Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China .,2 Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Science , Beijing, China
| | - Feng-Xia Ma
- 1 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases , Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - You-Wei Wang
- 1 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases , Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Fang Chen
- 1 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases , Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Shi-Hong Lu
- 1 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases , Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Ying Chi
- 1 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases , Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Wen-Jing Du
- 1 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases , Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Bao-Quan Song
- 1 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases , Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Liang-Ding Hu
- 2 Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Science , Beijing, China
| | - Hu Chen
- 2 Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Science , Beijing, China
| | - Zhong-Chao Han
- 1 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases , Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China .,3 H&B Group, Beijing Institute of Stem Cells , Beijing, China
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Protection against oxidative stress mediated by the Nrf2/Keap1 axis is impaired in Primary Biliary Cholangitis. Sci Rep 2017; 7:44769. [PMID: 28333129 PMCID: PMC5363061 DOI: 10.1038/srep44769] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 02/14/2017] [Indexed: 12/29/2022] Open
Abstract
In response to oxidative stress, nuclear factor (erythroid-derived 2)-like2 (Nrf2) induces expression of cytoprotective genes. The Nrf2 pathway is controlled by microRNAs and Kelch-like ECH-associated protein1 (Keap1). Nrf2 is stabilized when Keap1 is degraded through the autophagy pathway in a p62-dependent manner. The inhibition of autophagy causes protein accumulation, and Keap1 is inactivated by binding to p62. We investigated the role of the Nrf2/Keap1 axis in the amelioration of oxidative stress in primary biliary cholangitis (PBC). Liver specimens from patients with PBC, with (n = 24) or without cirrhosis (n = 14), and from controls (n = 16) were used for molecular analyses. We found that Nrf2 protein levels were elevated in PBC compared to controls, but Nrf2 gene expression was significantly reduced in cirrhotic PBC. Nrf2 target gene products, HO-1 and GCLC proteins, were reduced compared to controls and reduction of Nrf2 gene expression was associated with elevated levels of microRNA-132 and microRNA-34a. Both Keap1 and p62 protein levels were substantially increased in PBC compared to controls. PBC was associated with reduced Nrf2 expression and autophagy deterioration and these impairments were more advanced in patients with cirrhosis. Aberrant Nrf2/Keap1 system integrity may affect self-defence mechanisms against oxidative stress in PBC.
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Sasaki M, Nakanuma Y. Stress-induced cellular responses and cell death mechanisms during inflammatory cholangiopathies. Clin Res Hepatol Gastroenterol 2017; 41:129-138. [PMID: 27618480 DOI: 10.1016/j.clinre.2016.08.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 07/24/2016] [Accepted: 08/01/2016] [Indexed: 02/04/2023]
Abstract
Various cellular responses including apoptosis, necrosis, autophagy and cellular senescence are involved in the pathogenesis of inflammatory cholangiopathies, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and biliary atresia (BA). For example, dysregulated autophagy may play a role in abnormal expression of mitochondrial antigens and following autoimmune pathogenesis in bile duct lesions in PBC. Recently, new types of regulated cell death including necroptosis, parthanatos, pyroptosis, immunogenic cell death are the subject of numerous reports and they may play roles in pathogenesis of liver diseases, such as nonalcoholic steatohepatitis. Although there have been few studies on these new types of regulated cell death in inflammatory cholangiopathies, so far, they may play important roles in the pathophysiology of inflammatory cholangiopathies. Further studies on new types of regulated cell death are mandatory, since they could be targets of new therapeutic approaches for these diseases.
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Affiliation(s)
- Motoko Sasaki
- Department of human pathology, Kanazawa university graduate school of medicine, Kanazawa 920-8640, Japan.
| | - Yasuni Nakanuma
- Department of human pathology, Kanazawa university graduate school of medicine, Kanazawa 920-8640, Japan; Division of pathology, Shizuoka cancer center, Shizuoka, Japan
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Raghu KS, Shamprasad BR, Kabekkodu SP, Paladhi P, Joshi MB, Valiathan MS, Guruprasad KP, Satyamoorthy K. Age dependent neuroprotective effects of medhya rasayana prepared from Clitoria ternatea Linn. in stress induced rat brain. JOURNAL OF ETHNOPHARMACOLOGY 2017; 197:173-183. [PMID: 27469198 DOI: 10.1016/j.jep.2016.07.068] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 07/16/2016] [Accepted: 07/25/2016] [Indexed: 05/28/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Indian traditional medicinal system in Ayurveda suggests several preparations, known as medhya rasayanas, of diverse plant origin to enhance the health in general, reduce stress and improve brain function in particular during ageing. These effects in the context of contemporary knowledge and the underlying mechanisms are not clearly understood. Autophagy and DNA damage induced repair are inter-related quintessential pathways and are significantly altered during stress and ageing. Hence, medhya rasayana prepared from Clitoria ternatea (locally known as shankhpushpi) was used to test these effects in Wistar rat model of various age groups upon stereotaxic mediated kainic acid induced brain injury. MATERIALS AND METHODS The rodent experiments were carried out in one, twelve and eighteen months old male Wistar rats. The rats were orally fed with medhya rasayana prepared from Clitoria ternatea (3g per kg body weight/day) for 60 days. Stereotaxic mediated kainate stress to the hippocampus was performed on day 61. The rats were sacrificed on 66th day and the brain tissues were analyzed histologically and measured for autophagy, base excision repair and antioxidant enzyme activities. In addition, cognitive functions were analyzed by employing novel object recognition task and Morris water maze tests. The gene expression profile of hippocampus was assessed by microarray hybridization and two genes are validated. RESULTS Our study showed significant decrease of autophagy by medhya rasayana in both 12 and 18 months old rats. The hippocampal CA3 cellularity were increased in stereotaxic mediated stressed rats by medhya rasayana. There were no significant differences in constitutive base excision repair and antioxidant enzyme activities. Medhya rasayana treatment also significantly increased episodic memory in rats. Microarray experiments for pathway specific gene expression analysis showed altered expression of genes of long-term potentiation, axon guidance, neuroactive ligand-receptor interaction, regulation of autophagy, lysosome, homologous recombination and nucleotide excision repair pathways in adult rats by medhya rasayana. CONCLUSIONS In the present study, we show that reduction in autophagy is crucial for medhya rasayana induced protection of rat hippocampal cells and that artificially enhanced autophagy protects the brain cell damage by maintaining the selective DNA damage repair pathway and removal of reactive oxygen species to inhibit apoptosis. These findings suggest autophagy directed pathways by medhya rasayana prepared from C. ternatea protects the brain cells from stress induced injury.
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Affiliation(s)
- Kothanahalli S Raghu
- School of Life Sciences, Manipal University, Planetarium Complex, Manipal 576 104, Karnataka, India.
| | - Bhanuvalli R Shamprasad
- School of Life Sciences, Manipal University, Planetarium Complex, Manipal 576 104, Karnataka, India.
| | - Shama P Kabekkodu
- School of Life Sciences, Manipal University, Planetarium Complex, Manipal 576 104, Karnataka, India.
| | - Puspendu Paladhi
- School of Life Sciences, Manipal University, Planetarium Complex, Manipal 576 104, Karnataka, India.
| | - Manjunath B Joshi
- School of Life Sciences, Manipal University, Planetarium Complex, Manipal 576 104, Karnataka, India.
| | | | - Kanive P Guruprasad
- School of Life Sciences, Manipal University, Planetarium Complex, Manipal 576 104, Karnataka, India.
| | - Kapaettu Satyamoorthy
- School of Life Sciences, Manipal University, Planetarium Complex, Manipal 576 104, Karnataka, India.
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Sasaki M, Nakanuma Y. New concept: cellular senescence in pathophysiology of cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2017; 10:625-38. [PMID: 26680649 DOI: 10.1586/17474124.2016.1133291] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma, a malignant tumor arising in the hepatobiliary system, presents with poor prognosis because of difficulty in its early detection/diagnosis. Recent progress revealed that cellular senescence may be involved in the pathophysiology of cholangiocarcinoma. Cellular senescence is defined as permanent growth arrest caused by several cellular injuries, such as oncogenic mutations and oxidative stress. "Oncogene-induced" and/or stress-induced senescence may occur in the process of multi-step cholangiocarcinogenesis, and overexpression of a polycomb group protein EZH2 may play a role in the escape from, and/or bypassing of, senescence. Furthermore, senescent cells may play important roles in tumor development and progression via the production of senescence-associated secretory phenotypes. Cellular senescence may be a new target for the prevention, early diagnosis, and therapy of cholangiocarcinoma in the near future.
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Affiliation(s)
- Motoko Sasaki
- a Human Pathology , Kanazawa University Graduate School of Medical Sciences , Kanzawa , Japan
| | - Yasuni Nakanuma
- b Department of Diagnostic Pathology , Shizuoka Cancer Center , Shizuoka , Japan
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Hayat M. Overview of Autophagy. AUTOPHAGY: CANCER, OTHER PATHOLOGIES, INFLAMMATION, IMMUNITY, INFECTION, AND AGING 2017:3-90. [DOI: 10.1016/b978-0-12-805420-8.00001-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Hayat M. Overview of Autophagy. AUTOPHAGY: CANCER, OTHER PATHOLOGIES, INFLAMMATION, IMMUNITY, INFECTION, AND AGING 2017:1-122. [DOI: 10.1016/b978-0-12-812146-7.00001-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Baisantry A, Bhayana S, Wrede C, Hegermann J, Haller H, Melk A, Schmitt R. The impact of autophagy on the development of senescence in primary tubular epithelial cells. Cell Cycle 2016; 15:2973-2979. [PMID: 27715411 DOI: 10.1080/15384101.2016.1234547] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Autophagy and senescence are 2 distinct pathways that are importantly involved in acute kidney injury and renal repair. Recent data indicate that the 2 processes might be interrelated. To investigate the potential link between autophagy and senescence in the kidney we isolated primary tubular epithelial cells (PTEC) from wild-type mice and monitored the occurrence of cellular senescence during autophagy activation and inhibition. We found that the process of cell isolation and transfer into culture was associated with a strong basal autophagic activation in PTEC. Specific inhibition of autophagy by silencing autophagy-related 5 (Atg5) counteracted the occurrence of senescence hallmarks under baseline conditions. Reduced senescent features were also observed in Atg5 silenced PTEC after γ-irradiation and during H-Ras induced oncogenic senescence, but the response was less uniform in these stress models. Senescence inhibition was paralleled by better preservation of a mature epithelial phenotype in PTEC. Interestingly, treatment with rapamycin, which acts as an activator of autophagy, also counteracted the occurrence of senescence features in PTEC. While we interpret the anti-senescent effect of rapamycin as an autophagy-independent effect of mTOR-inhibition, the more specific approach of Atg5 silencing indicates that overactivated autophagy can have pro-senescent effects in PTEC. These results highlight the complex interaction between cell culture dependent stress mechanisms, autophagy and senescence.
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Affiliation(s)
- Arpita Baisantry
- a Department of Nephrology , Children's Hospital , Hannover , Germany.,b Department of Kidney , Liver and Metabolic Diseases, Children's Hospital , Hannover , Germany
| | - Sagar Bhayana
- a Department of Nephrology , Children's Hospital , Hannover , Germany
| | - Christoph Wrede
- c Institute of Functional and Applied Anatomy, Hannover Medical School , Hannover , Germany.,d Cluster of Excellence REBIRTH (Regenerative Biology to Reconstructive Therapy), Hannover Medical School , Hannover , Germany
| | - Jan Hegermann
- c Institute of Functional and Applied Anatomy, Hannover Medical School , Hannover , Germany.,d Cluster of Excellence REBIRTH (Regenerative Biology to Reconstructive Therapy), Hannover Medical School , Hannover , Germany
| | - Hermann Haller
- a Department of Nephrology , Children's Hospital , Hannover , Germany
| | - Anette Melk
- b Department of Kidney , Liver and Metabolic Diseases, Children's Hospital , Hannover , Germany
| | - Roland Schmitt
- a Department of Nephrology , Children's Hospital , Hannover , Germany
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Bhattacharya S, Das A, Datta S, Ganguli A, Chakrabarti G. Colchicine induces autophagy and senescence in lung cancer cells at clinically admissible concentration: potential use of colchicine in combination with autophagy inhibitor in cancer therapy. Tumour Biol 2016; 37:10653-64. [PMID: 26867767 DOI: 10.1007/s13277-016-4972-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 02/03/2016] [Indexed: 01/19/2023] Open
Abstract
Colchicine is a well-known and potent microtubule targeting agent, but the therapeutic value of colchicine against cancer is limited by its toxicity against normal cells. But, there is no report of its cytotoxic potential against lung cancer cell, at clinically permissible or lower concentrations, minimally toxic to non-cancerous cells. Hence, in the present study, we investigated the possible mechanism by which the efficacy of colchicine against lung cancer cells at less toxic dose could be enhanced. Colchicine at clinically admissible concentration of 2.5 nM had no cytotoxic effect and caused no G2/M arrest in A549 cells. However, at this concentration, colchicine strongly hindered the reformation of cold depolymerised interphase and spindle microtubule. Colchicine induced senescence and reactive oxygen species mediated autophagy in A549 cells at this concentration. Autophagy inhibitor 3-methyladenine (3-MA) sensitised the cytotoxicity of colchicine in A549 cells by switching senescence to apoptotic death, and this combination had reduced cytotoxicity to normal lung fibroblast cells (WI38). Together, these findings indicated the possible use of colchicine at clinically relevant dose along with autophagy inhibitor in cancer therapy.
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Affiliation(s)
- Surela Bhattacharya
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, WB, 700 019, India
| | - Amlan Das
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, WB, 700 019, India
| | - Satabdi Datta
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, WB, 700 019, India
| | - Arnab Ganguli
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, WB, 700 019, India
| | - Gopal Chakrabarti
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, WB, 700 019, India.
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p53 regulates autophagic activity in senescent rat mesenchymal stromal cells. Exp Gerontol 2016; 75:64-71. [PMID: 26792455 DOI: 10.1016/j.exger.2016.01.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Revised: 01/04/2016] [Accepted: 01/09/2016] [Indexed: 01/09/2023]
Abstract
The tumor suppressor protein p53 is an important player in the regulation of cell senescence, its functions are largely carried out by modulating its downstream genes. Emerging evidence has suggested that senescence and autophagy appear to be regulated by overlapping signaling pathways. Furthermore, autophagy markers have been observed in senescent cells. In this study, we sought to explore the effects of the expression pattern and function of p53 on the activity of autophagy and replicative senescence in bone marrow derived mesenchymal stromal cells (BMSCs). We found that more than 85% of BMSCs stained positive for SA-β-gal at passage 6 (senescent BMSCs) with increased expressions of senescence related genes (p16(ink4a) and p21(waf1)). These results were accompanied by the up-regulation of p53, down-regulation of mammalian target of rapamycin (mTOR) and phosphorylation of Rb. Senescent BMSCs displayed an increased monodansylcadaverine (MDC) staining and autophagy related genes (LC3 and atg12) level compared with BMSCs at passage 2. Knockdown of p53 alleviated the senescent state and reduced autophagic activity during the progression of BMSC senescence, which was accompanied by significantly up-regulated levels of mTOR and phosphorylation of Rb. These results demonstrate that autophagy increases when BMSCs enter the replicative senescence state, and p53 contributes a crucial role in the up-regulation of autophagy in this state.
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Hayat M. Overview of Autophagy. AUTOPHAGY: CANCER, OTHER PATHOLOGIES, INFLAMMATION, IMMUNITY, INFECTION, AND AGING 2016:1-71. [DOI: 10.1016/b978-0-12-802937-4.00001-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Hayat M. Overview of Autophagy. AUTOPHAGY: CANCER, OTHER PATHOLOGIES, INFLAMMATION, IMMUNITY, INFECTION, AND AGING 2016:3-84. [DOI: 10.1016/b978-0-12-805421-5.00001-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Hayat M. Overview of Autophagy. AUTOPHAGY: CANCER, OTHER PATHOLOGIES, INFLAMMATION, IMMUNITY, INFECTION, AND AGING 2016:3-73. [DOI: 10.1016/b978-0-12-802936-7.00001-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Ettel M, Eze O, Xu R. Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma. World J Hepatol 2015; 7:2563-2570. [PMID: 26557948 PMCID: PMC4635141 DOI: 10.4254/wjh.v7.i25.2563] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 07/10/2015] [Accepted: 10/19/2015] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CC) is primarily a malignant tumor of older adults most prevalent in Southeast Asia, where liver fluke infestation is high. However the etiology in western countries is unknown. Although the incidence of extrahepatic cholangiocarcinoma has remained constant, incidence of intrahepatic CC (ICC) which differs in morphology, pathogenesis, risk factors, treatment and prognosis is increasing. While this increase is associated with hepatitis C virus infection, chronic nonalcoholic liver disease, obesity, and smoking, the pathogenesis of ICC and molecular alterations underlying the carcinogenesis are not completely elucidated. Benign biliary lesions such as biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, von Meyenburg complex or bile duct hamartoma, and bile duct adenoma have been associated with ICC. For each of these entities, evidence suggests or supports a role as premalignant lesions. This article summarized the important biological significance of the precursor lesions of ICC and the molecular mechanisms that may be involved in intrahepatic cholangiocarcinogenesis.
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Baisantry A, Bhayana S, Rong S, Ermeling E, Wrede C, Hegermann J, Pennekamp P, Sörensen-Zender I, Haller H, Melk A, Schmitt R. Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments. J Am Soc Nephrol 2015; 27:1609-16. [PMID: 26487561 DOI: 10.1681/asn.2014111059] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 09/02/2015] [Indexed: 11/03/2022] Open
Abstract
Evidence suggests that autophagy promotes the development of cellular senescence. Because cellular senescence contributes to renal aging and promotes the progression from AKI to CKD, we investigated the potential effect of tubular autophagy on senescence induction. Compared with kidneys from control mice, kidneys from mice with conditional deletion of autophagy-related 5 (Atg5) for selective ablation of autophagy in proximal tubular S3 segments (Atg5(Δ) (flox/) (Δ) (flox)) presented with significantly less tubular senescence, reduced interstitial fibrosis, and superior renal function 30 days after ischemia/reperfusion injury. To correlate this long-term outcome with differences in the early injury process, kidneys were analyzed 2 hours and 3 days after reperfusion. Notably, compared with kidneys of control mice, Atg5(Δ) (flox/) (Δ) (flox) kidneys showed more cell death in outer medullary S3 segments at 2 hours but less tubular damage and inflammation at day 3. These data suggest that the lack of autophagy prevents early survival mechanisms in severely damaged tubular cells. However, if such compromised cells persist, then they may lead to maladaptive repair and proinflammatory changes, thereby facilitating the development of a senescent phenotype and CKD.
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Affiliation(s)
- Arpita Baisantry
- Department of Nephrology and Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover, Germany
| | | | | | - Esther Ermeling
- Department of Nephrology and Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover, Germany
| | - Christoph Wrede
- Institute of Functional and Applied Anatomy and Cluster of Excellence REBIRTH (Regenerative Biology to Reconstructive Therapy), Hannover Medical School, Hannover, Germany; and
| | - Jan Hegermann
- Institute of Functional and Applied Anatomy and Cluster of Excellence REBIRTH (Regenerative Biology to Reconstructive Therapy), Hannover Medical School, Hannover, Germany; and
| | - Petra Pennekamp
- Children's Hospital, University of Munster, Munster, Germany
| | | | | | - Anette Melk
- Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover, Germany
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Sasaki M, Yoshimura-Miyakoshi M, Sato Y, Nakanuma Y. A possible involvement of endoplasmic reticulum stress in biliary epithelial autophagy and senescence in primary biliary cirrhosis. J Gastroenterol 2015; 50:984-95. [PMID: 25552342 DOI: 10.1007/s00535-014-1033-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 12/11/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Deregulated autophagy followed by cellular senescence in biliary epithelial cells (BECs) may be closely related to the abnormal expression of mitochondrial antigens and following autoimmune pathogenesis in primary biliary cirrhosis (PBC). We examined an involvement of endoplasmic reticulum (ER) stress in the deregulated autophagy and cellular senescence in PBC. METHODS We examined the degree of ER stress using markers; glucose-regulated protein 78 (GRP78) and protein disulfide isomerases (PDI), autophagy and cellular senescence in cultured BECs treated with an ER stress inducer, tunicamycin (TM), glycochenodeoxycholic acid (GCDC), and palmitic acid (PA), and the effect of pretreatment with tauroursodeoxycholic acid (TUDCA). We examined the expression of PDI and GRP78 in livers taken from the patients with PBC (n = 43) and 75 control livers. RESULTS The expression of ER stress markers was significantly increased in cultured BECs treated with TM, GCDC or PA in BECs (p < 0.05), and pretreatment with TUDCA significantly suppressed the induced ER stress (p < 0.05). Autophagy, deregulated autophagy, and cellular senescence were induced in BECs treated with TM, GCDC, or PA. Pretreatment with TUDCA further increased autophagy in BECs treated with PA and suppressed cellular senescence caused by treatments with TM, GCDC, or PA (p < 0.05). A granular expression of PDI and GRP78 was significantly more extensive in small bile ducts in PBC, compared with control livers (p < 0.05). The expression of GRP78 was seen in senescent BECs in PBC. CONCLUSIONS ER stress may play a role in the pathogenesis of deregulated autophagy and cellular senescence in biliary epithelial lesions in PBC.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan,
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Sasaki M, Hsu M, Yeh MM, Nakanuma Y. In recurrent primary biliary cirrhosis after liver transplantation, biliary epithelial cells show increased expression of mitochondrial proteins. Virchows Arch 2015; 467:417-25. [PMID: 26259963 DOI: 10.1007/s00428-015-1819-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 07/06/2015] [Accepted: 07/28/2015] [Indexed: 12/17/2022]
Abstract
In biliary epithelial lesions in primary biliary cirrhosis (PBC), mitochondrial proteins associated with deregulated autophagy are abnormally expressed. We examined whether this could be used as a diagnostic marker for end-stage PBC and recurrent PBC after liver transplantation. We examined the expression of the mitochondrial protein pyruvate dehydrogenase complex-E2 component and cytochrome c oxidase, subunit I (CCO), the autophagy-related marker microtubule-associated protein-light chain 3 (LC3), and p62/sequestosome-1 and the senescence markers p16(Ink4a) and p21(WAF1/Cip1) in small bile ducts and bile ductules in explanted livers from patients with PBC (n = 20) in comparison with liver tissue from control patients (n = 21) and post-transplant samples including recurrent PBC and cellular rejection (n = 28). Intense granular expression of mitochondrial proteins was significantly more frequent in small bile ducts in explanted livers with PBC than in control livers (p < 0.05). Post-transplant samples comprised of three groups: group A (positive for mitochondrial proteins, n = 7), group B (positive for either autophagy-related or senescence markers but negative for mitochondrial proteins, n = 7), and group C (all negative, n = 14). All but one case of group A were clinically and histologically diagnosed as recurrent PBC. In contrast, all cases of group B were diagnosed as cellular rejection. This study suggests that the expression of mitochondrial proteins in small bile ducts may be a useful diagnostic marker for end-stage PBC and recurrent PBC after liver transplantation.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan.
| | - Maylee Hsu
- Department of Pathology, University of Washington, Seattle, WA, 98195, USA
| | - Matthew M Yeh
- Department of Pathology, University of Washington, Seattle, WA, 98195, USA
| | - Yasuni Nakanuma
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
- Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan
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Nakanuma Y, Sasaki M, Harada K. Autophagy and senescence in fibrosing cholangiopathies. J Hepatol 2015; 62:934-45. [PMID: 25435435 DOI: 10.1016/j.jhep.2014.11.027] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 11/08/2014] [Accepted: 11/16/2014] [Indexed: 12/16/2022]
Abstract
Fibrosing cholangiopathy such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) is characterized by biliary epithelial injuries and concentric fibrous obliteration of the biliary tree together with inflammatory cell infiltration. In these diseases, inappropriate innate immunity is reported to contribute more to bile duct pathology as compared with various aspects of "classical" autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by chronic cholangitis with bile duct loss and classical autoimmune features. Cellular senescence of cholangiocytes and a senescence-associated secretory phenotype lead to the production of proinflammatory cytokines and chemokines that may modify the milieu of the bile duct and then trigger fibroinflammatory responses in PSC and PBC. Furthermore, deregulated autophagy might be involved in cholangiocyte senescence and possibly in the autoimmune process in PBC, and the deregulated innate immunity against enteric microbes or their products that is associated with cholangiocyte senescence might result in the fibrosing cholangitis that develops in PBC and PSC. In BA, innate immunity against double-stranded RNA viruses might be involved in cholangiocyte apoptosis and also in the development of the epithelial-mesenchymal transition of cholangiocytes that results in fibrous obliteration of bile ducts. These recent advances in the understanding of immune-mediated biliary diseases represent a paradigm shift: the cholangiocyte is no longer viewed merely as a passive victim of injury; it is now also considered to function as a potential effector in bile duct pathology.
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Affiliation(s)
- Yasuni Nakanuma
- Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan; Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan.
| | - Motoko Sasaki
- Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan
| | - Kenichi Harada
- Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan
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Meng L, Quezada M, Levine P, Han Y, McDaniel K, Zhou T, Lin E, Glaser S, Meng F, Francis H, Alpini G. Functional role of cellular senescence in biliary injury. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:602-9. [PMID: 25619959 DOI: 10.1016/j.ajpath.2014.10.027] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 10/06/2014] [Accepted: 10/28/2014] [Indexed: 01/02/2023]
Abstract
Cellular senescence is a state of irreversible cell cycle arrest that has been involved in many gastrointestinal diseases, including human cholestatic liver disorders. Senescence may play a role in biliary atresia, primary sclerosing cholangitis, cellular rejection, and primary biliary cirrhosis, four liver diseases affecting cholangiocytes and the biliary system. In this review, we examine proposed mechanisms of senescence-related biliary diseases, including hypotheses associated with the senescence-associated phenotype, induction of senescence in nearby cells, and the depletion of stem cell subpopulations. Current evidence for the molecular mechanisms of senescence in the previously mentioned diseases is discussed in detail, with attention to recent advances on the role of pathways associated with senescence-associated phenotype, stress-induced senescence, telomere dysfunction, and autophagy.
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Affiliation(s)
- Luke Meng
- Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas; Doctor of Medicine Program, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Morgan Quezada
- Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas
| | - Phillip Levine
- Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas; Academic Operations, Scott & White Memorial Hospital, Baylor Scott & White Health, Temple, Texas
| | - Yuyan Han
- Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas
| | - Kelly McDaniel
- Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas; Academic Operations, Scott & White Memorial Hospital, Baylor Scott & White Health, Temple, Texas
| | - Tianhao Zhou
- Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas
| | - Emily Lin
- Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas
| | - Shannon Glaser
- Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas
| | - Fanyin Meng
- Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas; Academic Operations, Scott & White Memorial Hospital, Baylor Scott & White Health, Temple, Texas
| | - Heather Francis
- Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas; Academic Operations, Scott & White Memorial Hospital, Baylor Scott & White Health, Temple, Texas
| | - Gianfranco Alpini
- Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Digestive Disease Research Center, Scott & White Healthcare, Texas A&M Health Science Center, College of Medicine, Baylor Scott & White Health, Temple, Texas.
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