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Cominelli G, Lonati C, Pinto D, Rinaldi F, Franco C, Favero G, Rezzani R. Melatonin Attenuates Ferritinophagy/Ferroptosis by Acting on Autophagy in the Liver of an Autistic Mouse Model BTBR T +Itpr3 tf/J. Int J Mol Sci 2024; 25:12598. [PMID: 39684310 DOI: 10.3390/ijms252312598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/20/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
Autism spectrum disorders (ASDs) are a pool of neurodevelopment disorders in which social impairment is the main symptom. Presently, there are no definitive medications to cure the symptoms but the therapeutic strategies that are taken ameliorate them. The purpose of this study was to investigate the effects of melatonin (MLT) in treating ASDs using an autistic mouse model BTBR T+Itpr3tf/J (BTBR). We evaluated the hepatic cytoarchitecture and some markers of autophagy, ferritinophagy/ferroptosis, in BTBR mice treated and not-treated with MLT. The hepatic morphology and the autophagy and ferritinophagy/ferroptosis pathways were analyzed by histological, immunohistochemical, and Western blotting techniques. We studied p62 and microtubule-associated protein 1 light chain 3 B (LC3B) for evaluating the autophagy; nuclear receptor co-activator 4 (NCOA4) and long-chain-coenzyme synthase (ACSL4) for monitoring ferritinophagy/ferroptosis. The liver of BTBR mice revealed that the hepatocytes showed many cytoplasmic inclusions recognized as Mallory-Denk bodies (MDBs); the expression and levels of p62 and LC3B were downregulated, whereas ACSL4 and NCOA4 were upregulated, as compared to control animals. MLT administration to BTBR mice ameliorated liver damage and reduced the impairment of autophagy and ferritinophagy/ferroptosis. In conclusion, we observed that MLT alleviates liver damage in BTBR mice by improving the degradation of intracellular MDBs, promoting autophagy, and suppressing ferritinophagy/ferroptosis.
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Affiliation(s)
- Giorgia Cominelli
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
| | - Claudio Lonati
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
- Italian Society for the Study of Orofacial Pain (Società Italiana Studio Dolore Orofacciale-SISDO), 25123 Brescia, Italy
| | - Daniela Pinto
- Human Microbiome Advanced Project Institute, 20129 Milan, Italy
- Interdepartmental University Center of Research Adaption and Regeneration of Tissues and Organs-(ARTO), University of Brescia, 25123 Brescia, Italy
| | - Fabio Rinaldi
- Human Microbiome Advanced Project Institute, 20129 Milan, Italy
- Interdepartmental University Center of Research Adaption and Regeneration of Tissues and Organs-(ARTO), University of Brescia, 25123 Brescia, Italy
| | - Caterina Franco
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
| | - Gaia Favero
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
- Interdepartmental University Center of Research Adaption and Regeneration of Tissues and Organs-(ARTO), University of Brescia, 25123 Brescia, Italy
| | - Rita Rezzani
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
- Italian Society for the Study of Orofacial Pain (Società Italiana Studio Dolore Orofacciale-SISDO), 25123 Brescia, Italy
- Interdepartmental University Center of Research Adaption and Regeneration of Tissues and Organs-(ARTO), University of Brescia, 25123 Brescia, Italy
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Primavesi F, Senoner T, Schindler S, Nikolajevic A, Di Fazio P, Csukovich G, Eller S, Neumayer B, Anliker M, Braunwarth E, Oberhuber R, Resch T, Maglione M, Cardini B, Niederwieser T, Gasteiger S, Klieser E, Tilg H, Schneeberger S, Neureiter D, Öfner D, Troppmair J, Stättner S. The Interplay between Perioperative Oxidative Stress and Hepatic Dysfunction after Human Liver Resection: A Prospective Observational Pilot Study. Antioxidants (Basel) 2024; 13:590. [PMID: 38790695 PMCID: PMC11118143 DOI: 10.3390/antiox13050590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Post-hepatectomy liver failure (PHLF) remains the major contributor to death after liver resection. Oxidative stress is associated with postoperative complications, but its impact on liver function is unclear. This first in-human, prospective, single-center, observational pilot study evaluated perioperative oxidative stress and PHLF according to the ISGLS (International Study Group for Liver Surgery). Serum 8-isoprostane, 4-hydroxynonenal (4-HNE), total antioxidative capacity, vitamins A and E, and intraoperative, sequential hepatic tissue 4-HNE and UCP2 (uncoupling protein 2) immunohistochemistry (IHC) were assessed. The interaction with known risk factors for PHLF and the predictive potential of oxidative stress markers were analyzed. Overall, 52 patients were included (69.2% major liver resection). Thirteen patients (25%) experienced PHLF, a major factor for 90-day mortality (23% vs. 0%; p = 0.013). Post-resection, pro-oxidative 8-isoprostane significantly increased (p = 0.038), while 4-HNE declined immediately (p < 0.001). Antioxidative markers showed patterns of consumption starting post-resection (p < 0.001). Liver tissue oxidative stress increased stepwise from biopsies taken after laparotomy to post-resection in situ liver and resection specimens (all p < 0.001). Cholangiocarcinoma patients demonstrated significantly higher serum and tissue oxidative stress levels at various timepoints, with consistently higher preoperative values in advanced tumor stages. Combining intraoperative, post-resection 4-HNE serum levels and in situ IHC early predicted PHLF with an AUC of 0.855 (63.6% vs. 0%; p < 0.001). This was also associated with grade B/C PHLF (36.4% vs. 0%; p = 0.021) and 90-day mortality (18.2% vs. 0%; p = 0.036). In conclusion, distinct patterns of perioperative oxidative stress levels occur in patients with liver dysfunction. Combining intraoperative serum and liver tissue markers predicts subsequent PHLF. Cholangiocarcinoma patients demonstrated pronounced systemic and hepatic oxidative stress, with increasing levels in advanced tumor stages, thus representing a worthwhile target for future exploratory and therapeutic studies.
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Affiliation(s)
- Florian Primavesi
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.N.); (S.E.); (J.T.)
- Department of General, Visceral and Vascular Surgery, Salzkammergutklinikum, 4840 Vöcklabruck, Austria;
| | - Thomas Senoner
- Department of Anaesthesiology and Intensive Care Medicine, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Sophie Schindler
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
| | - Aleksandar Nikolajevic
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.N.); (S.E.); (J.T.)
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-Universität Marburg, 35043 Marburg, Germany;
| | - Georg Csukovich
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.N.); (S.E.); (J.T.)
- Small Animal Internal Medicine, Vetmeduni, 1210 Vienna, Austria
| | - Silvia Eller
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.N.); (S.E.); (J.T.)
| | - Bettina Neumayer
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), 5020 Salzburg, Austria; (B.N.); (E.K.); (D.N.)
| | - Markus Anliker
- Central Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Eva Braunwarth
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
| | - Thomas Resch
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
| | - Manuel Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.N.); (S.E.); (J.T.)
| | - Benno Cardini
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
| | - Thomas Niederwieser
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
| | - Silvia Gasteiger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
| | - Eckhard Klieser
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), 5020 Salzburg, Austria; (B.N.); (E.K.); (D.N.)
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), 5020 Salzburg, Austria; (B.N.); (E.K.); (D.N.)
| | - Dietmar Öfner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.S.); (E.B.); (R.O.); (T.R.); (M.M.); (B.C.); (S.G.); (S.S.); (D.Ö.)
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.N.); (S.E.); (J.T.)
| | - Jakob Troppmair
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.N.); (S.E.); (J.T.)
| | - Stefan Stättner
- Department of General, Visceral and Vascular Surgery, Salzkammergutklinikum, 4840 Vöcklabruck, Austria;
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Miyazaki K, Saito Y, Ichimura-Shimizu M, Imura S, Ikemoto T, Yamada S, Tokuda K, Morine Y, Tsuneyama K, Shimada M. Defective endoplasmic reticulum stress response via X box-binding protein 1 is a major cause of poor liver regeneration after partial hepatectomy in mice with non-alcoholic steatohepatitis. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2022; 29:1241-1252. [PMID: 35325502 DOI: 10.1002/jhbp.1142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 01/18/2022] [Accepted: 01/23/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Poor regeneration after hepatectomy in NAFLD is well recognized, but the mechanism is unclear. Endoplasmic reticulum (ER) stress plays an important role in the development of NAFLD. Here, we show that an impaired ER stress response contributes to poor liver regeneration in partially hepatectomized mice. METHODS Non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH) was induced in mice using our patented feed and 70% partial hepatectomy (PH) was performed. Mice were sacrificed 0, 4, 8, 24, or 48 hours, or 7 days after PH, and liver regeneration and the mRNA expression of ER stress markers were assessed. RESULTS Non-alcoholic fatty liver disease activity score was calculated as 4-6 points for NAFL and 7 points for NASH. NASH was characterized by inflammation and high ER stress marker expression before PH. After PH, NASH mice showed poorer liver regeneration than controls. High expression of proinflammatory cytokine genes was present in NASH mice 4 hours after PH. Xbp1-s mRNA expression was high in control and NAFL mice after PH, but no higher in NASH mice. CONCLUSIONS Dysfunction of the ER stress response might be a cause of poor liver regeneration in NASH.
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Affiliation(s)
| | - Yu Saito
- Department of Surgery, Tokushima University, Tokushima, Japan
| | | | - Satoru Imura
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Tokushima University, Tokushima, Japan
| | | | - Kazunori Tokuda
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Tokushima University, Tokushima, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
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Epigenetic Alterations under Oxidative Stress in Stem Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6439097. [PMID: 36071870 PMCID: PMC9444469 DOI: 10.1155/2022/6439097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 07/16/2022] [Accepted: 07/27/2022] [Indexed: 11/18/2022]
Abstract
Epigenetic regulation of gene expression, including DNA methylation and histone modifications, provides finely tuned responses for cells that undergo cellular environment changes. Abundant evidences have demonstrated the detrimental role of oxidative stress in various human pathogenesis since oxidative stress results from the imbalance between reactive oxygen species (ROS) accumulation and antioxidant defense system. Stem cells can self-renew themselves and meanwhile have the potential to differentiate into many other cell types. As some studies have described the effects of oxidative stress on homeostasis and cell fate decision of stem cells, epigenetic alterations have emerged crucial for mediating the stem cell behaviours under oxidative stress. Here, we review recent findings on the oxidative effects on DNA and histone modifications in stem cells. We propose that epigenetic alterations and oxidative stress may influence each other in stem cells.
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Kostyuk AI, Panova AS, Kokova AD, Kotova DA, Maltsev DI, Podgorny OV, Belousov VV, Bilan DS. In Vivo Imaging with Genetically Encoded Redox Biosensors. Int J Mol Sci 2020; 21:E8164. [PMID: 33142884 PMCID: PMC7662651 DOI: 10.3390/ijms21218164] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/13/2022] Open
Abstract
Redox reactions are of high fundamental and practical interest since they are involved in both normal physiology and the pathogenesis of various diseases. However, this area of research has always been a relatively problematic field in the context of analytical approaches, mostly because of the unstable nature of the compounds that are measured. Genetically encoded sensors allow for the registration of highly reactive molecules in real-time mode and, therefore, they began a new era in redox biology. Their strongest points manifest most brightly in in vivo experiments and pave the way for the non-invasive investigation of biochemical pathways that proceed in organisms from different systematic groups. In the first part of the review, we briefly describe the redox sensors that were used in vivo as well as summarize the model systems to which they were applied. Next, we thoroughly discuss the biological results obtained in these studies in regard to animals, plants, as well as unicellular eukaryotes and prokaryotes. We hope that this work reflects the amazing power of this technology and can serve as a useful guide for biologists and chemists who work in the field of redox processes.
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Affiliation(s)
- Alexander I. Kostyuk
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; (A.I.K.); (A.S.P.); (A.D.K.); (D.A.K.); (D.I.M.); (O.V.P.); (V.V.B.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Anastasiya S. Panova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; (A.I.K.); (A.S.P.); (A.D.K.); (D.A.K.); (D.I.M.); (O.V.P.); (V.V.B.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Aleksandra D. Kokova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; (A.I.K.); (A.S.P.); (A.D.K.); (D.A.K.); (D.I.M.); (O.V.P.); (V.V.B.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Daria A. Kotova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; (A.I.K.); (A.S.P.); (A.D.K.); (D.A.K.); (D.I.M.); (O.V.P.); (V.V.B.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Dmitry I. Maltsev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; (A.I.K.); (A.S.P.); (A.D.K.); (D.A.K.); (D.I.M.); (O.V.P.); (V.V.B.)
- Federal Center for Cerebrovascular Pathology and Stroke, 117997 Moscow, Russia
| | - Oleg V. Podgorny
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; (A.I.K.); (A.S.P.); (A.D.K.); (D.A.K.); (D.I.M.); (O.V.P.); (V.V.B.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Vsevolod V. Belousov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; (A.I.K.); (A.S.P.); (A.D.K.); (D.A.K.); (D.I.M.); (O.V.P.); (V.V.B.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
- Federal Center for Cerebrovascular Pathology and Stroke, 117997 Moscow, Russia
- Institute for Cardiovascular Physiology, Georg August University Göttingen, D-37073 Göttingen, Germany
| | - Dmitry S. Bilan
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; (A.I.K.); (A.S.P.); (A.D.K.); (D.A.K.); (D.I.M.); (O.V.P.); (V.V.B.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
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Han Su, Zhang Y, Chen Y, Fan B, Hao B, Li X. Effect of Sequestosome-1/p62 Expression on Autophagy of Human Periodontal Ligament Fibroblasts Induced by Porphyromonas gingivalis. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2020. [DOI: 10.1134/s1068162019060189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Ozaki M. Cellular and molecular mechanisms of liver regeneration: Proliferation, growth, death and protection of hepatocytes. Semin Cell Dev Biol 2019; 100:62-73. [PMID: 31669133 DOI: 10.1016/j.semcdb.2019.10.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 01/08/2023]
Abstract
Liver regeneration is an important and necessary process that the liver depends on for recovery from injury. The regeneration process consists of a complex network of cells and organs, including liver cells (parenchymal and non-parenchymal cells) and extrahepatic organs (thyroid, adrenal glands, pancreas, duodenum, spleen, and autonomic nervous system). The regeneration process of a normal, healthy liver depends mainly on hepatocyte proliferation, growth, and programmed cell death. Cell proliferation and growth are regulated in a cooperative manner by interleukin (IL)-6/janus kinase (Jak)/signal transducers and activators of transcription-3 (STAT3), and phosphoinositide 3-kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathways. The IL-6/Jak/STAT3 pathway regulates hepatocyte proliferation and protects against cell death and oxidative stress. The PI3-K/PDK1/Akt pathway is primarily responsible for the regulation of cell size, sending mitotic signals in addition to pro-survival, antiapoptotic and antioxidative signals. Though programmed cell death may interfere with liver regeneration in a pathological situation, it seems to play an important role during the termination phase, even in a normal, healthy liver regeneration. However, further study is needed to fully elucidate the mechanisms regulating the processes of liver regeneration with regard to cell-to-cell and organ-to-organ networks at the molecular and cellular levels.
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Affiliation(s)
- Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N12, W5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
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Bender D, Hildt E. Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis. Int J Mol Sci 2019; 20:ijms20184659. [PMID: 31546975 PMCID: PMC6769940 DOI: 10.3390/ijms20184659] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open
Abstract
With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). For both viruses chronic infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) play a central role in a variety of chronic inflammatory diseases. In light of this, this review summarizes the impact of both viruses on ROS-generating and ROS-inactivating mechanisms. The focus is on the effect of both viruses on the transcription factor Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2). By binding to its target sequence, the antioxidant response element (ARE), Nrf2 triggers the expression of a variety of cytoprotective genes including ROS-detoxifying enzymes. The review summarizes the literature about the pathways for the modulation of Nrf2 that are deregulated by HBV and HCV and describes the impact of Nrf2 deregulation on the viral life cycle of the respective viruses and the virus-associated pathogenesis.
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Affiliation(s)
- Daniela Bender
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straβe 51-59, D-63225 Langen, Germany.
| | - Eberhard Hildt
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straβe 51-59, D-63225 Langen, Germany.
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Jeong SJ, Zhang X, Rodriguez-Velez A, Evans TD, Razani B. p62/ SQSTM1 and Selective Autophagy in Cardiometabolic Diseases. Antioxid Redox Signal 2019; 31:458-471. [PMID: 30588824 PMCID: PMC6653798 DOI: 10.1089/ars.2018.7649] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Significance: p62/SQSTM1 is a multifunctional scaffolding protein involved in the regulation of various signaling pathways as well as autophagy. In particular, p62/SQSTM1 serves as an essential adaptor to identify and deliver specific organelles and protein aggregates to autophagosomes for degradation, a process known as selective autophagy. Critical Issues: With the emergence of autophagy as a critical process in cellular metabolism and the development of cardiometabolic diseases, it is increasingly important to understand p62's role in the integration of signaling and autophagic pathways. Recent Advances: This review first discusses the features that make p62/SQSTM1 an ideal chaperone in integrating signaling pathways with autophagy and details the current understanding of its diverse roles in selective autophagy processes. Distinct and overlapping roles of other chaperones with similar functions are then discussed in the context of p62/SQSTM1. Finally, the recent literature focusing on p62 and selective autophagy in metabolism and the spectrum of cardiometabolic diseases including atherosclerosis, fatty liver disease, and obesity is evaluated. Future Directions: A comprehensive understanding of the nuanced roles p62/SQSTM1 plays in mediating distinct autophagy pathways would provide new insights into the mechanisms of this critical degradative pathway. This will, in turn, facilitate our understanding of cardiovascular and cardiometabolic disease pathology and the development of novel autophagy-modulating therapeutic strategies.
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Affiliation(s)
- Se-Jin Jeong
- 1 Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Xiangyu Zhang
- 1 Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Astrid Rodriguez-Velez
- 1 Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Trent D Evans
- 1 Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Babak Razani
- 1 Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.,2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.,3 John Cochran VA Medical Center, St. Louis, Missouri
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Haga S, YiMin, Yamaki H, Jin S, Sogon T, Morita N, Ozaki M. Extracts of bilberry ( Vaccinium myrtillus L.) fruits improve liver steatosis and injury in mice by preventing lipid accumulation and cell death. Biosci Biotechnol Biochem 2019; 83:2110-2120. [PMID: 31244392 DOI: 10.1080/09168451.2019.1634514] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Bilberry has been reported to have anti-oxidant and anti-inflammatory properties. We studied the effect of bilberry (Vaccinium myrtillus L.) fruits extracts (BEs) on the pathogenesis caused by lipid accumulation in fatty liver and non-alcoholic steatohepatitis (NASH). 5 μg/ml of BEs was enough to suppress lipid accumulation in the fatty liver model of the mouse hepatic AML12 cells. BEs increased cell viability and anti-oxidant capacity, presumably by activating (phosphorylating) Akt/STAT3 and inducing MnSOD/catalase. BEs also significantly reduced Rubicon and induced p62/SQSTM1, possibly contributing to reduce cellular lipids (lipophagy). When the mice were fed supplemented with BEs (5% or 10%, w/w), hepatic steatosis, injury, and hypercholesterolemia/hyperglycemia were significantly improved. Furthermore, histological and cytokine studies indicated that BEs possibly suppress hepatic inflammation (hepatitis) and fibrosis. Therefore, BEs improved liver steatosis and injury, and potentially suppress fibrosis by suppressing inflammatory response, which therefore may prevent the progression of fatty liver to NASH.
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Affiliation(s)
- Sanae Haga
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University , Sapporo , Hokkaido , Japan
| | - YiMin
- Department of Advanced Medicine, Graduate School of Medicine, Hokkaido University , Sapporo , Hokkaido , Japan
| | - Hikari Yamaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University , Sapporo , Hokkaido , Japan
| | - Shigeki Jin
- Department of Forensic Medicine, Graduate School of Medicine, Hokkaido University , Sapporo , Hokkaido , Japan
| | | | - Naoki Morita
- Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) , Sapporo , Hokkaido , Japan
| | - Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University , Sapporo , Hokkaido , Japan.,Laboratory of Molecular and Functional Bio-imaging, Faculty of Health Sciences, Hokkaido University , Sapporo , Hokkaido , Japan
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11
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Associations of Oxidative Stress and Postoperative Outcome in Liver Surgery with an Outlook to Future Potential Therapeutic Options. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3950818. [PMID: 30906502 PMCID: PMC6393879 DOI: 10.1155/2019/3950818] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 01/02/2019] [Indexed: 12/16/2022]
Abstract
Several types of surgical procedures have shown to elicit an inflammatory stress response, leading to substantial cytokine production and formation of oxygen-based or nitrogen-based free radicals. Chronic liver diseases including cancers are almost always characterized by increased oxidative stress, in which hepatic surgery is likely to potentiate at least in the short term and hereby furthermore impair the hepatic redox state. During liver resection, intermittent inflow occlusion is commonly applied to prevent excessive blood loss but resulting ischemia and reperfusion of the liver have been linked to increased oxidative stress, leading to impairment of cell functions and subsequent cell death. In the field of liver transplantation, ischemia/reperfusion injury has extensively been investigated in the last decades and has recently been in the scientific focus again due to increased use of marginal donor organs and new machine perfusion concepts. Therefore, given the intriguing role of oxidative stress in the pathogenesis of numerous diseases and in the perioperative setting, the interest for a therapeutic antioxidative agent has been present for several years. This review is aimed at giving an introduction to oxidative stress in surgical procedures in general and then examines the role of oxidative stress in liver surgery in particular, discussing both transplantation and resection. Results from studies in the animal and human settings are included. Finally, potential therapeutic agents that might be beneficial in reducing the burden of oxidative stress in hepatic diseases and during surgery are presented. While there is compelling evidence from animal models and a limited number of clinical studies showing that oxidative stress plays a major role in both liver resection and transplantation and several recent studies have suggested a potential for antioxidative treatment in chronic liver disease (e.g., steatosis), the search for effective antioxidants in the field of liver surgery is still ongoing.
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12
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Ozawa Y, Tamura T, Owada Y, Shimizu Y, Kemmochi A, Hisakura K, Matsuzaka T, Shimano H, Isoda H, Ohkohchi N. Evaluation of safety for hepatectomy in a novel mouse model with nonalcoholic-steatohepatitis. World J Gastroenterol 2018; 24:1622-1631. [PMID: 29686469 PMCID: PMC5910545 DOI: 10.3748/wjg.v24.i15.1622] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 03/16/2018] [Accepted: 03/25/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether the liver resection volume in a newly developed nonalcoholic steatohepatitis (NASH) model influences surgical outcome.
METHODS For establishment of a NASH model, mice were fed a high-fat diet for 4 wk, administered CCl4 for the last 2 wk, and administered T0901317 for the last 5 d. We divided these mice into two groups: A 30% partial hepatectomy (PH) of NASH liver group and a 70% PH of NASH liver group. In addition, a 70% PH of normal liver group served as the control. Each group was evaluated for survival rate, regeneration, apoptosis, necrosis and DNA expression after PH.
RESULTS In the 70% PH of NASH group, the survival rate was significantly decreased compared with that in the control and 30% PH of NASH groups (P < 0.01). 10 of 32 mice in the NASH 70% PH group died within 48 h after PH. Serum aspartate aminotransferase (AST) levels and total bilirubin (T-Bil) in the NASH 70% PH group were significantly higher than the levels in the other two groups (AST: P < 0.05, T-Bil: P < 0.01). In both PH of NASH groups, signaling proteins involved in regeneration were expressed at lower levels than those in the control group (P < 0.01). The 70% PH of NASH group also exhibited a lower number of Ki-67-positive cells and higher rates of apoptosis and necrosis than the NASH 30% PH group (P < 0.01). In addition, DNA microarray assays showed differences in gene expression associated with cell cycle arrest and apoptosis.
CONCLUSION The function of the residual liver is impaired in fatty liver compared to normal liver. A larger residual volume is required to maintain liver functions in mice with NASH.
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Affiliation(s)
- Yusuke Ozawa
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Takafumi Tamura
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Yohei Owada
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Yoshio Shimizu
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Akira Kemmochi
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Katsuji Hisakura
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Takashi Matsuzaka
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Hiroko Isoda
- Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan
| | - Nobuhiro Ohkohchi
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
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Sun W, Yang J, Wang W, Hou J, Cheng Y, Fu Y, Xu Z, Cai L. The beneficial effects of Zn on Akt-mediated insulin and cell survival signaling pathways in diabetes. J Trace Elem Med Biol 2018; 46:117-127. [PMID: 29413101 DOI: 10.1016/j.jtemb.2017.12.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Revised: 12/06/2017] [Accepted: 12/21/2017] [Indexed: 12/11/2022]
Abstract
Zinc is one of the essential trace elements and participates in numerous physiological processes. Abnormalities in zinc homeostasis often result in the pathogenesis of various chronic metabolic disorders, such as diabetes and its complications. Zinc has insulin-mimetic and anti-diabetic effects and deficiency has been shown to aggravate diabetes-induced oxidative stress and tissue injury in diabetic rodent models and human subjects with diabetes. Akt signaling pathway plays a central role in insulin-stimulated glucose metabolism and cell survival. Anti-diabetic effects of zinc are largely dependent on the activation of Akt signaling. Zn is also an inducer of metallothionein that plays important role in anti-oxidative stress and damage. However, the exact molecular mechanisms underlying zinc-induced activation of Akt signaling pathway remains to be elucidated. This review summarizes the recent advances in deciphering the possible mechanisms of zinc on Akt-mediated insulin and cell survival signaling pathways in diabetes conditions. Insights into the effects of zinc on epigenetic regulation and autophagy in diabetic nephropathy are also discussed in the latter part of this review.
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Affiliation(s)
- Weixia Sun
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
| | - Jiaxing Yang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Wanning Wang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China; Pediatric Research Institute, The Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, The University of Louisville, Louisville, KY 40202, USA
| | - Jie Hou
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Yanli Cheng
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Yaowen Fu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Zhonggao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
| | - Lu Cai
- Pediatric Research Institute, The Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, The University of Louisville, Louisville, KY 40202, USA
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Long M, Li X, Li L, Dodson M, Zhang DD, Zheng H. Multifunctional p62 Effects Underlie Diverse Metabolic Diseases. Trends Endocrinol Metab 2017; 28:818-830. [PMID: 28966079 DOI: 10.1016/j.tem.2017.09.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 09/03/2017] [Accepted: 09/05/2017] [Indexed: 12/17/2022]
Abstract
p62, a protein capable of binding both ubiquitin and autophagy substrates, is well established as a key regulator in cancer and neurodegenerative diseases. Recently, there has been accumulating evidence that p62 is also a pivotal regulator in metabolic diseases, such as obesity, T2DM, NAFLD, metabolic bone disease, gout and thyroid disease. This review summarizes the emerging role of p62 on these diseases by considering its functional domains, phenotypes in genetically modified animals, clinically observed alterations, and its effects on downstream metabolic signaling pathways. At the same time, we highlight the need to explore the roles played by p62 in the gastrointestinal environment and immune system, and the extent to which its elevated expression may confer protection against metabolic disorders.
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Affiliation(s)
- Min Long
- Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; These authors contributed equally to this work
| | - Xing Li
- Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; These authors contributed equally to this work
| | - Li Li
- Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; These authors contributed equally to this work
| | - Matthew Dodson
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
| | - Donna D Zhang
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
| | - Hongting Zheng
- Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
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15
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Haga S, Kanno A, Ozawa T, Morita N, Asano M, Ozaki M. Detection of Necroptosis in Ligand-Mediated and Hypoxia-Induced Injury of Hepatocytes Using a Novel Optic Probe-Detecting Receptor-Interacting Protein (RIP)1/RIP3 Binding. Oncol Res 2017; 26:503-513. [PMID: 28770700 PMCID: PMC7844641 DOI: 10.3727/096504017x15005102445191] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Liver injury is often observed in various pathological conditions including posthepatectomy state and cancer chemotherapy. It occurs mainly as a consequence of the combined necrotic and apoptotic types of cell death. In order to study liver/hepatocyte injury by the necrotic type of cell death, we studied signal-regulated necrosis (necroptosis) by developing a new optic probe for detecting receptor-interacting protein kinase 1 (RIP)/RIP3 binding, an essential process for necroptosis induction. In the mouse hepatocyte cell line, TIB-73 cells, TNF-α/cycloheximide (T/C) induced RIP1/3 binding only when caspase activity was suppressed by the caspase-specific inhibitor z-VAD-fmk (zVAD). T/C/zVAD-induced RIP1/3 binding was inhibited by necrostatin-1 (Nec-1), an allosteric inhibitor of RIP1. The reduced cell survival by T/C/zVAD was improved by Nec-1. These facts indicate that T/C induces necroptosis of hepatocytes when the apoptotic pathway is inhibited/unavailable. FasL also induced cell death, which was only partially inhibited by zVAD, indicating the possible involvement of necroptosis rather than apoptosis. FasL activated caspase 3 and, similarly, induced RIP1/3 binding when the caspases were inactivated. Interestingly, FasL-induced RIP1/3 binding was significantly suppressed by the antioxidants Trolox and N-acetyl cysteine (NAC), suggesting the involvement of reactive oxygen species (ROS) in FasL-induced necroptotic cellular processes. H₂O₂, by itself, induced RIP1/3 binding that was suppressed by Nec-1, but not by zVAD. Hypoxia induced RIP1/3 binding after reoxygenation, which was suppressed by Nec-1 or by the antioxidants. Cell death induced by hypoxia/reoxygenation (H/R) was also improved by Nec-1. Similar to H₂O₂, H/R did not require caspase inhibition for RIP1/3 binding, suggesting the involvement of a caspase-independent mechanism for non-ligand-induced and/or redox-mediated necroptosis. These data indicate that ROS can induce necroptosis and mediate the FasL- and hypoxia-induced necroptosis via a molecular mechanism that differs from a conventional caspase-dependent pathway. In conclusion, necroptosis is potentially involved in liver/hepatocyte injury induced by oxidative stress and FasL in the absence of apoptosis.
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Affiliation(s)
- Sanae Haga
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido UniversitySapporoJapan
| | - Akira Kanno
- Department of Environmental Applied Chemistry, Faculty of Engineering, University of ToyamaToyamaJapan
| | - Takeaki Ozawa
- Department of Chemistry, School of Science, The University of TokyoTokyoJapan
| | - Naoki Morita
- Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)Sapporo, HokkaidoJapan
| | - Mami Asano
- Laboratory of Molecular and Functional Bio-Imaging, Faculty of Health Sciences, Hokkaido UniversitySapporoJapan
| | - Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido UniversitySapporoJapan
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Haga S, Yimin, Ozaki M. Relevance of FXR-p62/SQSTM1 pathway for survival and protection of mouse hepatocytes and liver, especially with steatosis. BMC Gastroenterol 2017; 17:9. [PMID: 28086800 PMCID: PMC5237313 DOI: 10.1186/s12876-016-0568-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 12/27/2016] [Indexed: 01/12/2023] Open
Abstract
Background Liver injury and regeneration involve complicated processes and are affected by various physio-pathological conditions. Surgically, severe liver injury after surgical resection often leads to fatal liver failure, especially with some underlying pathological conditions such as steatosis. Therefore, protection from the injury of hepatocytes and liver is a serious concern in various clinical settings. Methods We studied the effects of the farnesoid X receptor (FXR) on cell survival and steatosis in mouse hepatocytes (AML12 mouse liver cells) and investigated their molecular mechanisms. We next studied whether or not FXR improves liver injury, regeneration and steatosis in a mouse model of partial hepatectomy (PH) with steatosis. Results An FXR-specific agonist, GW4064, induced expressions of the p62/SQSTM1 gene and protein in AML12 mouse liver cells. Because we previously reported p62/SQSTM1 as a key molecule for antioxidation and cell survival in hepatocytes, we next examined the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) and induction of the antioxidant molecules by GW4064. GW4064 activated Nrf2 and subsequently induced antioxidant molecules (Nrf2, catalase, HO-1, and thioredoxin). We also examined expressions of pro-survival and cell protective molecules associated with p62/SQSTM1. Expectedly, GW4064 induced phosphorylation of Akt, expression of the anti-apoptotic
molecules (Bcl-xL and Bcl-2), and reduced harmful hepatic molecules (Fas ligand and Fas). GW4064 promoted
hepatocyte survival, which was cancelled by p62/SQSTM1 siRNA. These findings suggest the potential relevance of the FXR-p62/SQSTM1 pathway for the survival and protection of hepatocytes. Furthermore, GW4064 induced the expression of small heterodimer partners (SHP) and suppressed liver X receptor (LXR)-induced steatosis in hepatocytes, expecting the in vivo protective effect of FXR on liver injury especially with steatosis. In the hepatectomy model of db/db mice with fatty liver, pre-treatment by GW4064 significantly reduced post-PH liver injury (serum levels of LDH, AST & ALT and histological study) and improved steatosis. The key molecules, p62/SQSTM1, Nrf2 and SHP were upregulated in fatty liver tissue by GW4064 treatment. Conclusions The present study is the first to demonstrate the relevance of FXR-p62/SQSTM1 and -SHP in the protection against injury of hepatocytes and post-PH liver, especially with steatosis. Electronic supplementary material The online version of this article (doi:10.1186/s12876-016-0568-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sanae Haga
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N-12, W-5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan
| | - Yimin
- Department of Advanced Medicine, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N-12, W-5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
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17
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Moon JH, Lee JH, Lee YJ, Park SY. Autophagy flux induced by ginsenoside-Rg3 attenuates human prion protein-mediated neurotoxicity and mitochondrial dysfunction. Oncotarget 2016; 7:85697-85708. [PMID: 27911875 PMCID: PMC5349867 DOI: 10.18632/oncotarget.13730] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 11/11/2016] [Indexed: 12/19/2022] Open
Abstract
Mitochondrial quality control is a process by which mitochondria undergo successive rounds of fusion and fission with dynamic exchange of components to segregate functional and damaged elements. Removal of mitochondrion that contains damaged components is accomplished via autophagy. In this study, we investigated whether ginsenoside Rg3, an active ingredient of the herbal medicine ginseng that is used as a tonic and restorative agent, could attenuate prion peptide, PrP (106-126)-induced neurotoxicity and mitochondrial damage. To this end, western blot and GFP-LC3B puncta assay were performed to monitor autophagy flux in neuronal cells; LC3B-II protein level was found to increase after Rg3 treatment. In addition, electron microscopy analysis showed that Rg3 enhanced autophagic vacuoles in neuronal cells. By using autophagy inhibitors wortmannin and 3-methyladenine (3MA) or autophagy protein 5 (Atg5) small interfering RNA (siRNA), we demonstrated that Rg3 could protect neurons against PrP (106-126)-induced cytotoxicity via autophagy flux. We found that Rg3 could also attenuate PrP (106-126)-induced mitochondrial damage via autophagy flux. Taken together, our results suggest that Rg3 is a possible therapeutic agent in neurodegenerative disorders, including prion diseases.
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Affiliation(s)
- Ji-Hong Moon
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea
| | - Ju-Hee Lee
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea
| | - You-Jin Lee
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea
| | - Sang-Youel Park
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea
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18
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Nagakannan P, Iqbal MA, Yeung A, Thliveris JA, Rastegar M, Ghavami S, Eftekharpour E. Perturbation of redox balance after thioredoxin reductase deficiency interrupts autophagy-lysosomal degradation pathway and enhances cell death in nutritionally stressed SH-SY5Y cells. Free Radic Biol Med 2016; 101:53-70. [PMID: 27693380 DOI: 10.1016/j.freeradbiomed.2016.09.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 09/24/2016] [Accepted: 09/25/2016] [Indexed: 01/25/2023]
Abstract
Oxidative damage and aggregation of cellular proteins is a hallmark of neuronal cell death after neurotrauma and chronic neurodegenerative conditions. Autophagy and ubiquitin protease system are involved in degradation of protein aggregates, and interruption of their function is linked to apoptotic cell death in these diseases. Oxidative modification of cysteine groups in key molecular proteins has been linked to modification of cellular systems and cell death in these conditions. Glutathione and thioredoxin systems provide reducing protons that can effectively reverse protein modifications and promote cell survival. The central role of Thioredoxin in inhibition of apoptosis is well identified. Additionally, its involvement in initiation of autophagy has been suggested recently. We therefore aimed to investigate the involvement of Thioredoxin system in autophagy-apoptosis processes. A model of serum deprivation in SH-SY5Y was used that is associated with autophagy and apoptosis. Using pharmacological and RNA-editing technology we show that Thioredoxin reductase deficiency in this model enhances oxidative stress and interrupts the early protective autophagy and promotes apoptosis. This was associated with decreased protein-degradation in lysosomes due to altered lysosomal acidification and accumulation of autophagosomes as well as impairment in proteasome pathway. We further confirmed that the extent of oxidative stress is a determining factor in autophagy- apoptosis interplay, as upregulation of cellular reducing capacity by N-acetylcysteine prevented impairment in autophagy and proteasome systems thus promoted cell viability. Our study provides evidence that excessive oxidative stress inhibits protein degradation systems and affects the final stages of autophagy by inhibiting autolysosome maturation: a novel mechanistic link between protein aggregation and conversion of autophagy to apoptosis that can be applicable to neurodegenerative diseases.
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Affiliation(s)
- Pandian Nagakannan
- Spinal Cord Research Center, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Regenerative Medicine Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Mohamed Ariff Iqbal
- Spinal Cord Research Center, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Regenerative Medicine Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Albert Yeung
- Spinal Cord Research Center, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Regenerative Medicine Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - James A Thliveris
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Mojgan Rastegar
- Department of Biochemistry & Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Regenerative Medicine Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Eftekhar Eftekharpour
- Spinal Cord Research Center, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Regenerative Medicine Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
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19
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Taniguchi K, Yamachika S, He F, Karin M. p62/SQSTM1-Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer. FEBS Lett 2016; 590:2375-97. [PMID: 27404485 DOI: 10.1002/1873-3468.12301] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 07/08/2016] [Accepted: 07/09/2016] [Indexed: 12/17/2022]
Abstract
p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses, and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.
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Affiliation(s)
- Koji Taniguchi
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, USA.,Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Shinichiro Yamachika
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, USA
| | - Feng He
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, USA
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20
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Moon JH, Lee JH, Lee YJ, Park SY. Hinokitiol protects primary neuron cells against prion peptide-induced toxicity via autophagy flux regulated by hypoxia inducing factor-1. Oncotarget 2016; 7:29944-57. [PMID: 27074563 PMCID: PMC5058655 DOI: 10.18632/oncotarget.8670] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 03/31/2016] [Indexed: 12/19/2022] Open
Abstract
Prion diseases are fatal neurodegenerative disorders that are derived from structural changes of the native PrPc. Recent studies indicated that hinokitiol induced autophagy known to major function that keeps cells alive under stressful conditions. We investigated whether hinokitiol induces autophagy and attenuates PrP (106-126)-induced neurotoxicity. We observed increase of LC3-II protein level, GFP-LC3 puncta by hinokitiol in neuronal cells. Addition to, electron microscopy showed that hinokitiol enhanced autophagic vacuoles in neuronal cells. We demonstrated that hinokitiol protects against PrP (106-126)-induced neurotoxicity via autophagy by using autophagy inhibitor, wortmannin and 3MA, and ATG5 small interfering RNA (siRNA). We checked hinokitiol activated the hypoxia-inducible factor-1α (HIF-1α) and identified that hinokitiol-induced HIF-1α regulated autophagy. Taken together, this study is the first report demonstrating that hinokitiol protected against prion protein-induced neurotoxicity via autophagy regulated by HIF-1α. We suggest that hinokitiol is a possible therapeutic strategy in neuronal disorders including prion disease.
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Affiliation(s)
- Ji-Hong Moon
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea
| | - Ju-Hee Lee
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea
| | - You-Jin Lee
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea
| | - Sang-Youel Park
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea
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Bartz RR, Suliman HB, Piantadosi CA. Redox mechanisms of cardiomyocyte mitochondrial protection. Front Physiol 2015; 6:291. [PMID: 26578967 PMCID: PMC4620408 DOI: 10.3389/fphys.2015.00291] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Accepted: 10/02/2015] [Indexed: 12/30/2022] Open
Abstract
Oxidative and nitrosative stress are primary contributors to the loss of myocardial tissue in insults ranging from ischemia/reperfusion injury from coronary artery disease and heart transplantation to sepsis-induced myocardial dysfunction and drug-induced myocardial damage. This cell damage caused by oxidative and nitrosative stress leads to mitochondrial protein, DNA, and lipid modifications, which inhibits energy production and contractile function, potentially leading to cell necrosis and/or apoptosis. However, cardiomyocytes have evolved an elegant set of redox-sensitive mechanisms that respond to and contain oxidative and nitrosative damage. These responses include the rapid induction of antioxidant enzymes, mitochondrial DNA repair mechanisms, selective mitochondrial autophagy (mitophagy), and mitochondrial biogenesis. Coordinated cytoplasmic to nuclear cell-signaling and mitochondrial transcriptional responses to the presence of elevated cytoplasmic oxidant production, e.g., H2O2, allows nuclear translocation of the Nfe2l2 transcription factor and up-regulation of downstream cytoprotective genes such as heme oxygenase-1 which generates physiologic signals, such as CO that up-regulates Nfe212 gene transcription. Simultaneously, a number of other DNA binding transcription factors are expressed and/or activated under redox control, such as Nuclear Respiratory Factor-1 (NRF-1), and lead to the induction of genes involved in both intracellular and mitochondria-specific repair mechanisms. The same insults, particularly those related to vascular stress and inflammation also produce elevated levels of nitric oxide, which also has mitochondrial protein thiol-protective functions and induces mitochondrial biogenesis through cyclic GMP-dependent and perhaps other pathways. This brief review provides an overview of these pathways and interconnected cardiac repair mechanisms.
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Affiliation(s)
- Raquel R Bartz
- Department of Anesthesiology, Duke University School of Medicine Durham, NC, USA ; Department of Medicine, Duke University School of Medicine Durham, NC, USA
| | - Hagir B Suliman
- Department of Anesthesiology, Duke University School of Medicine Durham, NC, USA ; Department of Pathology, Duke University School of Medicine Durham, NC, USA
| | - Claude A Piantadosi
- Department of Anesthesiology, Duke University School of Medicine Durham, NC, USA ; Department of Medicine, Duke University School of Medicine Durham, NC, USA ; Department of Pathology, Duke University School of Medicine Durham, NC, USA ; Durham Veterans Affairs Hospital Durham, NC, USA
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