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Holmes TL, Chabronova A, Denning C, James V, Peffers MJ, Smith JGW. Footprints in the Sno: investigating the cellular and molecular mechanisms of SNORD116. Open Biol 2025; 15:240371. [PMID: 40101781 PMCID: PMC11919532 DOI: 10.1098/rsob.240371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/11/2025] [Accepted: 02/04/2025] [Indexed: 03/20/2025] Open
Abstract
The small nucleolar RNA (snoRNA) SNORD116 is a small non-coding RNA of interest across multiple biomedical fields of research. Much of the investigation into SNORD116 has been undertaken in the context of the congenital disease Prader-Willi syndrome, wherein SNORD116 expression is lost. However, emerging evidence indicates wider roles in various disease and tissue contexts such as cellular growth, metabolism and signalling. Nevertheless, a conclusive mechanism of action for SNORD116 remains to be established. Here, we review the key findings from these investigations, with the aim of identifying common elements from which to elucidate potential targets and mechanisms of SNORD116. A key recurring element identified is disruption to the insulin/IGF-1 and PI3K/mTOR signalling pathways, contributing to many of the phenotypes associated with SNORD116 modulation explored in this review.
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Affiliation(s)
- Terri L. Holmes
- Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich, NorfolkNR4 7UQ, UK
| | - Alzbeta Chabronova
- Department of Musculoskeletal Ageing Science, University of Liverpool, Liverpool, UK
| | - Chris Denning
- Department of Stem Cell Biology, University of Nottingham, Nottingham, UK
| | - Victoria James
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK
| | - Mandy J. Peffers
- Department of Musculoskeletal Ageing Science, University of Liverpool, Liverpool, UK
| | - James G. W. Smith
- Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich, NorfolkNR4 7UQ, UK
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Li Y, Huang J, Ge C, Zhu S, Wang H, Zhang Y. The effects of prenatal azithromycin exposure on offspring ovarian development at different stages, doses, and courses. Biomed Pharmacother 2024; 172:116246. [PMID: 38359487 DOI: 10.1016/j.biopha.2024.116246] [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: 11/29/2023] [Revised: 01/29/2024] [Accepted: 02/01/2024] [Indexed: 02/17/2024] Open
Abstract
Azithromycin, a commonly used macrolide antibiotic for treating chlamydial infections during pregnancy, has sparked investigations into its potential effects on offspring development. Despite these inquiries, there remains uncertainty about the specific impact of prenatal azithromycin exposure (PAzE) on offspring ovarian development and the precise "effect window". Pregnant mice, following clinical guidelines for azithromycin dosing, were orally administered azithromycin at different gestational stages [(gestational day, GD) 10-12 or GD 15-17], doses (50, 100, or 200 mg/kg·d), and courses (single or multiple). On GD 18, we collected offspring blood and ovaries to examine changes in fetal serum estradiol (E2) levels, fetal ovarian morphology, pre-granulosa cell function, and oocyte development. Multiple courses of PAzE resulted in abnormal fetal ovarian morphological development, disorganized germ cell nests, enhanced ovarian cell proliferation, and reduced apoptosis. Simultaneously, multiple courses of PAzE significantly increased fetal serum E2 levels, elevated ovarian steroidogenic function (indicated by Star, 3β-hsd, and Cyp19 expression), disrupted oocyte development (indicated by Figlα and Nobox expression), and led to alterations in the MAPK signal pathway in fetal ovaries, particularly in the high-dose treatment group. In contrast, a single course of PAzE reduced fetal ovarian cell proliferation, decreased steroidogenic function, and inhibited oocyte development, particularly through the downregulation of Mek2 expression in the MAPK signal pathway. These findings suggest that PAzE can influence various aspects of fetal mouse ovarian cell development. Multiple courses enhance pre-granulosa cell estrogen synthesis function and advance germ cell development, while a single terminal gestation dose inhibits germ cell development. These differential effects may be associated with changes in the MAPK signal pathway.
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Affiliation(s)
- Yating Li
- Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Jing Huang
- Department of Otorhinolaryngology Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
| | - Caiyun Ge
- Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
| | - Sen Zhu
- Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China
| | - Hui Wang
- Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
| | - Yuanzhen Zhang
- Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
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Chew HY, Cvetkovic G, Tepic S, Wells JW. Arginase-induced cell death pathways and metabolic changes in cancer cells are not altered by insulin. Sci Rep 2024; 14:4112. [PMID: 38374190 PMCID: PMC10876525 DOI: 10.1038/s41598-024-54520-z] [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: 11/03/2023] [Accepted: 02/13/2024] [Indexed: 02/21/2024] Open
Abstract
Arginine, a semi-essential amino acid, is critical for cell growth. Typically, de novo synthesis of arginine is sufficient to support cellular processes, however, it becomes vital for cancer cells that are unable to synthesise arginine due to enzyme deficiencies. Targeting this need, arginine depletion with enzymes such as arginase (ARG) has emerged as a potential cancer therapeutic strategy. Studies have proposed using high dose insulin to induce a state of hypoaminoacidaemia in the body, thereby further reducing circulating arginine levels. However, the mitogenic and metabolic properties of insulin could potentially counteract the therapeutic effects of ARG. Our study examined the combined impact of insulin and ARG on breast, lung, and ovarian cell lines, focusing on cell proliferation, metabolism, apoptosis, and autophagy. Our results showed that the influence of insulin on ARG uptake varied between cell lines but failed to promote the proliferation of ARG-treated cells or aid recovery post-ARG treatment. Moreover, insulin was largely ineffective in altering ARG-induced metabolic changes and did not prevent apoptosis. In vitro, at least, these findings imply that insulin does not offer a growth or survival benefit to cancer cells being treated with ARG.
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Affiliation(s)
- Hui Yi Chew
- Faculty of Medicine, Frazer Institute, The University of Queensland, 37 Kent Street, Brisbane, QLD, 4102, Australia
| | | | | | - James W Wells
- Faculty of Medicine, Frazer Institute, The University of Queensland, 37 Kent Street, Brisbane, QLD, 4102, Australia.
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de Oliveira Pereira FS, Santos AG, Neto JSS, Silva GMM, Pinton S, Zeni GR, Nogueira CW, Ávila DS, Quines CB. (p-ClPhSe) 2 modulation on carbohydrate and lipid metabolism requires the insulin-like signaling in Caenorhabditis elegans. Biochem Biophys Res Commun 2024; 696:149514. [PMID: 38237233 DOI: 10.1016/j.bbrc.2024.149514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 02/02/2024]
Abstract
Organoselenium compounds modulate the metabolism by regulating carbohydrate and lipid syntheses and degradation in the liver, muscle, and adipose tissue. Notably, p-chloro-diphenyl diselenide (p-ClPhSe)2 can directly regulate the activities of enzymes involved in glucose metabolism, suggesting an insulin-like effect in rodents; however, there is still a lack of scientific evidence to confirm this hypothesis. The objective of this study was to investigate (p-ClPhSe)2 effects on glucose and lipid metabolism in Caenorhabditis elegans. The contribution of AGE-1/PI3K, AKT-1, AKT-2, PFK-1, DAF-16, and DAF-2 in the (p-ClPhSe)2 effects were also investigated. Our results demonstrate that (p-ClPhSe)2 acute exposure presented some toxicity to the worms, and therefore, lower concentrations were further used. (p-ClPhSe)2 reduced glucose and triglyceride levels to the baseline levels, after induction with glucose or fructose, in wild-type worms. This effect required proteins involved in the insulin/IGF-1 like signaling, such as the DAF-2, AGE-1, AKT-1 and AKT-2, PFK-1, but also DAF-16, which would be negatively regulated by DAF-2 activation. Moreover, the reduction in glucose and triglyceride levels, caused by (p-ClPhSe)2per se was lost in age-1/daf-16 worms, suggesting that insulin/IGF-1-like signaling in a DAF-2 and AGE-1/DAF-16 dependent-manner in C. elegans are necessary to effects of (p-ClPhSe)2. In conclusion, (p-ClPhSe)2 requires proteins involved in the IIS pathway to modulate carbohydrate and lipid metabolism.
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Affiliation(s)
| | | | - José S S Neto
- Chemistry Institute, Federal University of Goiás, Goiânia, GO, Brazil.
| | | | - Simone Pinton
- Federal University of Pampa, Uruguaiana, RS, Brazil.
| | - Gilson R Zeni
- Federal University of Santa Maria, Santa Maria, RS, Brazil.
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Talati CP, Lee JW, Lu S, Ojeda NB, Prakash V, Dankhara N, Nielson TC, Sandifer SP, Bidwell GL, Pang Y, Fan LW, Bhatt AJ. Intranasal insulin attenuates hypoxia-ischemia-induced short-term sensorimotor behavioral disturbances, neuronal apoptosis, and brain damage in neonatal rats. CURRENT RESEARCH IN NEUROBIOLOGY 2023; 6:100123. [PMID: 38235171 PMCID: PMC10793091 DOI: 10.1016/j.crneur.2023.100123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/10/2023] [Accepted: 12/14/2023] [Indexed: 01/19/2024] Open
Abstract
There is a significant need for additional therapy to improve outcomes for newborns with acute Hypoxic-ischemic (HI) encephalopathy (HIE). New evidence suggests that insulin could be neuroprotective. This study aimed to investigate whether intranasal insulin attenuates HI-induced brain damage and neurobehavioral dysfunction in neonatal rats. Postnatal day 10 (P10), Sprague-Dawley rat pups were randomly divided into Sham + Vehicle, Sham + Insulin, HI + Vehicle, and HI + Insulin groups with equal male-to-female ratios. Pups either had HI by permanent ligation of the right common carotid artery followed by 90 min of hypoxia (8% O2) or sham surgery followed by room air exposure. Immediately after HI or Sham, pups were given fluorescence-tagged insulin (Alex-546-insulin)/vehicle, human insulin (25 μg), or vehicle in each nare under anesthesia. Shortly after administration, widespread Alex-546-insulin-binding cells were detected in the brain, primarily co-localized with neuronal nuclei-positive neurons on double-immunostaining. In the hippocampus, phospho-Akt was activated in a subset of Alex-546-insulin double-labeled cells, suggesting activation of the Akt/PI3K pathway in these neurons. Intranasal insulin (InInsulin) reduced HI-induced sensorimotor behavioral disturbances at P11. InInsulin prevented HI-induced increased Fluoro-Jade C+ degenerated neurons, cleaved caspase 3+ neurons, and volume loss in the ipsilateral brain at P11. There was no sex-specific response to HI or insulin. The findings confirm that intranasal insulin provides neuroprotection against HI brain injury in P10 rats associated with activation of intracellular cell survival signaling. If further pre-clinical research shows long-term benefits, intranasal insulin has the potential to be a promising non-invasive therapy to improve outcomes for newborns with HIE.
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Affiliation(s)
- Chirag P. Talati
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Jonathan W. Lee
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Silu Lu
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Department of Neurology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Norma B. Ojeda
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Varsha Prakash
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Nilesh Dankhara
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Tanner C. Nielson
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Sara P. Sandifer
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Gene L. Bidwell
- Department of Neurology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Yi Pang
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Lir-Wan Fan
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Abhay J. Bhatt
- Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
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Na D, Lim DH, Hong JS, Lee HM, Cho D, Yu MS, Shaker B, Ren J, Lee B, Song JG, Oh Y, Lee K, Oh KS, Lee MY, Choi MS, Choi HS, Kim YH, Bui JM, Lee K, Kim HW, Lee YS, Gsponer J. A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration. Mol Syst Biol 2023; 19:e11801. [PMID: 37984409 DOI: 10.15252/msb.202311801] [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: 06/05/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 11/22/2023] Open
Abstract
The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3β), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.
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Affiliation(s)
- Dokyun Na
- Department of Biomedical Engineering, Chung-Ang University, Seoul, Republic of Korea
| | - Do-Hwan Lim
- College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
- School of Systems Biomedical Science, Soongsil University, Seoul, Republic of Korea
| | - Jae-Sang Hong
- College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Hyang-Mi Lee
- Department of Biomedical Engineering, Chung-Ang University, Seoul, Republic of Korea
| | - Daeahn Cho
- Department of Biomedical Engineering, Chung-Ang University, Seoul, Republic of Korea
| | - Myeong-Sang Yu
- Department of Biomedical Engineering, Chung-Ang University, Seoul, Republic of Korea
| | - Bilal Shaker
- Department of Biomedical Engineering, Chung-Ang University, Seoul, Republic of Korea
| | - Jun Ren
- Department of Biomedical Engineering, Chung-Ang University, Seoul, Republic of Korea
| | - Bomi Lee
- College of Life Sciences, Sejong University, Seoul, Republic of Korea
| | - Jae Gwang Song
- College of Life Sciences, Sejong University, Seoul, Republic of Korea
| | - Yuna Oh
- Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Kyungeun Lee
- Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Kwang-Seok Oh
- Information-based Drug Research Center, Korea Research Institute of Chemical Technology, Deajeon, Republic of Korea
| | - Mi Young Lee
- Information-based Drug Research Center, Korea Research Institute of Chemical Technology, Deajeon, Republic of Korea
| | - Min-Seok Choi
- College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Han Saem Choi
- College of Life Sciences, Sejong University, Seoul, Republic of Korea
| | - Yang-Hee Kim
- College of Life Sciences, Sejong University, Seoul, Republic of Korea
| | - Jennifer M Bui
- Department of Biochemistry and Molecular Biology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
| | - Kangseok Lee
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Hyung Wook Kim
- College of Life Sciences, Sejong University, Seoul, Republic of Korea
| | - Young Sik Lee
- College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Jörg Gsponer
- Department of Biochemistry and Molecular Biology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
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7
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Yap KY, Chi H, Ng S, Ng DHL, Shelat VG. Effect of perioperative branched chain amino acids supplementation in liver cancer patients undergoing surgical intervention: A systematic review. World J Gastrointest Surg 2023; 15:2596-2618. [PMID: 38111761 PMCID: PMC10725538 DOI: 10.4240/wjgs.v15.i11.2596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/15/2023] [Accepted: 10/23/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Branched chain amino acid (BCAA) supplementation has been associated with favourable outcomes in liver malignancies requiring definitive resection or liver transplantation. Currently, there are no updated systematic reviews evaluating the efficacy of perioperative BCAA supplementation in patients undergoing surgery for liver cancer. AIM To evaluate the efficacy of perioperative BCAA supplementation in patients undergoing surgery for liver cancer. METHODS A systematic review of randomized control trials and observational studies was conducted on PubMed, Embase, Cochrane Library, Scopus, and Web of Science to evaluate the effect of perioperative BCAA supplementation compared to standard in-hospital diet, in liver cancer patients undergoing surgery. Clinical outcomes were extracted, and a meta-analysis was performed on relevant outcomes. RESULTS 16 studies including 1389 patients were included. Perioperative BCAA administration was associated with reduced postoperative infection [risk ratio (RR) = 0.58 95% confidence intervals (CI): 0.39 to 0.84, P = 0.005] and ascites [RR = 0.57 (95%CI: 0.38 to 0.85), P = 0.005]. There was also a reduction in length of hospital stay (LOS) [weighted mean difference (WMD) = -3.03 d (95%CI: -5.49 to -0.57), P = 0.02] and increase in body weight [WMD = 1.98 kg (95%CI: 0.35 to 3.61, P = 0.02]. No significant differences were found in mortality, cancer recurrence and overall survival. No significant safety concerns were identified. CONCLUSION Perioperative BCAA administration is efficacious in reducing postoperative infection, ascites, LOS, and increases body weight in liver cancer patients undergoing surgical resection.
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Affiliation(s)
- Kwan Yi Yap
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - HongHui Chi
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Sherryl Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Doris HL Ng
- Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, Singapore 308433, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore
| | - Vishal G Shelat
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
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Yan J, Xie B, Tian Y, Huang L, Zou S, Peng Z, Liu Z, Li L. iTRAQ-Based Proteome Profiling of Differentially Expressed Proteins in Insulin-Resistant Human Hepatocellular Carcinoma. Front Cell Dev Biol 2022; 10:836041. [PMID: 35281088 PMCID: PMC8914942 DOI: 10.3389/fcell.2022.836041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/11/2022] [Indexed: 11/13/2022] Open
Abstract
Recently, the incidences of insulin resistance (IR) and IR-related complications have increased throughout the world, which also associate with poor prognosis in hepatocellular carcinoma (HCC). Numerous studies had been focused on the role of IR in tumorigenesis and prognosis of HCC. The proteomic analysis of IR related hepatocellular carcinoma had not been reported by now. In the present study, 196 differentially expressed proteins (DEPs) were identified between insulin resistant HepG2 cells and their parental cells, of which 109 proteins were downregulated and 87 proteins were upregulated. Bioinformatics analysis indicated that these DEPs were highly enriched in process of tumorigenesis and tumor progression. PPI network analysis showed that SOX9, YAP1 and GSK3β as the key nodes, were involved in Wnt and Hippo signaling pathways. Survival analysis revealed that high expression of SOX9 and PRKD3 were strongly associated with reduced patient survival rate. parallel reaction monitoring (PRM) and Western blot analysis were applied to verify the protein level of these four key nodes mentioned above, which showed the same trend as quantified by isobaric tags for relative and absolute quantitation (iTRAQ) and confirmed the reliability of our Proteome Profiling analysis. Our results indicated that IR related dysregulation of protein expression might participated in tumorigenesis and malignant phenotype of hepatocarcinoma cells.
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Affiliation(s)
- Jing Yan
- Department of Clinical Laboratory Center, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Bei Xie
- Department of Medical Laboratory Animal Science, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Ye Tian
- Department of Clinical Laboratory Center, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Li Huang
- Department of Pediatric Nephrology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Shuli Zou
- Department of Medicine, Brookdale University Hospital Medical Center, Brooklyn, NY, United States
| | - Zhiheng Peng
- Department of Clinical Laboratory Center, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhuan Liu
- Department of Clinical Laboratory Center, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Linjing Li
- Department of Clinical Laboratory Center, The Second Hospital of Lanzhou University, Lanzhou, China
- *Correspondence: Linjing Li,
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Abstract
Endotoxaemia is an inflammatory condition which happens due to the presence of outer cell wall layer of Gram-negative bacteria in blood circulation, containing lipopolysaccharide commonly known as endotoxin. This condition causes high mortality in affected animals and sheep are highly susceptible in this regard. Several researchers have emphasised the therapeutic regimens of endotoxaemia and its sequels in sheep. Furthermore, sheep are among the most commonly used animal species in experimental studies on endotoxaemia, and for the past five decades, ovine models have been employed to evaluate different aspects of endotoxaemia. Currently, there are several studies on experimentally induced endotoxaemia in sheep, and information regarding novel therapeutic protocols in this species contributes to better understanding and treating the condition. This review aims to specifically introduce various treatment methods of endotoxaemia in sheep.
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Affiliation(s)
- A. Chalmeh
- Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
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10
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Girdhar K, Powis A, Raisingani A, Chrudinová M, Huang R, Tran T, Sevgi K, Dogus Dogru Y, Altindis E. Viruses and Metabolism: The Effects of Viral Infections and Viral Insulins on Host Metabolism. Annu Rev Virol 2021; 8:373-391. [PMID: 34586876 PMCID: PMC9175272 DOI: 10.1146/annurev-virology-091919-102416] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Over the past decades, there have been tremendous efforts to understand the cross-talk between viruses and host metabolism. Several studies have elucidated the mechanisms through which viral infections manipulate metabolic pathways including glucose, fatty acid, protein, and nucleotide metabolism. These pathways are evolutionarily conserved across the tree of life and extremely important for the host's nutrient utilization and energy production. In this review, we focus on host glucose, glutamine, and fatty acid metabolism and highlight the pathways manipulated by the different classes of viruses to increase their replication. We also explore a new system of viral hormones in which viruses mimic host hormones to manipulate the host endocrine system. We discuss viral insulin/IGF-1-like peptides and their potential effects on host metabolism. Together, these pathogenesis mechanisms targeting cellular signaling pathways create a multidimensional network of interactions between host and viral proteins. Defining and better understanding these mechanisms will help us to develop new therapeutic tools to prevent and treat viral infections.
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Affiliation(s)
- Khyati Girdhar
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Amaya Powis
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Amol Raisingani
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Martina Chrudinová
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Ruixu Huang
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Tu Tran
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Kaan Sevgi
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Yusuf Dogus Dogru
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Emrah Altindis
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
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11
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Abhinav RP, Williams J, Livingston P, Anjana RM, Mohan V. Burden of diabetes and oral cancer in India. J Diabetes Complications 2020; 34:107670. [PMID: 32651032 DOI: 10.1016/j.jdiacomp.2020.107670] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 06/26/2020] [Indexed: 02/07/2023]
Abstract
Oral cancer and diabetes are highly prevalent among the Indian population and are part of the top four non-communicable diseases responsible for mortality and morbidity. Their numbers are so great that they pose a unique burden to the socioeconomic growth of the country. In recent years, there has been an increase in the number of studies examining the role of diabetes in oral cancer reporting co-existence of diabetes and cancer. There is also growing evidence of a higher risk for developing a number of cancers among individuals with diabetes, including pancreatic, liver, gynecologic, colorectal, oral and breast cancer, and consequently 'diabetic oncopathy' is emerging as one of the complications of diabetes. Diabetes may lead to the development of cancer through oxidative damage leading to accumulation of DNA mutations and/or through immune dysfunction, which predisposes to viral infection. Cancer and diabetes may co-occur due to shared risk factors such as increased insulin-like growth factor-1 and obesity, but there is no clear biologic link between the two disorders. This literature review aims to review the evidence showing the current burden of two non-communicable diseases, diabetes and oral cancer and their potential association, with particular reference to India.
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Affiliation(s)
- Rajendra Prabhu Abhinav
- School of Health and Social Development, Deakin University, Geelong, Victoria, Australia; Madras Diabetes Research Foundation, Chennai, India
| | - Joanne Williams
- School of Health and Social Development, Deakin University, Geelong, Victoria, Australia
| | - Patricia Livingston
- School of Nursing and Midwifery, Deakin University, Geelong, Victoria, Australia
| | - Ranjit Mohan Anjana
- Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, Chennai, India
| | - Viswanathan Mohan
- Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, Chennai, India.
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12
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Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis. Biomolecules 2020; 10:biom10030402. [PMID: 32150849 PMCID: PMC7175142 DOI: 10.3390/biom10030402] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/26/2020] [Accepted: 03/02/2020] [Indexed: 12/13/2022] Open
Abstract
Apoptosis is the physiological mechanism of cell death and can be modulated by endogenous and exogenous factors, including stress and metabolic alterations. Reactive oxygen species (ROS), as well as ROS-dependent lipid peroxidation products (including isoprostanes and reactive aldehydes including 4-hydroxynonenal) are proapoptotic factors. These mediators can activate apoptosis via mitochondrial-, receptor-, or ER stress-dependent pathways. Phospholipid metabolism is also an essential regulator of apoptosis, producing the proapoptotic prostaglandins of the PGD and PGJ series, as well as the antiapoptotic prostaglandins of the PGE series, but also 12-HETE and 20-HETE. The effect of endocannabinoids and phytocannabinoids on apoptosis depends on cell type-specific differences. Cells where cannabinoid receptor type 1 (CB1) is the dominant cannabinoid receptor, as well as cells with high cyclooxygenase (COX) activity, undergo apoptosis after the administration of cannabinoids. In contrast, in cells where CB2 receptors dominate, and cells with low COX activity, cannabinoids act in a cytoprotective manner. Therefore, cell type-specific differences in the pro- and antiapoptotic effects of lipids and their (oxidative) products might reveal new options for differential bioanalysis between normal, functional, and degenerating or malignant cells, and better integrative biomedical treatments of major stress-associated diseases.
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Comparative Anti-inflammatory Effects of Insulin and Flunixin on Acute-Phase Responses and Cardiovascular Biomarkers During Inflammatory Phase in Miniature Donkeys. J Equine Vet Sci 2019; 81:102788. [PMID: 31668307 DOI: 10.1016/j.jevs.2019.102788] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 07/15/2019] [Accepted: 07/18/2019] [Indexed: 12/27/2022]
Abstract
The objective of this study was to comparatively evaluate the anti-inflammatory effects of intravenous administration of insulin (in different doses) and flunixin on physiological variables, acute-phase responses, and cardiovascular biomarkers during inflammatory phase which was induced by Escherichia coli lipopolysaccharide (LPS) serotype O55:B5 in miniature donkeys. A total of twenty-four clinically healthy male adult miniature donkeys aged 5 ± 1 year and weighing 120 ± 10 kg were studied. The animals were assigned randomly to four experimental groups (three treatment and one positive control groups). Six hours after induction of inflammatory phase (by 20 ng kg-1 LPS), donkeys in groups Insln 1.5, Insln 3, and Flnx received insulin at 1.5 IU kg-1, insulin at 3 IU kg-1, and flunixin at 2.2 mg kg-1, respectively. Animals in the positive control group were assigned to receive LPS without any anti-inflammatory drugs. We have shown that serum concentrations of cardiovascular, acute-phase proteins and cytokines were increased during inflammatory phase in miniature donkeys. Our results revealed that insulin at 3 IU kg-1 as well as flunixin at 2.2 mg kg-1 can improve almost all of the physiological variables and hematobiochemical variables (including serum concentrations of tumor necrosis factor-alpha, interferon-gamma, haptoglobin, serum amyloid A, cardiac troponin I, hemocysteine, white blood cell, and packed cell volume) after 24 hours. Unlike insulin at 1.5 IU kg-1, insulin at 3 IU kg-1 may be considered useful for inflammatory conditions in miniature donkeys.
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The wonders of BMP9: From mesenchymal stem cell differentiation, angiogenesis, neurogenesis, tumorigenesis, and metabolism to regenerative medicine. Genes Dis 2019; 6:201-223. [PMID: 32042861 PMCID: PMC6997590 DOI: 10.1016/j.gendis.2019.07.003] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/07/2019] [Accepted: 07/10/2019] [Indexed: 12/15/2022] Open
Abstract
Although bone morphogenetic proteins (BMPs) initially showed effective induction of ectopic bone growth in muscle, it has since been determined that these proteins, as members of the TGF-β superfamily, play a diverse and critical array of biological roles. These roles include regulating skeletal and bone formation, angiogenesis, and development and homeostasis of multiple organ systems. Disruptions of the members of the TGF-β/BMP superfamily result in severe skeletal and extra-skeletal irregularities, suggesting high therapeutic potential from understanding this family of BMP proteins. Although it was once one of the least characterized BMPs, BMP9 has revealed itself to have the highest osteogenic potential across numerous experiments both in vitro and in vivo, with recent studies suggesting that the exceptional potency of BMP9 may result from unique signaling pathways that differentiate it from other BMPs. The effectiveness of BMP9 in inducing bone formation was recently revealed in promising experiments that demonstrated efficacy in the repair of critical sized cranial defects as well as compatibility with bone-inducing bio-implants, revealing the great translational promise of BMP9. Furthermore, emerging evidence indicates that, besides its osteogenic activity, BMP9 exerts a broad range of biological functions, including stem cell differentiation, angiogenesis, neurogenesis, tumorigenesis, and metabolism. This review aims to summarize our current understanding of BMP9 across biology and the body.
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Gupta AP, Singh P, Garg R, Valicherla GR, Riyazuddin M, Syed AA, Hossain Z, Gayen JR. Pancreastatin inhibitor activates AMPK pathway via GRP78 and ameliorates dexamethasone induced fatty liver disease in C57BL/6 mice. Biomed Pharmacother 2019; 116:108959. [PMID: 31108350 DOI: 10.1016/j.biopha.2019.108959] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 05/02/2019] [Accepted: 05/03/2019] [Indexed: 12/16/2022] Open
Abstract
AIMS To investigate the role of pancreastatin inhibitor (PSTi8) in lipid homeostasis and insulin sensitivity in dexamethasone induced fatty liver disease associated type 2 diabetes. MAIN METHODS Glucose releases assay, lipid O staining and ATP/AMP ratio were performed in HepG2 cells. Twenty four mice were randomly divided into 4 groups: Control group (saline), DEX (1 mg/kg, im) for 17 days, DEX+PSTi8 (acute 5 mg/kg and chronic 2 mg/kg, ip) for 10 days. The glucose, insulin and pyruvate tolerance tests (GTT, ITT and PTT), biochemical parameters and Oxymax-CLAMS were performed. Further to elucidate the action mechanisms of PSTi8, we performed genes expression and western blotting of biological samples. KEY FINDINGS We found that PSTi8 suppresses hepatic glucose release, lipid deposition, oxidative stress induced by DEX, stimulates the cellular energy level in hepatocytes and enhances GRP78 activity. It reduces lipogensis and enhances fatty acid oxidation to improve insulin sensitivity and glucose tolerance in DEX induced diabetic mice. The above cellular effects are the result of activated AMPK signalling pathway in liver, which increases Srebp1c and ACC phosphorylation. The increased ACC phosphorylation suppresses protein kinase C activity and enhances insulin sensitivity. The increased expression of UCP3 in liver elicits fatty acid oxidation and energy expenditure, which suppress oxidative stress. SIGNIFICANCE Thus the activation of AMPK signalling through GRP78, improves lipid homeostasis, enhances insulin sensitivity via inhibition of PKC activity. PSTi8 suppresses inflammation associated with incomplete fatty acid oxidation. Hence, PSTi8 may be a potential therapeutic agent to treat glucocorticoid-induced fatty liver associated type 2 diabetes.
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Affiliation(s)
- Anand P Gupta
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Pragati Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Richa Garg
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
| | - Guru R Valicherla
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
| | - Mohammed Riyazuddin
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Anees A Syed
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
| | - Zakir Hossain
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
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Dibaba DT, Ogunsina K, Braithwaite D, Akinyemiju T. Metabolic syndrome and risk of breast cancer mortality by menopause, obesity, and subtype. Breast Cancer Res Treat 2018; 174:209-218. [PMID: 30465158 DOI: 10.1007/s10549-018-5056-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 11/16/2018] [Indexed: 12/17/2022]
Abstract
PURPOSE To investigate the association between metabolic syndrome (MetS) and risk of breast cancer mortality by menopausal status, obesity, and subtype. METHODS Data from 94,555 women free of cancer at baseline in the National Institute of Health-American Association of Retired Persons Diet and Health Study cohort (NIH-AARP) were used to investigate the prospective associations of baseline MetS and components with risk of breast cancer mortality using Cox proportional hazard regression models adjusted for baseline behavioral and demographic covariates. RESULTS During a mean follow-up duration of 14 years, 607 women in the cohort died of breast cancer. Overall, MetS was associated with a 73% increased risk of breast cancer mortality (HR 1.73; 95% CI 1.09-2.75); the association remained significant among post-menopausal women overall (HR 2.07, 95% CI 1.32, 3.25), and among those with overweight/obesity (HR 1.15, 95% CI 0.81, 1.64). MetS was associated with increased risk of breast cancer mortality for ER+/PR+ (HR 1.28, 95% CI 0.52, 3.16) and lower risk for ER-/PR- (HR 0.44, 95% CI 0.11, 1.75) subtypes; however, the associations were not statistically significant. Of the individual MetS components, high waist circumference (HR 1.32, 95% CI 1.03, 1.70), high cholesterol (HR 1.24, 95% CI 1.05, 1.46), and hypertension (HR 1.24, 95% CI 1.05, 1.46) were independently associated with increased risk of breast cancer mortality. CONCLUSIONS MetS was associated with increased risk of breast cancer mortality, especially among post-menopausal women. Further studies with larger sample sizes are needed to definitively determine the extent to which these associations vary by breast cancer subtype.
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Affiliation(s)
- Daniel T Dibaba
- Department of Epidemiology, University of Kentucky, Lexington, KY, USA
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Kemi Ogunsina
- Department of Public Health Sciences, University of Miami, Miami, FL, USA
| | | | - Tomi Akinyemiju
- Department of Epidemiology, University of Kentucky, Lexington, KY, USA.
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
- College of Public Health and Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
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Abdelhalim NY, Shehata MH, Gadallah HN, Sayed WM, Othman AA. Morphological and ultrastructural changes in the placenta of the diabetic pregnant Egyptian women. Acta Histochem 2018; 120:490-503. [PMID: 29871770 DOI: 10.1016/j.acthis.2018.05.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 05/05/2018] [Accepted: 05/09/2018] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus (DM) is a chronic metabolic disease in which the body fails to produce enough insulin or increased tissue resistance to insulin. The diabetes may have profound effects on placental development and function. This study was designed to detect the placental changes in pregnancy associated with DM comparing these changes with normal placenta. The study was carried out on sixty full-term placentae; divided into three equal groups; control group (group I): placentae of normal pregnancy, uncontrolled diabetes (group II): placentae from pregnant women whose blood glucose is poorly controlled during pregnancy. Controlled diabetes (group III): includes placentae from diabetic women whose blood glucose is controlled during pregnancy. The placentae from group II tend to be heavier and exhibited immaturity of villi, villous edema, fibrosis, excessive syncytial knots formation and infarctions. In addition to, fibrinoid necrosis, increased thickness of vasculosyncytial membrane, syncytial basement membrane, microvillous abnormalities and vascular endothelial changes were demonstrated. The syncytial multivesicular knots were present in placentae of group II. The nuclei within these syncytial knots display condensed chromatin, either dispersed throughout the nucleus or in the form of dense peripheral clumps with and numerous cytoplasmic vacuoles. The syncytial basement membrane showed focal areas of increase in its thickness and irregularity. Villous cytotrophoblasts showed increased number and activity in the form of numerous secretory granules, abundant dilated RER, larger distorted mitochondria. Villous vessels showed various degrees of abnormalities in the form of endothelial cell enlargement, folding, thickening and protrusion of their luminal surfaces into vascular lumen making it narrower in caliber. In placentae of group III, most of these abnormalities decreased. In most of placentae of group III, the VSM appeared nearly normal in thickness and showed nearly normal composition of one layer of syncytiotrophoblastic cells, one layer of smooth, regular capillary endothelium and the space between them. Mild microvillous abnormalities were noted in few placentae as they appeared short and blunted with mild decrease in their number per micron. The electron picture of syncytial knots appeared nearly normal containing aggregations of small, condensed hyperchromatic nuclei, minimal vacuoles could be seen in the cytoplasm of syncytial knots. Syncytial basement membrane appeared regular and nearly normal in its thickness and composition coming in direct contact with fetal blood capillaries but mild abnormalities were noted in the basement membrane in few placentae as increased its thickness and deposition of fibers or fibrinoid. Regarding cytotrophoblasts in the terminal villi of placentae with controlled diabetes, these cells appeared nearly normal. They were scattered beneath the syncytium and were active containing mitochondria, rough endoplasmic reticulum, free ribosomes and a large nucleus with fine dispersed chromatin. The vascular ultrastructural pattern in terminal villi of placentae of this group showed no significant abnormalities and was normally distributed in the villous tree. The luminal surface of the vascular endothelium appeared regular smooth in the majority of placentae of this group. The endothelial cells appeared connected to each other with tight junctions. It could be concluded that whether if long-term diabetes is controlled or not, placentae of diabetic mother showed a variety of significant histological structural changes seen more frequently than in the placentae of pregnant women without diabetes.
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Affiliation(s)
| | | | - Hanan Nabih Gadallah
- Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Egypt
| | - Walaa Mohamed Sayed
- Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Egypt.
| | - Aref Ali Othman
- Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Egypt
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Miyazaki T, Shirakami Y, Kubota M, Ideta T, Kochi T, Sakai H, Tanaka T, Moriwaki H, Shimizu M. Sodium alginate prevents progression of non-alcoholic steatohepatitis and liver carcinogenesis in obese and diabetic mice. Oncotarget 2016; 7:10448-58. [PMID: 26871288 PMCID: PMC4891131 DOI: 10.18632/oncotarget.7249] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 01/25/2016] [Indexed: 12/13/2022] Open
Abstract
Obesity and related metabolic abnormalities play a key role in liver carcinogenesis. Non-alcoholic steatohepatitis (NASH), which is often complicated with obesity and diabetes mellitus, is associated with the development of hepatocellular carcinoma (HCC). Sodium alginate (SA), which is extracted from brown seaweeds, is marketed as a weight loss supplement because of its high viscosity and gelling properties. In the present study, we examined the effects of SA on the progression of NASH and related liver carcinogenesis in monosodium glutamate (MSG)-treated mice, which show obesity, diabetes mellitus, and NASH-like histopathological changes. Male MSG-mice were intraperitoneally injected with diethylnitrosamine at 2 weeks of age, and, thereafter, they received a basal diet containing high- or low-molecular-weight SA throughout the experiment (16 weeks). At sacrifice, control MSG-treated mice fed the basal-diet showed significant obesity, hyperinsulinemia, steatosis and hepatic tumor development. SA administration suppressed body weight gain; improved insulin sensitivity, hyperinsulinemia, and hyperleptinemia; attenuated inflammation in the liver and white adipose tissue; and inhibited hepatic lipogenesis and progression of NASH. SA also reduced oxidative stress and increased anti-oxidant enzyme levels in the liver. Development of hepatic tumors, including liver cell adenoma and HCC, and hepatic pre-neoplastic lesions was significantly inhibited by SA supplementation. In conclusion, oral SA supplementation improves liver steatosis, insulin resistance, chronic inflammation, and oxidative stress, preventing the development of liver tumorigenesis in obese and diabetic mice. SA may have ability to suppress steatosis-related liver carcinogenesis in obese and diabetic subjects.
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Affiliation(s)
- Tsuneyuki Miyazaki
- Department of Gastroenterology/Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yohei Shirakami
- Department of Gastroenterology/Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.,Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masaya Kubota
- Department of Gastroenterology/Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takayasu Ideta
- Department of Gastroenterology/Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takahiro Kochi
- Department of Gastroenterology/Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hiroyasu Sakai
- Department of Gastroenterology/Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takuji Tanaka
- Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hisataka Moriwaki
- Department of Gastroenterology/Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masahito Shimizu
- Department of Gastroenterology/Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
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Ling WLW, Bai Y, Cheng C, Padawer I, Wu C. Development and manufacturability assessment of chemically-defined medium for the production of protein therapeutics in CHO cells. Biotechnol Prog 2015; 31:1163-71. [DOI: 10.1002/btpr.2108] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Revised: 05/13/2015] [Indexed: 12/31/2022]
Affiliation(s)
- Wai Lam W. Ling
- Process Development and Engineering, Biologics BioProcess Development; Merck Research Laboratories, Kenilworth; NJ
| | - Yunling Bai
- Process Development and Engineering, Biologics BioProcess Development; Merck Research Laboratories, Kenilworth; NJ
| | - Cheng Cheng
- Process Development and Engineering, Biologics BioProcess Development; Merck Research Laboratories, Kenilworth; NJ
| | - Ishai Padawer
- Process Development and Engineering, Biologics BioProcess Development; Merck Research Laboratories, Kenilworth; NJ
| | - Changjian Wu
- Process Development and Engineering, Biologics BioProcess Development; Merck Research Laboratories, Kenilworth; NJ
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Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-+Leprdb/+Leprdb mice. PLoS One 2015; 10:e0124081. [PMID: 25879666 PMCID: PMC4399835 DOI: 10.1371/journal.pone.0124081] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 03/03/2015] [Indexed: 12/22/2022] Open
Abstract
Obesity and related metabolic disorders, such as diabetes mellitus, raise the risk of liver carcinogenesis. Metformin, which is widely used in the treatment of diabetes, ameliorates insulin sensitivity. Metformin is also thought to have antineoplastic activities and to reduce cancer risk. The present study examined the preventive effect of metformin on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db) obese and diabetic mice. The mice were given a single injection of DEN at 2 weeks of age and subsequently received drinking water containing metformin for 20 weeks. Metformin administration significantly reduced the multiplicity of hepatic premalignant lesions and inhibited liver cell neoplasms. Metformin also markedly decreased serum levels of insulin and reduced insulin resistance, and inhibited phosphorylation of Akt, mammalian target of rapamycin (mTOR), and p70S6 in the liver. Furthermore, serum levels of leptin were decreased, while those of adiponectin were increased by metformin. These findings suggest that metformin prevents liver tumorigenesis by ameliorating insulin sensitivity, inhibiting the activation of Akt/mTOR/p70S6 signaling, and improving adipokine imbalance. Therefore, metformin may be a potent candidate for chemoprevention of liver tumorigenesis in patients with obesity or diabetes.
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Liu J, Wang X, Peng Z, Zhang T, Wu H, Yu W, Kong D, Liu Y, Bai H, Liu R, Zhang X, Hai C. The effects of insulin pre-administration in mice exposed to ethanol: alleviating hepatic oxidative injury through anti-oxidative, anti-apoptotic activities and deteriorating hepatic steatosis through SRBEP-1c activation. Int J Biol Sci 2015; 11:569-586. [PMID: 25892964 PMCID: PMC4400388 DOI: 10.7150/ijbs.11039] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 01/21/2015] [Indexed: 12/20/2022] Open
Abstract
Alcoholic liver disease (ALD) has become an important liver disease hazard to public and personal health. Oxidative stress is believed to be responsible for the pathological changes in ALD. Previous studies have showed that insulin, a classic regulator of glucose metabolism, has significant anti-oxidative function and plays an important role in maintaining the redox balance. For addressing the effects and mechanisms of insulin pre-administration on ethanol-induced liver oxidative injury, we investigated histopathology, inflammatory factors, apoptosis, mitochondrial dysfunction, oxidative stress, antioxidant defense system, ethanol metabolic enzymes and lipid disorder in liver of ethanol-exposed mice pretreatment with insulin or not. There are several novel findings in our study. First, we found insulin pre-administration alleviated acute ethanol exposure-induced liver injury and inflammation reflected by the decrease of serum AST and ALT activities, the improvement of pathological alteration and the inhibition of TNF-α and IL-6 expressions. Second, insulin pre-administration could significantly reduce apoptosis and ameliorate mitochondrial dysfunction in liver of mice exposed to ethanol, supporting by decreasing caspases-3 activities and the ratio of Bax/Bcl-2, increasing mitochondrial viability and mitochondrial oxygen consumption, inhibition of the decline of ATP levels and mitochondrial ROS accumulation. Third, insulin pre-administration prevented ethanol-mediated oxidative stress and enhance antioxidant defense system, which is evaluated by the decline of MDA levels and the rise of GSH/GSSG, the up-regulations of antioxidant enzymes CAT, SOD, GR through Nrf-2 dependent pathway. Forth, the modification of ethanol metabolism pathway such as the inhibition of CYP2E1, the activation of ALDH might be involved in the anti-oxidative and protective effects exerted by insulin pre-administration against acute ethanol exposure in mice. Finally, insulin pre-administration deteriorated hepatic steatosis in mice exposed to ethanol might be through SRBEP-1c activation. In summary, these results indicated that insulin pre-administration effectively alleviated liver oxidative injury through anti-inflammatory, anti-oxidative and anti-apoptotic activities but also deteriorated hepatic steatosis through SRBEP-1c activation in mice exposed to ethanol. Our study provided novel insight about the effects and mechanisms of insulin on ethanol-induced liver injury.
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Affiliation(s)
- Jiangzheng Liu
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Xin Wang
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Zhengwu Peng
- 2. Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Tao Zhang
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Hao Wu
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Weihua Yu
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Deqing Kong
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Ying Liu
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Hua Bai
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Rui Liu
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Xiaodi Zhang
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Chunxu Hai
- 1. Department of Toxicology, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Shaanxi Provincial Key Lab of Free radical biology and medicine, School of Public Health, The Fourth Military Medical University, Xi'an, 710032, P. R. China
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Picone P, Nuzzo D, Caruana L, Messina E, Barera A, Vasto S, Di Carlo M. Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: Use of insulin to attenuate metformin's effect. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2015; 1853:1046-59. [PMID: 25667085 DOI: 10.1016/j.bbamcr.2015.01.017] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 01/21/2015] [Accepted: 01/25/2015] [Indexed: 12/14/2022]
Abstract
Clinical and experimental biomedical studies have shown Type 2 diabetes mellitus (T2DM) to be a risk factor for the development of Alzheimer's disease (AD). This study demonstrates the effect of metformin, a therapeutic biguanide administered for T2DM therapy, on β-amyloid precursor protein (APP) metabolism in in vitro, ex vivo and in vivo models. Furthermore, the protective role of insulin against metformin is also demonstrated. In LAN5 neuroblastoma cells, metformin increases APP and presenilin levels, proteins involved in AD. Overexpression of APP and presenilin 1 (Pres 1) increases APP cleavage and intracellular accumulation of β-amyloid peptide (Aβ), which, in turn, promotes aggregation of Aβ. In the experimental conditions utilized the drug causes oxidative stress, mitochondrial damage, decrease of Hexokinase-II levels and cytochrome C release, all of which lead to cell death. Several changes in oxidative stress-related genes following metformin treatment were detected by PCR arrays specific for the oxidative stress pathway. These effects of metformin were found to be antagonized by the addition of insulin, which reduced Aβ levels, oxidative stress, mitochondrial dysfunction and cell death. Similarly, antioxidant molecules, such as ferulic acid and curcumin, are able to revert metformin's effect. Comparable results were obtained using peripheral blood mononuclear cells. Finally, the involvement of NF-κB transcription factor in regulating APP and Pres 1 expression was investigated. Upon metformin treatment, NF-κB is activated and translocates from the cytoplasm to the nucleus, where it induces increased APP and Pres 1 transcription. The use of Bay11-7085 inhibitor suppressed the effect of metformin on APP and Pres 1 expression.
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Affiliation(s)
- Pasquale Picone
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy
| | - Domenico Nuzzo
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy
| | - Luca Caruana
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy
| | - Elisa Messina
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy
| | - Annalisa Barera
- Department of STEBICEF, University of Palermo, 90100 Palermo, Italy
| | - Sonya Vasto
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy; Department of STEBICEF, University of Palermo, 90100 Palermo, Italy
| | - Marta Di Carlo
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, Italy.
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Insulin blocks glutamate-induced neurotoxicity in differentiated SH-SY5Y neuronal cells. Behav Neurol 2014; 2014:674164. [PMID: 25018588 PMCID: PMC4082871 DOI: 10.1155/2014/674164] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 05/04/2014] [Accepted: 05/26/2014] [Indexed: 12/30/2022] Open
Abstract
Insulin is a cytokine which promotes cell growth. Recently, a few published reports on insulin in different cell lines support the antiapoptotic effect of insulin. But the reports fail to explain the role of insulin in modulating glutamate-mediated neuronal cell death through excitotoxicity. Thus, we examined the neuroprotective effect of insulin on glutamate-induced toxicity on differentiated SH-SY5Y neuronal cells. Changes in cell viability were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) based assay, while apoptotic damage was detected by acridine orange/ethidium bromide and Hoechst staining. Intracellular reactive oxygen species (ROS) accumulation and morphological alterations were also measured. Treatment with glutamate induced apoptosis, elevated ROS levels and caused damage to neurons. Insulin was able to attenuate the glutamate-induced excitotoxic damage to neuronal cells.
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Anai C, Kawaguchi M, Eto K. Effects of culture media on the susceptibility of cells to apoptotic cell death. In Vitro Cell Dev Biol Anim 2014; 50:683-7. [PMID: 24789725 DOI: 10.1007/s11626-014-9756-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 04/06/2014] [Indexed: 01/04/2023]
Abstract
Whether responses of cells to extracellular environments affect the induction of apoptotic cell death is poorly understood. The current study aimed to unravel the different effects of culture media employed in vitro as extracellular environments on the susceptibility of cells to apoptosis. We found that apoptosis is stimulated to the higher levels by culturing human HeLa cells in Opti-MEM with unknown components, a medium that is specifically used for transfections, than by culturing cells in Dulbecco's modified Eagle's medium, a medium that is generally used for maintenance of cells. We showed that apoptosis is suppressed partially by culturing cells in heat-treated Opti-MEM, implicating a heat-sensitive component(s) in stimulating the apoptotic response of cells. Thus, different extracellular environments may contribute to different responses of cells to apoptosis, and this should be considered to evaluate the incidences of apoptotic cell death and could be applied to develop an efficient treatment for curing diseases such as cancer.
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Affiliation(s)
- Chikara Anai
- Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto, 860-8555, Japan
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25
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Zheng Y, Wang X, Wang H, Yan W, Zhang Q, Chang X. Bone morphogenetic protein 2 inhibits hepatocellular carcinoma growth and migration through downregulation of the PI3K/AKT pathway. Tumour Biol 2014; 35:5189-98. [PMID: 24573607 DOI: 10.1007/s13277-014-1673-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Accepted: 01/22/2014] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Previous studies have suggested that abnormal expression of BMP-4, BMP-7, and BMP-9 is correlated with tumor progression in HCC, but the role played by BMP-2 in HCC has not yet been reported. To determine the role of BMP-2 in HCC, we first investigated the effect of exogenous BMP-2 on the growth of the cell lines HCC SK-Hep-1, Hep G2, and Hep 3B. Next, we studied the function of BMP-2 in SK-Hep-1 HCC cell line using a recombinant lentivirus vector to deliver BMP-2. We also used siRNA to silence endogenous BMP-2 expression in the HCC Hep 3B cell line. Then, cell growth and migration were assayed in vitro using WST-8, wound-healing, and transwell invasion assays. Cellular apoptosis and cell-cycle distribution were assessed using flow cytometry. We also investigated the effects of BMP-2 overexpression and knockdown on the expression of proliferating cell nuclear antigen (PCNA), matrix metallopeptidase-2 (MMP-2), phosphorylated AKT (p-AKT), phosphoinositide 3-kinase p85α (PI3Kp85α), Bax, Bcl-2, caspase-3, cleaved caspase-3, p21, and cyclin E. As a result, we observed that BMP-2 inhibited the proliferation of HCC cells. Furthermore, HCC cell proliferation and migration were significantly diminished by BMP-2 overexpression, as was indicated by WST-8, would healing, and transwell assays, while knockdown of BMP-2 led to an increase in proliferation and migration of Hep 3B cells. BMP-2 overexpression significantly increased the susceptibility of SK-Hep-1 cells to low-serum-induced apoptosis, while BMP-2 knockdown reduced the susceptibility of Hep 3B cells. Overexpression of BMP-2 induced G1 phase arrest through upregulation of p21. When BMP-2 expression was elevated in SK-Hep-1 cells, the expression of PI3Kp85α, p-AKT, PCNA, and MMP-2 declined. These results suggest that BMP-2 exerts an inhibitory effect on the growth and migration of HCC cells, possibly via a blockade of PI3K/AKT signaling.
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Affiliation(s)
- Ying Zheng
- Department of Anesthesia, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu, 223300, People's Republic of China,
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26
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Low expression of ERK signaling pathway affecting proliferation, cell cycle arrest and apoptosis of human gastric HGC-27 cells line. Mol Biol Rep 2014; 41:3659-69. [PMID: 24554029 DOI: 10.1007/s11033-014-3230-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 02/04/2014] [Indexed: 10/25/2022]
Abstract
This study was carried out for the first time to examine the potential role and the underlying mechanisms of Lycopene in the gastric cancer HGC-27 cells. HGC-27 cells were seeded onto heat-sterilized coverslips in six-well plates and exposed to Lycopene (5, 10, 20, 30 and 40 μmol/L) for periods of 72 h at 37 °C. Results showed that Lycopene (5, 10, 20, 30 and 40 μmol/L) dose-dependently increased NBT positive rate and decreased lactate dehydrogenase activity in HGC-27 cells. In addition, Lycopene (5, 10, 20, 30 and 40 μmol/L) inhibited proliferation and induced G0-G1 phase cell cycle arrest in HGC-27 cells. Western blot and FQRT-PCR analysis showed that Lycopene decreased pERK and extracellular signal-regulated kinase (ERK) protein and mRNA expression in a dose-dependent manner. These findings demonstrate that Lycopene inhibited gastric cancer HGC-27 cells growth and stimulated its apoptosis via the suppressing ERK signaling pathway.
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27
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Esposito K, Chiodini P, Capuano A, Bellastella G, Maiorino MI, Giugliano D. Metabolic syndrome and endometrial cancer: a meta-analysis. Endocrine 2014; 45:28-36. [PMID: 23640372 DOI: 10.1007/s12020-013-9973-3] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 04/24/2013] [Indexed: 01/16/2023]
Abstract
We performed a systematic review and meta-analysis on the association of metabolic syndrome with endometrial cancer. A systematic literature search of electronic databases (Medline, ISI Web of Knowledge and Scopus) was conducted and complemented by cross-referencing to identify studies published before 31 January 2013. Core items of identified studies were independently extracted by two reviewers, and results were summarized by random effects meta-analysis. We identified six studies, which reported on 3,132 cancer cases. Metabolic syndrome was associated with an increased risk of endometrial cancer (RR: 1.89, 95 % CI 1.34-2.67, P < 0.001), with significant heterogeneity among studies (I (2) = 92 %, P < 0.001), but no indication for publication bias in the Egger's test (P = 0.240). A sensitivity analysis omitting two studies produced no heterogeneity (I (2) = 0 %) and attenuated the association (RR: 1.39, 1.31-1.48, P < 0.001). The risk estimates for any single factor of the syndrome were 2.21 (P < 0.001) for higher values of body mass index and/or waist, 1.81 (P = 0.044) for hyperglycemia, 1.81 (P = 0.024) for higher blood pressure values, and 1.17 (P < 0.001) for high triglyceride levels; there was no significant association with low HDL-cholesterol. Metabolic syndrome is associated with an increased risk of endometrial cancer; among the components of the syndrome, obesity/high waist is that more strongly associated with endometrial cancer.
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Affiliation(s)
- Katherine Esposito
- Division of Endocrinology, Diabetes, and Metabolic Diseases, Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Piazza L. Miraglia 2, 80138, Naples, Italy,
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28
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Pichiri G, Coni P, Nemolato S, Cabras T, Fanari MU, Sanna A, Di Felice E, Messana I, Castagnola M, Faa G. Cellular trafficking of thymosin beta-4 in HEPG2 cells following serum starvation. PLoS One 2013; 8:e67999. [PMID: 23967050 PMCID: PMC3743897 DOI: 10.1371/journal.pone.0067999] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Accepted: 05/26/2013] [Indexed: 12/16/2022] Open
Abstract
Thymosin beta-4 (Tβ4) is an ubiquitous multi-functional regenerative peptide, related to many critical biological processes, with a dynamic and flexible conformation which may influence its functions and its subcellular distribution. For these reasons, the intracellular localization and trafficking of Tβ4 is still not completely defined and is still under investigation in in vivo as well as in vitro studies. In the current study we used HepG2 cells, a human hepatoma cell line; cells growing in normal conditions with fetal bovine serum expressed high levels of Tβ4, restricted to the cytoplasm until 72 h. At 84 h, a diffuse Tβ4 cytoplasmic immunostaining shifted to a focal perinuclear and nuclear reactivity. In the absence of serum, nuclear reactivity was localized in small granules, evenly dispersed throughout the entire nuclear envelop, and was observed as earlier as at 48 h. Cytoplasmic immunostaining for Tβ4 in HepG2 cells under starvation appeared significantly lower at 48 h and decreased progressively at 72 and at 84 h. At these time points, the decrease in cytoplasmic staining was associated with a progressive increase in nuclear reactivity, suggesting a possible translocation of the peptide from the cytoplasm to the nuclear membrane. The normal immunocytochemical pattern was restored when culture cells submitted to starvation for 84 h received a new complete medium for 48 h. Mass spectrometry analysis, performed on the nuclear and cytosolic fractions of HepG2 growing with and without serum, showed that Tβ4 was detectable only in the cytosolic and not in the intranuclear fraction. These data suggest that Tβ4 is able to translocate from different cytoplasmic domains to the nuclear membrane and back, based on different stress conditions within the cell. The punctuate pattern of nuclear Tβ4 immunostaining associated with Tβ4 absence in the nucleoplasm suggest that this peptide might be localized in the nuclear pores, where it could regulate the pore permeability.
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Affiliation(s)
- Giuseppina Pichiri
- Divisione di Anatomia Patologica, Dipartimento di Citomorfologia, University of Cagliari, Cagliari, Italy.
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29
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Herrera B, García-Álvaro M, Cruz S, Walsh P, Fernández M, Roncero C, Fabregat I, Sánchez A, Inman GJ. BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells. PLoS One 2013; 8:e69535. [PMID: 23936038 PMCID: PMC3720667 DOI: 10.1371/journal.pone.0069535] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Accepted: 06/11/2013] [Indexed: 12/15/2022] Open
Abstract
TGF-β family members play a relevant role in tumorigenic processes, including hepatocellular carcinoma (HCC), but a specific implication of the Bone Morphogenetic Protein (BMP) subfamily is still unknown. Although originally isolated from fetal liver, little is known about BMP9, a BMP family member, and its role in liver physiology and pathology. Our results show that BMP9 promotes growth in HCC cells, but not in immortalized human hepatocytes. In the liver cancer cell line HepG2, BMP9 triggers Smad1,5,8 phosphorylation and inhibitor of DNA binding 1 (Id1) expression up- regulation. Importantly, by using chemical inhibitors, ligand trap and gene silencing approaches we demonstrate that HepG2 cells autocrinely produce BMP9 that supports their proliferation and anchorage independent growth. Additionally, our data reveal that in HepG2 cells BMP9 triggers cell cycle progression, and strikingly, completely abolishes the increase in the percentage of apoptotic cells induced by long-term incubation in low serum. Collectively, our data unveil a dual role for BMP9, both promoting a proliferative response and exerting a remarkable anti-apoptotic function in HepG2 cells, which result in a robust BMP9 effect on liver cancer cell growth. Finally, we show that BMP9 expression is increased in 40% of human HCC tissues compared with normal human liver as revealed by immunohistochemistry analysis, suggesting that BMP9 signaling may be relevant during hepatocarcinogenesis in vivo. Our findings provide new clues for a better understanding of BMPs contribution, and in particular BMP9, in HCC pathogenesis that may result in the development of effective and targeted therapeutic interventions.
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Affiliation(s)
- Blanca Herrera
- Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
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30
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Modulation of inflammatory responses following insulin therapy in experimentally bolus intravenous Escherichia coli lipopolysaccharide serotype O55:B5 induced endotoxemia in Iranian fat-tailed sheep. Small Rumin Res 2013. [DOI: 10.1016/j.smallrumres.2013.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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31
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Chalmeh A, Badiei K, Pourjafar M, Nazifi S. Anti-inflammatory effects of insulin regular and flunixin meglumine on endotoxemia experimentally induced by Escherichia coli serotype O55:B5 in an ovine model. Inflamm Res 2012; 62:61-7. [PMID: 22960692 DOI: 10.1007/s00011-012-0551-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Revised: 07/06/2012] [Accepted: 08/27/2012] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Endotoxemia is a major cause of mortality in large animals and there are several therapeutic regimens for the treatment of endotoxemia. Recent studies have suggested the anti-inflammatory effects of insulin in endotoxemic human and laboratory animal models but to the best of our knowledge there is no report on the possible therapeutic effect of insulin in large animal endotoxemia. OBJECTIVE This experiment was conducted to evaluate the anti-inflammatory effects of insulin regular compared with flunixin meglumine on the treatment of endotoxemia in sheep. METHODS Lipopolysaccharide from Escherichia coli was administered intravenously to ewes. Anti-inflammatory effects of flunixin meglumine (at 2.2 mg/kg) and insulin regular (at 1.5 and 3 IU/kg) were evaluated by determination of serum concentrations of acute phase proteins, inflammatory cytokines and oxidative stress biomarkers. RESULTS Insulin regular at 3 IU/kg controlled the acute phase response following endotoxemia induction. The anti-inflammatory potency of insulin regular at 3 IU/kg was significantly higher than at 1.5 IU/kg and of flunixin meglumine at 2.2 mg/kg (P < 0.05). CONCLUSION Insulin regular induces its anti-inflammatory effects in a dose-dependent manner. Intravenous use of insulin regular can be a potential new therapeutic regimen for endotoxemia in large animal medicine.
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Affiliation(s)
- Aliasghar Chalmeh
- Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran.
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32
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Shimizu M, Tanaka T, Moriwaki H. Obesity and hepatocellular carcinoma: targeting obesity-related inflammation for chemoprevention of liver carcinogenesis. Semin Immunopathol 2012; 35:191-202. [PMID: 22945457 DOI: 10.1007/s00281-012-0336-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Accepted: 08/16/2012] [Indexed: 02/08/2023]
Abstract
Obesity and related metabolic abnormalities, including a state of chronic inflammation, increase the risk of hepatocellular carcinoma (HCC). Adipose tissue constitutively expresses the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are important tumor promoters in inflammation-related carcinogenesis. Dysregulation of TNF-α and IL-6 is associated with the development of steatosis and inflammation within the liver. These cytokines also lie at the core of the association between obesity and insulin resistance, which is a key factor in the development of obesity-related HCC. Here we present a detailed review of the relationship between metabolic abnormalities and the development of HCC, focusing on the role played by inflammation. Drawing from our basic and clinical research, the present report also reviews evidence that targeting metabolic abnormalities, such as attenuation of chronic inflammation and improvement of insulin resistance by either pharmaceutical or nutritional intervention, may be an effective strategy in preventing the development of HCC in obese individuals.
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Affiliation(s)
- Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
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33
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Downregulation of galectin-3 by EGF mediates the apoptosis of HepG2 cells. Mol Cell Biochem 2012; 369:157-65. [PMID: 22761016 DOI: 10.1007/s11010-012-1378-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2011] [Accepted: 06/20/2012] [Indexed: 12/15/2022]
Abstract
Epidermal growth factor (EGF) in high concentrations induces apoptosis of the tumor cells which express high levels of epidermal growth factor receptor. However, the precise mechanism for this induction is not clear. Galectin-3 is the most probable candidate for mediating this effect, as it is known to induce anti-apoptotic activity in a variety of tumor cells exposed to diverse apoptotic stimuli. In this study, we determined whether galectin-3 plays a role in high concentrations of EGF-induced apoptosis of HepG2 cells. We found that EGF in high concentrations led to the growth inhibition of HepG2 cells, which were associated with promotion of cell death. High concentrations of EGF suppressed cytoplasmic expression of galectin-3. Moreover, we demonstrated overexpression of galectin-3 could reduce EGF-induced apoptosis in HepG2 cells. Our study demonstrated for the first time that downregulation of cytoplasmic galectin-3 was essential for high concentrations of EGF-induced apoptosis in HepG2 cells.
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Zhan Y, Wang J, Ma Y, Liu Z, Xu H, Lu S, Lu B. Serum insulin-like, growth factor binding protein-related protein 1 (IGFBP-rP1) and endometrial cancer risk in Chinese women. Int J Cancer 2012; 132:411-6. [PMID: 22544761 DOI: 10.1002/ijc.27622] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Accepted: 03/28/2012] [Indexed: 11/08/2022]
Abstract
Hyperinsulinemia and the metabolic syndrome confer increased risks of endometrial carcinoma. The roles of insulin, and, insulin-like growth factor-binding proteins (IGFBPs) in the etiology of endometrial carcinoma, remain unclear. We recruited 206 patients with endometrial carcinoma and 350 healthy women to a case-control study of fasting insulin and IGFBP-related protein 1 (IGFBP-rP1) in a Chinese tertiary centre. Patients with endometrial carcinoma had higher insulin concentrations (14.8 ± 16.7 vs. 8.1 ± 9.4 μU/mL; p < 0.001) and lower IGFBP-rP1 levels (17.5 ± 17.2 vs. 22.4 ± 22.8 μg/L; p = 0.018) than controls. High insulin and IGFBP-rP1 levels were both positively and negatively associated with endometrial cancer (odds ratio for the highest tertile versus the lowest tertile: insulin: 4.11; 95% CI = 2.61-6.47; IGFBP-rP1: 0.38; 95% CI = 0.24-0.60). Logistic regression analysis confirmed the associations between endometrial carcinoma and fasting insulin or IGFBP-rP1 after adjustments for age, BMI, serum glucose, cholesterol, triglycerides and high-density lipoprotein cholesterol (odds ratio for the highest tertile versus the lowest tertile: insulin: 2.13; 95% CI = 1.30-3.49; IGFBP-rP1: 0.57; 95% CI = 0.34-0.94). Hyperinsulinemia and high IGFBP-rP1 levels confer altered risks for endometrial carcinoma.
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Affiliation(s)
- Yan Zhan
- Department of Clinical Laboratory, The Affiliated Women's Hospital, School of Medicine, Zhejiang University, China
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35
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Wang Y, Zhu Y, Zhang L, Tian W, Hua S, Zhao J, Zhang H, Xue F. Insulin promotes proliferation, survival, and invasion in endometrial carcinoma by activating the MEK/ERK pathway. Cancer Lett 2012; 322:223-31. [PMID: 22459351 DOI: 10.1016/j.canlet.2012.03.026] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2011] [Revised: 03/21/2012] [Accepted: 03/21/2012] [Indexed: 11/24/2022]
Abstract
The involvement of insulin in endometrial carcinoma (EC) was investigated using radioimmunoassay, Western blot, immunoprecipitation, MTT, and Annexin V-FITC/PI assays in tissue samples and cultured cells. Serum levels of insulin, p-p52Shc, p-p46Shc, Shc·Grb2 complexes, p-MEK, p-ERK, and cyclin D1 were elevated in patients with EC. Expression of key proteins in the MEK/ERK pathway, including p-p52Shc, Shc·Grb2 complexes, p-MEK, p-ERK, and cyclin D1, was significantly higher in patients with advanced FIGO stage, high grade, and lymph-node metastasis and correlated positively with serum insulin concentration. Insulin promotes Ishikawa 3-H-12 cell proliferation, survival, and invasion, and these effects induced by insulin were significantly blocked by MEK inhibitor PD98059. Insulin thus promotes EC cell proliferation, survival, and invasion via the MEK/ERK pathway.
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Affiliation(s)
- Yingmei Wang
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, China
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36
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Wang X, Tao L, Hai CX. Redox-regulating role of insulin: the essence of insulin effect. Mol Cell Endocrinol 2012; 349:111-27. [PMID: 21878367 DOI: 10.1016/j.mce.2011.08.019] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 08/10/2011] [Accepted: 08/14/2011] [Indexed: 11/18/2022]
Abstract
It is well-known that insulin acts as an important hormone, controlling energy metabolism, cellular proliferation and biosynthesis of functional molecules to maintain a biological homeostasis. Over the past few years, intensive insulin therapy has been believed to be benefit for the outcome of diabetic patients, in which the suppression of oxidative stress plays a role. Moreover, insulin is accepted as a key component of glucose-insulin-potassium, a treatment which has been believed to exert significant cardiovascular protective effect via the reduction of oxidative stress. Furthermore, accumulating evidence has suggested that insulin exerts important redox-regulating actions in various insulin-sensitive target organs, implying the systematic antioxidative role of insulin as a hormone. It is time for us to revisit insulin effects, through summarizing and evaluating the novel functions of insulin and their mechanisms. This review focuses on the antioxidative effect of insulin and highlights insulin-induced regulation of various antioxidant enzymes via insulin signaling pathways and the cross talk between key transcription factors, including nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NF-κB) which are responsible for the transcription of antioxidant enzymes, leading to reduced generation of reactive oxygen species (ROS) and the enhancement of the elimination of ROS.
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Affiliation(s)
- Xin Wang
- Department of Toxicology, School of Preventive Medicine, The Fourth Military Medical University, Xi'an 710032, China
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37
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Duarte AI, Moreira PI, Oliveira CR. Insulin in central nervous system: more than just a peripheral hormone. J Aging Res 2012; 2012:384017. [PMID: 22500228 PMCID: PMC3303591 DOI: 10.1155/2012/384017] [Citation(s) in RCA: 217] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Revised: 10/12/2011] [Accepted: 11/23/2011] [Indexed: 12/14/2022] Open
Abstract
Insulin signaling in central nervous system (CNS) has emerged as a novel field of research since decreased brain insulin levels and/or signaling were associated to impaired learning, memory, and age-related neurodegenerative diseases. Thus, besides its well-known role in longevity, insulin may constitute a promising therapy against diabetes- and age-related neurodegenerative disorders. More interestingly, insulin has been also faced as the potential missing link between diabetes and aging in CNS, with Alzheimer's disease (AD) considered as the "brain-type diabetes." In fact, brain insulin has been shown to regulate both peripheral and central glucose metabolism, neurotransmission, learning, and memory and to be neuroprotective. And a future challenge will be to unravel the complex interactions between aging and diabetes, which, we believe, will allow the development of efficient preventive and therapeutic strategies to overcome age-related diseases and to prolong human "healthy" longevity. Herewith, we aim to integrate the metabolic, neuromodulatory, and neuroprotective roles of insulin in two age-related pathologies: diabetes and AD, both in terms of intracellular signaling and potential therapeutic approach.
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Affiliation(s)
- Ana I. Duarte
- CNC, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
| | - Paula I. Moreira
- CNC, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
- Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal
| | - Catarina R. Oliveira
- CNC, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
- Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal
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Shimizu M, Kubota M, Tanaka T, Moriwaki H. Nutraceutical approach for preventing obesity-related colorectal and liver carcinogenesis. Int J Mol Sci 2012; 13:579-595. [PMID: 22312273 PMCID: PMC3269707 DOI: 10.3390/ijms13010579] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 12/20/2011] [Accepted: 12/27/2011] [Indexed: 12/27/2022] Open
Abstract
Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals.
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Affiliation(s)
- Masahito Shimizu
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; E-Mails: (M.K.); (H.M.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +81-58-230-6313; Fax: +81-58-230-6310
| | - Masaya Kubota
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; E-Mails: (M.K.); (H.M.)
| | - Takuji Tanaka
- The Tohkai Cytopathology Institute: Cancer Research and Prevention (TCI-CaRP), Gifu 500-8285, Japan; E-Mail:
| | - Hisataka Moriwaki
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; E-Mails: (M.K.); (H.M.)
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Picone P, Giacomazza D, Vetri V, Carrotta R, Militello V, San Biagio PL, Di Carlo M. Insulin-activated Akt rescues Aβ oxidative stress-induced cell death by orchestrating molecular trafficking. Aging Cell 2011; 10:832-43. [PMID: 21624038 DOI: 10.1111/j.1474-9726.2011.00724.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Increasing evidence indicates that Alzheimer's disease, one of the most diffused aging pathologies, and diabetes may be related. Here, we demonstrate that insulin signalling protects LAN5 cells by amyloid-β42 (Aβ)-induced toxicity. Aβ affects both activation of insulin receptors and the levels of phospho-Akt, a critical signalling molecule in this pathway. In contrast, oxidative stress induced by Aβ can be antagonized by active Akt that, in turn, inhibits Foxo3a, a pro-apoptotic transcription factor activated by reactive oxygen species generation. Insulin cascade protects against mitochondrial damage caused by Aβ treatment, restoring the mitochondrial membrane potential. Moreover, we show that the recovery of the organelle integrity recruits active Akt translocation to the mitochondrion. Here, it plays a role both by maintaining unimpaired the permeability transition pore through increase in HK-II levels and by blocking apoptosis through phosphorylation of Bad, coming from cytoplasm after Aβ stimulus. Together, these results indicate that the Akt survival signal antagonizes the Aβ cell death process by balancing the presence and modifications of common molecules in specific cellular environments.
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Affiliation(s)
- Pasquale Picone
- Istituto di Biomedicina ed Immunologia Molecolare Alberto Monroy, Consiglio Nazionale delle Ricerche, via Ugo La Malfa 153, Palermo, Italy
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40
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Cui ZG, Hong NY, Guan J, Kang HK, Lee DH, Lee YK, Park DB. cAMP antagonizes ERK-dependent antiapoptotic action of insulin. BMB Rep 2011; 44:205-10. [PMID: 21429300 DOI: 10.5483/bmbrep.2011.44.3.205] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Insulin has antiapoptotic activity in various cell types. However, the signaling pathways underlying the antiapoptotic activity of insulin is not yet known. This study was conducted to determine if cAMP affects the antiapoptotic activity of insulin and the activity of PI3K and ERK in CHO cells expressing human insulin receptors (CHO-IR). Insulin-stimulated ERK activity was completely suppressed by cAMP-elevating agents like as pertussis toxin (Ptx) and cholera toxin (Ctx) after 4 h treatment. Insulin-stimulated PKB/Akt activity was not affected at all. Ptx treatment together with insulin increased the number of apoptotic cells and the degree of DNA fragmentation. Ctx or 8-brcAMP treatment also increased the number of apoptotic cells and stimulated the cleavage of caspase-3 and the hydrolysis of PARP. Taken together, cAMP antagonizes the antiapoptotic activity of insulin and the main target molecule of cAMP in this process is likely ERK, not PI3K-dependent PKB/Akt.
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Affiliation(s)
- Zhi Gang Cui
- Department of Medicine, School of Medicine and Institute of Medical Science, Jeju National University, Korea
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Numata T, Araya J, Fujii S, Hara H, Takasaka N, Kojima J, Minagawa S, Yumino Y, Kawaishi M, Hirano J, Odaka M, Morikawa T, Nishimura SL, Nakayama K, Kuwano K. Insulin-dependent phosphatidylinositol 3-kinase/Akt and ERK signaling pathways inhibit TLR3-mediated human bronchial epithelial cell apoptosis. THE JOURNAL OF IMMUNOLOGY 2011; 187:510-9. [PMID: 21646299 DOI: 10.4049/jimmunol.1004218] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
TLR3, one of the TLRs involved in the recognition of infectious pathogens for innate and adaptive immunity, primarily recognizes viral-associated dsRNA. Recognition of dsRNA byproducts released from apoptotic and necrotic cells is a recently proposed mechanism for the amplification of toxicity, suggesting a pivotal participation of TLR3 in viral infection, as well as in lung diseases where apoptosis plays a critical role, such as asthma and chronic obstructive pulmonary disease. In addition to metabolic control, insulin signaling was postulated to be protective by inhibiting apoptosis. Therefore, we explored the role of insulin signaling in protecting against TLR3-mediated apoptosis of human bronchial epithelial cells. Significant TLR3-mediated apoptosis was induced by polyinosinic-polycytidylic acid, a dsRNA analog, via caspase-8-dependent mechanisms. However, insulin efficiently inhibited TLR3/polyinosinic-polycytidylic acid-induced human bronchial epithelial cell apoptosis via PI3K/Akt and ERK pathways, at least in part, via upregulation of cellular FLIPs and through protein synthesis-independent mechanisms. These results indicate the significance of TLR3-mediated dsRNA-induced apoptosis in the pathogenesis of apoptosis-driven lung disease and provide evidence for a novel protective role of insulin.
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Affiliation(s)
- Takanori Numata
- Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan
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Sampson SR, Bucris E, Horovitz-Fried M, Parnas A, Kahana S, Abitbol G, Chetboun M, Rosenzweig T, Brodie C, Frankel S. Insulin increases H2O2-induced pancreatic beta cell death. Apoptosis 2010; 15:1165-76. [PMID: 20544287 DOI: 10.1007/s10495-010-0517-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Insulin resistance results, in part, from impaired insulin signaling in insulin target tissues. Consequently, increased levels of insulin are necessary to control plasma glucose levels. The effects of elevated insulin levels on pancreatic beta (β) cell function, however, are unclear. In this study, we investigated the possibility that insulin may influence survival of pancreatic β cells. Studies were conducted on RINm, RINm5F and Min-6 pancreatic β-cells. Cell death was induced by treatment with H(2)O(2), and was estimated by measurements of LDH levels, viability assay (Cell-Titer Blue), propidium iodide staining and FACS analysis, and mitochondrial membrane potential (JC-1). In addition, levels of cleaved caspase-3 and caspase activity were determined. Treatment with H(2)O(2) increased cell death; this effect was increased by simultaneous treatment of cells with insulin. Insulin treatment alone caused a slight increase in cell death. Inhibition of caspase-3 reduced the effect of insulin to increase H(2)O(2)-induced cell death. Insulin increased ROS production by pancreatic β cells and increased the effect of H(2)O(2). These effects were increased by inhibition of IR signaling, indicative of an effect independent of the IR cascade. We conclude that elevated levels of insulin may act to exacerbate cell death induced by H(2)O(2) and, perhaps, other inducers of apoptosis.
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Affiliation(s)
- S R Sampson
- Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
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The α-isoform of class II phosphoinositide 3-kinase is necessary for the activation of ERK but not Akt/PKB. Mol Cell Biochem 2010; 346:95-101. [PMID: 20924651 DOI: 10.1007/s11010-010-0596-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2010] [Accepted: 09/18/2010] [Indexed: 01/02/2023]
Abstract
Phosphoinositide 3-kinases (PI3Ks) are key enzymes that activate intracellular signaling molecules when a number of different growth factors bind to cell surface receptors. PI3Ks are divided into three classes (I, II, III), and enzymes of each class have different tissue specificities and physiological functions. The α-isoform (PI3K-C2α) of class II PI3Ks is considered ubiquitous and preferentially activated by insulin. Our previous study showed that suppression of PI3K-C2α leads to apoptotic cell death. The aim of this study is to determine whether depletion of PI3K-C2α affects ERK or PKB/Akt activity following stimulation with serum and insulin growth factors in Chinese hamster ovary cells expressing human insulin receptors (CHO-IR) and human HepG2 liver cells. Different antisense oligonucleotides (ODNs), which were designed based on the sequence of the C2 domain of the human PI3K-C2α gene, were transfected into cells to inhibit PI3K-C2α expression. Insulin- or serum-induced stimulation of ERK was significantly suppressed by depletion of PI3K-C2α, whereas phosphorylation of IRS-1 and the stimulation of PKB/Akt by insulin were not affected. The number of apoptotic cells was also increased by depletion of PI3K-C2α protein levels. Taken together, our data indicate that PI3K-C2α may be a crucial factor in the stimulation of ERK activity in response to serum or insulin, whereas it is less important for the stimulation of PKB/Akt activity in response to insulin.
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Iwasa J, Shimizu M, Shiraki M, Shirakami Y, Sakai H, Terakura Y, Takai K, Tsurumi H, Tanaka T, Moriwaki H. Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Sci 2010; 101:460-7. [PMID: 19906067 PMCID: PMC11159020 DOI: 10.1111/j.1349-7006.2009.01402.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Obesity and related metabolic abnormalities, including insulin resistance, are risk factors for hepatocellular carcinoma in non-alcoholic steatohepatitis as well as in chronic viral hepatitis. Branched-chain amino acids (BCAA), which improve insulin resistance, inhibited obesity-related colon carcinogenesis in a rodent model, and also reduced the incidence of hepatocellular carcinoma in obese patients with liver cirrhosis. In the present study, we determined the effects of BCAA on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in obese C57BL/KsJ-db/db (db/db) mice with diabetes mellitus. Male db/db mice were given tap water containing 40 ppm DEN for an initial 2 weeks and thereafter they received a basal diet containing 3.0% of BCAA or casein, which served as a nitrogen content-matched control of BCAA, throughout the experiment. Supplementation with BCAA significantly reduced the total number of foci of cellular alteration, a premalignant lesion of the liver, and the expression of insulin-like growth factor (IGF)-1, IGF-2, and IGF-1 receptor in the liver when compared to the casein supplementation. BCAA supplementation for 34 weeks also significantly inhibited both the development of hepatocellular neoplasms and the proliferation of hepatocytes in comparison to the basal diet or casein-fed groups. Supplementation with BCAA improved liver steatosis and fibrosis and inhibited the expression of alpha-smooth muscle actin in the DEN-treated db/db mice. The serum levels of glucose and leptin decreased by dietary BCAA, whereas the value of the quantitative insulin sensitivity check index increased by this agent, indicating the improvement of insulin resistance and hyperleptinemia. In conclusion, oral BCAA supplementation improves insulin resistance and prevents the development of liver tumorigenesis in obese and diabetic mice.
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Affiliation(s)
- Junpei Iwasa
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
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Thakkar NV, Jain SM. A comparative study of DNA damage in patients suffering from diabetes and thyroid dysfunction and complications. Clin Pharmacol 2010; 2:199-205. [PMID: 22291505 PMCID: PMC3262371 DOI: 10.2147/cpaa.s11366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Objective The apoptotic DNA levels in blood leukocytes of patients with type 2 diabetes (T2D) and thyroid dysfunctionism were evaluated. Materials and methods Single-cell gel electrophoresis (comet assay) detects migration of DNA from individual cell nuclei following alkaline treatment. Comet assay pattern was studied in individuals with T2D, hypothyroid (HT), hyperthyroid (HeT), and patients suffering from both diabetes mellitus and HT (HT + DM). Results were compared with the normal subjects (n = 9 in each group). The percentage apoptotic cell populations were calculated from the tail length. Results T2D patients showed 92.24% of cell damage compared to HT or HeT patients (51.04% or 54.64%, respectively). Further, increase in cell damage was also observed in HT + DM subjects (P < 0.05). Pharmacologic therapy significantly influenced cell damage. However, age and duration of disease did not show any definite influence on apoptosis. Conclusion Dependence of disease seems to be the major contributor of the cell damage. However, thyroid dysfunction did not show any deleterious effects on individual cells under the study.
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Affiliation(s)
- Nima V Thakkar
- Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India
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Brown-Bryan TA, Leoh LS, Ganapathy V, Pacheco FJ, Mediavilla-Varela M, Filippova M, Linkhart TA, Gijsbers R, Debyser Z, Casiano CA. Alternative splicing and caspase-mediated cleavage generate antagonistic variants of the stress oncoprotein LEDGF/p75. Mol Cancer Res 2008; 6:1293-307. [PMID: 18708362 DOI: 10.1158/1541-7786.mcr-08-0125] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
There is increasing evidence that an augmented state of cellular oxidative stress modulates the expression of stress genes implicated in diseases associated with health disparities such as certain cancers and diabetes. Lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 autoantigen, is emerging as a survival oncoprotein that promotes resistance to oxidative stress-induced cell death and chemotherapy. We previously showed that LEDGF/p75 is targeted by autoantibodies in prostate cancer patients and is overexpressed in prostate tumors, and that its stress survival activity is abrogated during apoptosis. LEDGF/p75 has a COOH-terminally truncated splice variant, p52, whose role in stress survival and apoptosis has not been thoroughly investigated. We observed unbalanced expression of these proteins in a panel of tumor cell lines, with LEDGF/p75 generally expressed at higher levels. During apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the NH(2)-terminal PWWP domain and failed to transactivate the Hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of LEDGF/p75. Overexpression of p52 or its variants with truncated PWWP domains in several tumor cell lines induced apoptosis, an activity that was linked to the presence of an intron-derived COOH-terminal sequence. These results implicate the PWWP domain of p52 in transcription function but not in chromatin association and proapoptotic activities. Consistent with their unbalanced expression in tumor cells, LEDGF/p75 and p52 seem to play antagonistic roles in the cellular stress response and could serve as targets for novel antitumor therapies.
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Affiliation(s)
- Terry A Brown-Bryan
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
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Lebed YV, Orlovsky MA, Lushnikova IV, Skibo GG. Neurodegenerative changes in the hippocampus within the early period of experimental diabetes mellitus. NEUROPHYSIOLOGY+ 2008. [DOI: 10.1007/s11062-008-9019-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Zhang R, Kang KA, Piao MJ, Lee KH, Jang HS, Park MJ, Kim BJ, Kim JS, Kim YS, Ryu SY, Hyun JW. Rhapontigenin from Rheum undulatum protects against oxidative-stress-induced cell damage through antioxidant activity. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2007; 70:1155-1166. [PMID: 17558811 DOI: 10.1080/15287390701252766] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
The antioxidant properties of rhapontigenin and rhaponticin isolated from Rheum undulatum were investigated. Rhapontigenin was found to scavenge intracellular reactive oxygen species (ROS), the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, and hydrogen peroxide (H2O2). The radical scavenging effect of rhapontigenin was more effective than rhaponticin. Rhapontigenin protected against H2O2-induced membrane lipid peroxidation and cellular DNA damage, which are the main targets of oxidative stress-induced cellular damage. The radical scavenging activity of rhapontigenin protected Chinese hamster lung fibroblast (V79-4) cells exposed to H2O2 by inhibiting apoptosis. Rhapontigenin inhibited cell damage induced by serum starvation and was also found to increase the activity of catalase and its protein expression. Further, rhapontigenin increased phosphorylation of extracellular signal-regulated kinase (ERK) and inhibited the activity of activator protein 1 (AP-1), a redox-sensitive transcription factor. In summary, these results suggest that rhapontigenin protects V79-4 cells against oxidative damage by enhancing the cellular antioxidant activity and modulating cellular signal pathways.
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Affiliation(s)
- Rui Zhang
- Department of Biochemistry, College of Medicine and Applied Radiological Science Research Institute, Cheju National University, Jeju-si, Korea
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Bai J, Cederbaum AI. Cycloheximide protects HepG2 cells from serum withdrawal-induced apoptosis by decreasing p53 and phosphorylated p53 levels. J Pharmacol Exp Ther 2006; 319:1435-43. [PMID: 16971506 DOI: 10.1124/jpet.106.110007] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Cycloheximide (CHX), an inhibitor of protein synthesis, has been reported to prevent cell death in a wide variety of cell types and produced by different apoptotic stimuli. However, the mechanisms by which CHX protects cells from apoptosis are still unclear. In this study, we investigated whether p53 plays a role in the protection by CHX against serum withdrawal-induced apoptosis. Deprivation of serum from the culture medium causes apoptosis in HepG2 cells, and CHX dramatically protects cells from death. p53, p21, and Bax protein levels were elevated, and cell cycle arrest was produced after serum withdrawal. CHX abolished this elevation of p53, p21, and Bax as well as the cell cycle arrest induced by serum deprivation. The p53 inhibitor pifithrin-alpha protects HepG2 cells against apoptosis induced by serum withdrawal. HepG2 cells expressing a dominant negative form of mutant p53 and Hep3B cells lacking p53 were resistant to serum withdrawal-induced apoptosis. Lowering of p53 by small interfering RNA protects HepG2 cells from serum withdrawal-induced apoptosis. p53 phosphorylation was induced by serum withdrawal and other chemotherapeutic reagents such as actinomycin D, doxorubicin, and etoposide. CHX decreases the levels of phosphorylated p53 (pp53) even in the presence of a proteasome inhibitor, which maintains the total p53 levels, whereas it does not affect the dephosphorylation of pp53. These results suggest the possibility that kinases that phosphorylate p53 might be affected by CHX administration. In summary, CHX protects HepG2 cells from serum withdrawal-induced apoptosis through inhibiting the synthesis of p53 and the phosphorylation of p53.
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Affiliation(s)
- Jingxiang Bai
- Department of Pharmacology and Biological Chemistry, Box 1603, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
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