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Shi L, Ge H, Ye F, Li X, Jiang Q. The role of pericyte in ocular vascular diseases. J Biomed Res 2024; 38:1-10. [PMID: 38808554 PMCID: PMC11629158 DOI: 10.7555/jbr.37.20230314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 04/15/2024] [Accepted: 04/18/2024] [Indexed: 05/30/2024] Open
Abstract
Pericytes are located in the stromal membrane of the capillary outer wall and contain endothelial cells (ECs). They are pivotal in regulating blood flow, enhancing vascular stability, and maintaining the integrity of the blood-retina barrier (BRB)/blood-brain barrier (BBB). The pluripotency of pericytes allows them to differentiate into various cell types, highlighting their significance in vascular disease pathogenesis, as demonstrated by previous studies. This potential enables pericytes to be a potential biomarker for the diagnosis and a target for treatment of vascular disorders. The retina, an essential part of the eyeball, is an extension of cerebral tissue with a transparent refractive medium. It offers a unique window for assessing systemic microvascular lesions. Routine fundus examination is necessary for patients with diabetes and hypertension. Manifestations, such as retinal artery tortuosity, dilation, stenosis, and abnormal arteriovenous anastomosis, serve as typical hallmarks of retinal vasculopathy. Therefore, studies of ocular vascular diseases significantly facilitate the exploration of systemic vascular diseases.
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Affiliation(s)
- Lianjun Shi
- The Affiliated Eye Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Huimin Ge
- The Affiliated Eye Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Fan Ye
- The Affiliated Eye Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Xiumiao Li
- The Affiliated Eye Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Qin Jiang
- The Affiliated Eye Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
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A. Gabr G, El-Sayed SM, M. Alharth K, Devanathad V, M.M. Hassa N. Hepatoprotective Effect of Spirulina platensis on Liver Functions of Diabetic Rats via TNF-α and IL-6 Pathway. INT J PHARMACOL 2022. [DOI: 10.3923/ijp.2022.915.923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Rutin Attenuates Hepatotoxicity in High-Cholesterol-Diet-Fed Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:5436745. [PMID: 27239252 PMCID: PMC4863108 DOI: 10.1155/2016/5436745] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 02/29/2016] [Accepted: 03/10/2016] [Indexed: 01/06/2023]
Abstract
Background and Objective. High-cholesterol diet (HCD) intends to increase the oxidative stress in liver tissues inducing hepatotoxicity. Rutin is a natural flavonoid (vitamin p) which is known to have antioxidative properties. The aim of the present study was to investigate the potential effects of Rutin on hypercholesterolemia-induced hepatotoxicity in rats. Materials and Methods. Male Wistar rats were divided into four groups: G-I control, G-II Rutin, G-III HCD, and G-IV Rutin + HCD. The liver functions and lipid profile were used to evaluate the HCD-induced hepatotoxicity. Quantitative real time-PCR was carried out to evaluate the expression levels of genes in TGF-β/Smad signaling pathway. Results. Rutin in combination with HCD showed a significant protective effect against hepatotoxicity. HCD caused significant increase in the mRNA expression of transforming growth factor beta (TGF-β), Mothers Against Decapentaplegic Homolog 2 (Smad-2), Mothers Against Decapentaplegic Homolog 4 (Smad-4), Bcl-2-binding component 3 (Bbc3), caspase-3, P53 and Interleukin-6 (IL-6) and decrease in the expression levels of Cyclin depended kinase inhibitor (P21) and Interleukin-3 (IL-3) in hepatic cells. Conclusion. TGF-β/Smad signaling pathway is involved in HCD-induced hepatotoxicity and Rutin inhibits the hepatotoxicity via suppressing this pathway. Therefore, Rutin might be considered as a protective agent for hepatotoxicity.
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Hafez MM, Al-Harbi NO, Al-Hoshani AR, Al-Hosaini KA, Al Shrari SD, Al Rejaie SS, Sayed-Ahmed MM, Al-Shabanah OA. Hepato-protective effect of rutin via IL-6/STAT3 pathway in CCl4-induced hepatotoxicity in rats. Biol Res 2015; 48:30. [PMID: 26062544 PMCID: PMC4477598 DOI: 10.1186/s40659-015-0022-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Accepted: 06/03/2015] [Indexed: 01/20/2023] Open
Abstract
Background Carbon tetrachloride (CCl4) induces hepatotoxicity in animal models, including the increased blood flow and cytokine accumulation that are characteristic of tissue inflammation. The present study investigates the hepato-protective effect of rutin on CCl4-induced hepatotoxicity in rats. Results Forty male Wistar rats were divided into four groups. Group I (control group) received 1 mL/kg of dimethyl sulfoxide intragastrically and 3 mL/kg olive oil intraperitoneally twice a week for 4 weeks. Group II received 70 mg/kg rutin intragastrically. Groups III and IV received CCl4 (3 mL/kg, 30 % in olive oil) intraperitoneally twice a week for 4 weeks. Group IV received 70 mg/kg rutin intragastrically after 48 h of CCl4 treatment. Liver enzyme levels were determined in all studied groups. Expression of the following genes were monitored with real-time PCR: interleukin-6 (IL-6), dual-specificity protein kinase 5 (MEK5), Fas-associated death domain protein (FADD), epidermal growth factor (EGF), signal transducer and activator of transcription 3 (STAT3), Janus kinase (JAK), B-cell lymphoma 2 (Bcl2) and B-cell lymphoma-extra-large (Bcl-XL). The CCl4 groups showed significant increases in biochemical markers of hepatotoxicity and up-regulation of expression levels of IL-6, Bcl-XL, MEK5, FADD, EGF, STAT3 and JAK compared with the control group. However, CCl4 administration resulted in significant down-regulation of Bcl2 expression compared with the control group. Interestingly, rutin supplementation completely reversed the biochemical markers of hepatotoxicity and the gene expression alterations induced by CCl4. Conclusion CCl4 administration causes alteration in expression of IL-6/STAT3 pathway genes, resulting in hepatotoxicity. Rutin protects against CCl4-induced hepatotoxicity by reversing these expression changes.
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Affiliation(s)
- Mohamed M Hafez
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
| | - Naif O Al-Harbi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
| | - Ali Rashed Al-Hoshani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
| | - Khaled A Al-Hosaini
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
| | - Shakir D Al Shrari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
| | - Salim S Al Rejaie
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
| | - Mohamed M Sayed-Ahmed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
| | - Othman A Al-Shabanah
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
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Sano E, Tashiro S, Tsumoto K, Ueda T. Differential Effects of IFN-β on the Survival and Growth of Human Vascular Smooth Muscle and Endothelial Cells. Biores Open Access 2015; 4:1-15. [PMID: 26309778 PMCID: PMC4497630 DOI: 10.1089/biores.2014.0052] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
It has been documented that interferon (IFN)-β is effective against the genesis of atherosclerosis or hyperplastic arterial disease in animal model. The main mechanism of the efficacy was antiproliferative action on the growth of vascular smooth muscle cells (SMC). To understand more about the mechanisms that are responsible for the efficacy, we examined minutely the effects of IFN-β on the apoptosis and growth of vascular SMC and endothelial cells (EC). IFN-β enhanced SMC apoptosis in serum starved medium. Conversely, EC apoptosis induced by serum and growth factor deprivation was inhibited by IFN-β. The induction of SMC apoptosis and anti-apoptotic effect on EC linked to the expression of pro-apoptotic bax mRNA and caspase-3 activities. Anti-apoptotic bcl-2 mRNA was also up-regulated in EC. IFN-β inhibited SMC growth in a dose dependent manner. However, the growth of EC was rather enhanced by a low dose of IFNs. The antiproliferative effect on SMC associated with the activation of p21 and increase of G0/G1 arrested cells. The growth stimulation on EC was considered to link with increase of S and G2/M phase cells. SMC produced IFN-β in response to various stimulants. However, IFN-β was not induced in EC. These suggested that endogenous IFN-β from SMC may act on EC and affect to EC functions. In this study, it was clarified that IFN-β enhances SMC apoptosis and inhibits the EC apoptosis, and stimulates the EC growth. These effects were considered to contribute to a cure against hyperplastic arterial diseases as the mechanisms in the efficacy of IFN-β.
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Affiliation(s)
- Emiko Sano
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo , Chiba, Japan
| | - Shinya Tashiro
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo , Chiba, Japan . ; Department of Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Kouhei Tsumoto
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo , Chiba, Japan . ; Department of Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo , Tokyo, Japan . ; Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo , Tokyo, Japan
| | - Takuya Ueda
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo , Chiba, Japan
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JAK2-targeted anti-inflammatory effect of a resveratrol derivative 2,4-dihydroxy-N-(4-hydroxyphenyl)benzamide. Biochem Pharmacol 2013; 86:1747-61. [PMID: 24144632 DOI: 10.1016/j.bcp.2013.10.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 10/10/2013] [Accepted: 10/10/2013] [Indexed: 02/06/2023]
Abstract
Chemical derivatization of resveratrol has been widely conducted in an effort to overcome its chemical instability and therapeutic potential. In the present study, we examined the anti-inflammatory effects of resveratrol derivatives containing an amide functionality using in vitro macrophage models that were stimulated by Toll-like receptor (TLR) ligands, and using several animal inflammatory disease models. Of the resveratrol derivatives tested, compound 8 (2,4-dihydroxy-N-(4-hydroxyphenyl)benzamide) most strongly inhibited the production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and prostaglandin E2 (PGE2), as well as the mRNA expression of inducible NO synthase (iNOS), TNF-α, and cyclooxygenase (COX)-2 in lipopolysaccharide (LPS)-activated RAW264.7 cells, differentiated U937 cells, and peritoneal macrophages. The inhibitory activity of compound 8 was apparently mediated by suppressing the phosphorylation of signal transducer and activator of transcription (STAT)-1, STAT-3, STAT-5, and interferon regulatory factor (IRF)-3. The direct target of compound 8 was revealed to be Janus kinase 2 (JAK2) but not TANK-binding kinase (TBK) 1 using the direct kinase assay and analyses of complex formation with these molecules. Additionally, upstream kinase of TBK1 seems to be also inhibited by compound 8. This compound also strongly ameliorated mouse inflammatory symptoms seen in arachidonic acid-induced ear edema, dextran sodium sulfate (DSS)-treated colitis, EtOH/HCl-induced gastritis, collagen type II-triggered arthritis, and acetic acid-induced writhing. Therefore, of the resveratrol derivatives that we tested, compound 8 was determined to have the strongest anti-inflammatory activities in vitro and in vivo and may potentially be developed for use as a novel anti-inflammatory drug.
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Aspirin enhances IFN-α-induced growth inhibition and apoptosis of hepatocellular carcinoma via JAK1/STAT1 pathway. Cancer Gene Ther 2013; 20:366-74. [PMID: 23703473 DOI: 10.1038/cgt.2013.29] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
STAT1 has a key role in exerting the antiproliferative and proapoptotic effects of interferon (IFN)-α on tumors, and its defects in expression is associated with IFN-α resistance. In this study we want to investigate whether aspirin can improve the antitumor efficiency of IFN-α on hepatocellular carcinoma (HCC) through the activation of STAT1. We found that aspirin not only significantly enhanced IFN-α-induced antiproliferation and apoptosis of HCC in vitro study but also enhanced tumor growth inhibition in nude mice. Although IFN-α alone resulted in significant phosphorylation of both STAT1 and STAT3, aspirin only prompted the IFN-α-induced phosphorylation of STAT1. Further study revealed that aspirin-prompted phosphorylation of STAT1 was activated through phosphorylation of JAK1. Furthermore, aspirin-activated STAT1 upregulated the transcription of proapoptotic IFN-stimulated gene (ISG) of X-linked inhibitor of apoptosis-associated factor-1 and downregulated the transcription of antiapoptotic ISG of G1P3, which in turn promoted the expression of Bax and activation of caspase-9 and caspase-3, thereby sensitizing HCC cells to IFN-α-induced apoptosis. Taken together, our findings suggest a novel strategy of using aspirin to overcome tumor resistance and enhance the effectiveness of IFN-α in HCC treatment through activating STAT1 gene, and have potential implications for improving future IFN-α protein and gene therapy.
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Sano E, Tashiro S, Tadakuma H, Takei T, Ueda T, Tsumoto K. Type 1 IFN inhibits the growth factor deprived apoptosis of cultured human aortic endothelial cells and protects the cells from chemically induced oxidative cytotoxicity. J Cell Biochem 2013; 113:3823-34. [PMID: 22821369 DOI: 10.1002/jcb.24259] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
It has been shown that the genesis of atherosclerotic lesions is resulted from the injury of vascular endothelial cells and the cell damage is triggered by oxygen radicals generated from various tissues. Human vascular endothelial cells can survive and proliferate depending on growth factors such as VEGF or basic FGF and are induced apoptosis by the deprivation of growth factor or serum. It was found that type 1 IFN inhibits the growth factor deprived cell death of human aortic endothelial cells (HAEC) and protects the cells from chemically induced oxidative cytotoxicity. The anti-apoptotic effects of type 1 IFN were certified by flow cytometry using annexin-V-FITC/PI double staining and cell cycle analysis, fluorescence microscopy using Hoechst33342 and PI, colorimetric assay for caspase-3 activity, p53 and bax mRNA expressions, and cell counts. It was considered that IFN-β inhibits the executive late stage apoptosis from the results of annexin-V-FITC/PI double staining and the inhibition of caspase-3 activity, and that the anti-apoptotic effect might be owing to the direct inhibition of the apoptotic pathway mediated by p53 from the transient down-regulation of bax mRNA expression. Whereas, type 1 IFN protected the cells from the oxidative cytotoxicity induced by tertiary butylhydroperoxide (TBH) under the presence of Ca(2+). The effects of IFN-β is more potent inhibitor of cell death than IFN-α. These results indicate that type 1 IFN, especially IFN-β may be useful for the diseases with vascular endothelium damage such as atherosclerosis or restenosis after angioplasty as a medical treatment or a prophylactic.
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Affiliation(s)
- Emiko Sano
- Department of Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, Shirokanedai, Tokyo, 108-8639, Japan.
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Bukovsky A, Caudle MR. Immunoregulation of follicular renewal, selection, POF, and menopause in vivo, vs. neo-oogenesis in vitro, POF and ovarian infertility treatment, and a clinical trial. Reprod Biol Endocrinol 2012; 10:97. [PMID: 23176151 PMCID: PMC3551781 DOI: 10.1186/1477-7827-10-97] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2012] [Accepted: 11/11/2012] [Indexed: 12/13/2022] Open
Abstract
The immune system plays an important role in the regulation of tissue homeostasis ("tissue immune physiology"). Function of distinct tissues during adulthood, including the ovary, requires (1) Renewal from stem cells, (2) Preservation of tissue-specific cells in a proper differentiated state, which differs among distinct tissues, and (3) Regulation of tissue quantity. Such morphostasis can be executed by the tissue control system, consisting of immune system-related components, vascular pericytes, and autonomic innervation. Morphostasis is established epigenetically, during morphogenetic (developmental) immune adaptation, i.e., during the critical developmental period. Subsequently, the tissues are maintained in a state of differentiation reached during the adaptation by a "stop effect" of resident and self renewing monocyte-derived cells. The later normal tissue is programmed to emerge (e.g., late emergence of ovarian granulosa cells), the earlier its function ceases. Alteration of certain tissue differentiation during the critical developmental period causes persistent alteration of that tissue function, including premature ovarian failure (POF) and primary amenorrhea. In fetal and adult human ovaries the ovarian surface epithelium cells called ovarian stem cells (OSC) are bipotent stem cells for the formation of ovarian germ and granulosa cells. Recently termed oogonial stem cells are, in reality, not stem but already germ cells which have the ability to divide. Immune system-related cells and molecules accompany asymmetric division of OSC resulting in the emergence of secondary germ cells, symmetric division, and migration of secondary germ cells, formation of new granulosa cells and fetal and adult primordial follicles (follicular renewal), and selection and growth of primary/preantral, and dominant follicles. The number of selected follicles during each ovarian cycle is determined by autonomic innervation. Morphostasis is altered with advancing age, due to degenerative changes of the immune system. This causes cessation of oocyte and follicular renewal at 38 +/-2 years of age due to the lack of formation of new granulosa cells. Oocytes in primordial follicles persisting after the end of the prime reproductive period accumulate genetic alterations resulting in an exponentially growing incidence of fetal trisomies and other genetic abnormalities with advanced maternal age. The secondary germ cells also develop in the OSC cultures derived from POF and aging ovaries. In vitro conditions are free of immune mechanisms, which prevent neo-oogenesis in vivo. Such germ cells are capable of differentiating in vitro into functional oocytes. This may provide fresh oocytes and genetically related children to women lacking the ability to produce their own follicular oocytes. Further study of "immune physiology" may help us to better understand ovarian physiology and pathology, including ovarian infertility caused by POF or by a lack of ovarian follicles with functional oocytes in aging ovaries. The observations indicating involvement of immunoregulation in physiological neo-oogenesis and follicular renewal from OSC during the fetal and prime reproductive periods are reviewed as well as immune system and age-independent neo-oogenesis and oocyte maturation in OSC cultures, perimenopausal alteration of homeostasis causing disorders of many tissues, and the first OSC culture clinical trial.
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Affiliation(s)
- Antonin Bukovsky
- The Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
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Yu CC, Ko FY, Yu CS, Lin CC, Huang YP, Yang JS, Lin JP, Chung JG. Norcantharidin triggers cell death and DNA damage through S-phase arrest and ROS-modulated apoptotic pathways in TSGH 8301 human urinary bladder carcinoma cells. Int J Oncol 2012; 41:1050-60. [PMID: 22684608 DOI: 10.3892/ijo.2012.1511] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 04/27/2012] [Indexed: 11/05/2022] Open
Abstract
Norcantharidin (NCTD) is one of the ingredients of blister beetles which have been used in Chinese medicine for a long time. The purpose of this study was to investigate the inhibitory effects of NCTD on TSGH 8301 human bladder cancer cells in vitro and the mechanisms through which it exerts its anticancer action. Cell morphological analysis was performed using a phase-contrast microscope. The percentage of viable cells, cell cycle distribution, sub-G1 phase (apoptosis), reactive oxygen species (ROS) production and the levels of mitochondrial membrane potential (∆Ψ(m)) were analyzed by flow cytometry. DNA condensation and damage were determined by DAPI staining and comet assay. Apoptosis-associated protein level changes in TSGH 8301 cells following exposure to NCTD were examined, measured and determined by western blotting. Analysis of protein translocation was conducted by immunostaining and confocal laser microscopy. The results indicated that NCTD promoted cytotoxic effects, including the induction of cell morphological changes and the decrease in the percentage of viability, the induction of S-phase arrest as well as sub-G1 phase (apoptosis) in TSGH 8301 cells. The activities of caspase-3 and -9 were upregulated following NCTD treatment. Western blotting indicated that NCTD upregulated Fas, FasL, Bax, Bid, cytochrome c, caspase-3, -8 and -9 that led to the induction of apoptosis through the Fas extrinsic pathway. Furthermore, NCTD induced AIF and Endo G that were released from mitochondria to induce apoptosis through the mitochondrial-independent pathway. NCTD upregulated ROS production, downregulated ∆Ψ(m) and ERK, JNK, p38 protein kinases in TSGH 8301 cells. These findings suggest that NCTD triggers apoptosis in TSGH 8301 human bladder cancer cells via the Fas receptor, activation of the caspse-8, -9 and -3, mitochondrial-dependent and -independent pathways. NCTD may be useful for developing new therapeutic regimens for the treatment of bladder cancer.
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Affiliation(s)
- Chien-Chih Yu
- School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C
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Abstract
Hepatic fibrosis is a common pathological change occurring in chronic liver disease which is induced by a variety of etiological factors. Hepatic fibrosis is a dynamic process, and a reversible pathological change. However, when it has progressed to hepatic cirrhosis, it is irreversible. Therefore, to block or reverse the course of hepatic fibrosis is a very significant target for the treatment of chronic liver disease. Interferon (IFN) has extensive functions, including anti-viral, anti-tumor and immunological roles. Recent research has reported that IFN possesses an anti-hepatic fibrosis function, with potential clinical application. However, the exact mechanism underlying its anti-hepatic fibrosis action remains unknown. Some scholars believe that this mechanism involves interferon's anti-viral effects, the inhibition of hepatic stellate cell (HSC) activation, the promotion of HSC apoptosis, the inhibition of extracellular matrix (ECM) synthesis and the promotion of ECM degradation.
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Kocic G, Bjelakovic G, Pavlovic D, Jevtovic T, Pavlovic V, Sokolovic D, Basic J, Cekic S, Cvetkovic T, Kocic R, Stojanovic S. Protective effect of interferon-alpha on the DNA- and RNA-degrading pathway in anti-Fas-antibody induced apoptosis. Hepatol Res 2007; 37:637-46. [PMID: 17517072 DOI: 10.1111/j.1872-034x.2007.00090.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Fas membrane-associated polypeptide antigen is a receptor molecule responsible for apoptosis-mediated signals. In animal models of acute viral hepatitis, apoptosis of hepatocytes is mediated by Fas-death receptors; therefore, the aim of this study was to evaluate the effect of interferon (IFN)-alpha on apoptotic markers and nuclease activity against different coding and non-coding single and double stranded RNAs during Fas-induced liver apoptosis. METHODS An in vivo experiment was performed with simultaneous administration of anti-Fas (CD95) antibodies and IFN-alpha, and an in vitro experiment was performed in hepatocyte cultures treated with anti-Fas antibodies and IFN-alpha. RESULTS Detection of apoptosis using Annexin V-FITC/propidium iodide, Bcl-2 and Bax expression in hepatocyte cultures confirmed the appearance of early apoptotic events and progression toward late apoptosis after anti-Fas antibody treatment. IFN-alpha had a tendency to retard the apoptosis process in Fas-induced apoptosis by increasing the number of viable cells and decreasing the number of cells in late apoptosis, by increasing the percentage of Bcl-2 positive cells, by decreasing the percentage of Bax positive cells, and by decreasing the nuclease activity compared to the anti-Fas antibody treated group. Total DNA and RNA concentration was much reduced in the Fas group and DNA fragmentation assay provided evidence for increased DNA degradation. Enhanced nuclease activity against DNA, rRNA, poly(A), poly(C), poly(U), poly(I:C), and poly(A:U) was manifested in the anti-Fas antibody treated group, except for the inhibitory-bound alkaline RNase. CONCLUSIONS The results demonstrate that the RNA-degrading pathway in Fas-induced apoptosis can accelerate the liberation of the latent enzyme from the inhibitor complex. IFN-alpha prevented enormous, Fas-ligand induced degradation of all the substrates used in this experimental study, most probably due to similarities in the signal transduction pathways. Investigations of death receptor-induced apoptosis may lead to novel treatment combinations for patients with acute or chronic liver diseases.
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Affiliation(s)
- Gordana Kocic
- Institute of Biochemistry and Institute of Physiology, Medical Faculty, University of Nis, Serbia and Montenegro
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Du SL, Pan H, Lu WY, Wang J, Wu J, Wang JY. Cyclic Arg-Gly-Asp peptide-labeled liposomes for targeting drug therapy of hepatic fibrosis in rats. J Pharmacol Exp Ther 2007; 322:560-8. [PMID: 17510318 DOI: 10.1124/jpet.107.122481] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Targeting hepatic stellate cells (HSCs) has been challenging due to the lack of specific receptors or motifs on the cells. The aim of the present study was to develop a HSC-specific system for improving drug delivery to HSCs. The affinity of a cyclic peptide containing Arg-Gly-Asp (cRGD) to collagen type VI receptor on HSCs was examined in both in vitro and in vivo experiments. Sterically stable liposomes (SSLs) were modified with this peptide to yield a new carrier, cRGD-SSL. The targeting efficiency of this carrier in delivering interferon (IFN)-alpha1b was investigated in a rat model of liver fibrosis induced by bile duct ligation (BDL). When incubating HSCs or hepatocytes with cyclic RGD peptide, the peptide was bound preferentially to activated HSCs. Biodistribution study showed that the accumulation of cRGD peptide-labeled liposomes in HSCs isolated from BDL rats was 10-fold more than unlabeled SSLs. BDL rats receiving injections of IFN-alpha1b entrapped in cRGD-SSL exhibited significantly reduced extent of liver fibrosis compared with BDL control rats or BDL rats treated with IFN-alpha1b entrapped in SSLs. Thus, cRGD-SSL is an efficient drug carrier, which selectively targets activated HSCs and improves drug therapy for liver fibrosis to a significant extent. This liposomal formulation represents a new means of targeting drug carrier for the treatment of liver fibrosis, and it may have potential clinical applications.
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Affiliation(s)
- Shi-Lin Du
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai 200032, China
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Tasci I, Mas MR, Vural SA, Deveci S, Comert B, Alcigir G, Mas N, Akay C, Bozdayi M, Yurdaydin C, Bozkaya H, Uzunalimoglu O, Isik AT, Said HM. Pegylated interferon-alpha plus taurine in treatment of rat liver fibrosis. World J Gastroenterol 2007; 13:3237-3244. [PMID: 17589904 PMCID: PMC4436611 DOI: 10.3748/wjg.v13.i23.3237] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2006] [Revised: 02/02/2007] [Accepted: 02/08/2007] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the antifibrotic effects of peginterferon-alpha 2b and taurine on oxidative stress markers and hepatocellular apoptosis. METHODS Sixty rats with CCl4-induced liver fibrosis were divided into 4 groups (n=15). Group 1 was left for spontaneous recovery (SR). Groups 2-4 received peginterferon-alpha 2b, taurine, and their combination, respectively, for four weeks. Histological fibrosis scores, histomorphometric analysis, tissue hydroxyproline, tissue MDA, GPx and SOD activities were determined. Activated stellate cells and hepatocellular apoptosis were also evaluated. RESULTS The degree of fibrosis decreased in all treatment groups compared to spontaneous recovery group. Taurine alone and in combination with peginterferon-alpha 2b reduced oxidative stress markers, but peginterferon-alpha 2b alone did not. Apoptotic hepatocytes and activated stellate cells were higher in groups 2-4 than in group 1. Combined taurine and peginterferon-alpha 2b further reduced fibrosis and increased activated stellate cell apoptosis, but could not improve oxidative stress more than taurine alone. CONCLUSION Peginterferon-alpha 2b exerts anti-fibrotic effects on rat liver fibrosis. It seems ineffective against oxidative stress in vivo. Peginterferon-alpha 2b in combination with taurine seems to be an antifibrotic strategy.
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Affiliation(s)
- Ilker Tasci
- Department of Internal Medicine, Gulhane School of Medicine Etlik 06018 Ankara, Turkey.
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Davis GL, Krawczynski K, Szabo G. Hepatitis C virus infection--pathobiology and implications for new therapeutic options. Dig Dis Sci 2007; 52:857-75. [PMID: 17333350 DOI: 10.1007/s10620-006-9484-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2006] [Accepted: 06/12/2006] [Indexed: 12/23/2022]
Abstract
Despite progress in therapeutic approaches for the elimination of hepatitis C, chronic hepatitis C virus infection remains an important cause of liver disease. Therapeutic intervention with the currently available interferon-based treatment regimens is quite successful, but treatment is difficult to tolerate and is contraindicated in many patients. A better understanding of the HCV biology, immunopathology, and liver disease will help to design better therapeutic strategies. The American Association for the Study of Liver Diseases sponsored a single-topic conference on hepatitis C virus infection on March 4 and 5, 2005, to enhance our current knowledge in the areas of basic and clinical research related to antiviral and immunomodulatory therapies in hepatitis C disease. The faculty consisted of 23 invited experts in the field of viral hepatitis. The program was divided into four sections including: (a) replicative mechanisms and models; (b) viral-host interactions; and (c) antiviral drug development and new strategies; and (d) back to the bedside-current issues. This report summarizes each of the presentations sections.
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Affiliation(s)
- Gary L Davis
- 4 Roberts, Hepatology, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA.
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17
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Molodtsov VN, Senchenkov EV, Bazhanova ED. Apoptosis and expression of vasopressin, insulin, and Bcl-2 in the neurosecretory system of aged mice. J EVOL BIOCHEM PHYS+ 2006. [DOI: 10.1134/s002209300603015x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 2006; 10:927-39. [PMID: 16151628 DOI: 10.1007/s10495-005-1055-4] [Citation(s) in RCA: 311] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver by a variety of etiological factors including viruses, alcohol and drug abuse, the metabolic syndrome, autoimmune disease and hereditary disorders of metabolism. Fibrosis is a progressive pathological process in which wound-healing myofibroblasts of the liver respond to injury by promoting replacement of the normal hepatic tissue with a scar-like matrix composed of cross-linked collagen. Until recently it was believed that this process was irreversible. However emerging experimental and clinical evidence is starting to show that even cirrhosis is potentially reversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of hepatic stellate cells (HSC) by apoptosis. Furthermore, proof-of-concept studies in rodents have demonstrated that experimental augmentation of HSC apoptosis will promote the resolution of fibrosis. Consequently there is now considerable interest in determining the molecular events that regulate HSC apoptosis and the discovery of drugs that will stimulate HSC apoptosis in a selective manner. This review will consider the regulatory role played by growth factors (e.g. NGF, IGF-1, TGFbeta), death receptor ligands (TRAIL, FAS), components and regulators of extracellular matrix (integrins, collagen, matrix metalloproteinases and their tissue inhibitors) and signal transduction proteins and transcription factors (Rho/Rho kinase, Jun N-terminal Kinase (JNK), IkappaKinase (IKK), NF-kappa B). The potential for known pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I to induce HSC apoptosis and therefore to be used therapeutically will be explored.
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Affiliation(s)
- A M Elsharkawy
- Liver Group, Division of Infection, Inflammation and Repair, University of Southampton, Southampton General Hospital, Level D, South Academic Block, Southampton, SO16 6YD, UK
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Saile B, Eisenbach C, Dudas J, El-Armouche H, Ramadori G. Interferon-gamma acts proapoptotic on hepatic stellate cells (HSC) and abrogates the antiapoptotic effect of interferon-alpha by an HSP70-dependant pathway. Eur J Cell Biol 2005; 83:469-76. [PMID: 15540463 DOI: 10.1078/0171-9335-00409] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The activated hepatic stellate cell (HSC) is an important fibrogenic cell type of the liver. Interferon-alpha (IFN-alpha) has recently been shown to elicit an antiapoptotic effect on activated HSC by a JAK-2-dependent inhibition of caspase-8 activation. As JAK-2 has so far been shown to be a member of the IFN-gamma signal transduction pathway we studied the effect of IFN-gamma on apoptosis as well as on its signaling in primary cultured rat HSC. IFN-gamma elicited a proapoptotic effect in activated HSC. The combination of both, IFN-gamma and IFN-alpha, however, completely cancelled each other's effect. No effect of the two cytokines on major members of apoptosis-regulating systems (CD95, CD95L, bcl-2, bax, bcl-xL, p53, p21WAF1, p27, NFkappaB) could be observed. Western Blot analysis revealed that gene expression of the chaperone HSP70 was found to be downregulated by IFN-gamma but upregulated by IFN-alpha. The effect could be abrogated by administration of both. After transfection of activated HSC with a pCMV-HSP70 M expression vector the proapoptotic effect of IFN-gamma was cancelled. Using HSP70 antisense, the antiapoptotic effect of IFN-alpha was cancelled as well. However IFN-gamma had no effect on upregulation of JAK-2 and pJAK-2 by IFN-alpha. Taken together IFN-gamma and IFN-alpha exert opposite effects on apoptosis in HSC. This effect is mediated by their counteracting effect on HSP70 expression which acts antiapoptotic at the level of caspase-8.
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Affiliation(s)
- Bernhard Saile
- University of Göttingen, Department of Internal Medicine, Section of Gastroenterology and Endocrinology, Göttingen, Germany
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N/A, 魏 来. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13:440-442. [DOI: 10.11569/wcjd.v13.i4.440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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N/A, 朱 焱, 林 勇, 谢 渭. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13:367-370. [DOI: 10.11569/wcjd.v13.i3.367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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22
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Proell V, Mikula M, Fuchs E, Mikulits W. The plasticity of p19 ARF null hepatic stellate cells and the dynamics of activation. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2005; 1744:76-87. [PMID: 15878400 DOI: 10.1016/j.bbamcr.2004.12.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2004] [Revised: 12/16/2004] [Accepted: 12/20/2004] [Indexed: 02/08/2023]
Abstract
In the healthy adult liver, quiescent hepatic stellate cells (HSCs) present the major site for vitamin A storage in cytoplasmic lipid droplets. During liver injury due to viral infection or alcohol intoxication, HSCs get activated and produce high amounts of extracellular matrix components for tissue repair and fibrogenesis. Employing p19 ARF deficiency, we established a non-transformed murine HSC model to investigate their plasticity and the dynamics of HSC activation. Primary HSCs isolated from livers of adult p19 ARF null mice underwent spontaneous activation through long-term passaging without an obvious replicative limit. The immortalized cell line, referred to as M1-4HSC, showed stellate cell characteristics including the expression of desmin, glial fibrillary acidic protein, alpha-smooth muscle actin and pro-collagen I. Treatment of these non-tumorigenic M1-4HSC with pro-fibrogenic TGF-beta1 provoked a morphological transition to a myofibroblastoid cell type which was accompanied by enhanced cellular turnover and impaired migration. In addition, M1-4HSCs expressed constituents of cell adhesion complexes such as p120(ctn) and beta-catenin at cell borders, which dislocalized in the cytoplasm during stimulation to myofibroblasts, pointing to the epitheloid characteristics of HSCs. By virtue of its non-transformed phenotype and unlimited availability of cells, the p19(ARF) deficient model of activated HSCs and corresponding myofibroblasts render this system a highly valuable tool for studying the cellular and molecular basis of hepatic fibrogenesis.
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Affiliation(s)
- Verena Proell
- Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschke-Gasse 8a, A-1090 Vienna, Austria
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23
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N/A. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12:2660-2663. [DOI: 10.11569/wcjd.v12.i11.2660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Jaster R. Molecular regulation of pancreatic stellate cell function. Mol Cancer 2004; 3:26. [PMID: 15469605 PMCID: PMC524499 DOI: 10.1186/1476-4598-3-26] [Citation(s) in RCA: 126] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2004] [Accepted: 10/06/2004] [Indexed: 12/11/2022] Open
Abstract
Until now, no specific therapies are available to inhibit pancreatic fibrosis, a constant pathological feature of chronic pancreatitis and pancreatic cancer. One major reason is the incomplete knowledge of the molecular principles underlying fibrogenesis in the pancreas. In the past few years, evidence has been accumulated that activated pancreatic stellate cells (PSCs) are the predominant source of extracellular matrix (ECM) proteins in the diseased organ. PSCs are vitamin A-storing, fibroblast-like cells with close morphological and biochemical similarities to hepatic stellate cells (also known as Ito-cells). In response to profibrogenic mediators such as various cytokines, PSCs undergo an activation process that involves proliferation, exhibition of a myofibroblastic phenotype and enhanced production of ECM proteins. The intracellular mediators of activation signals, and their antagonists, are only partially known so far. Recent data suggest an important role of enzymes of the mitogen-activated protein kinase family in PSC activation. On the other hand, ligands of the nuclear receptor PPARγ (peroxisome proliferator-activated receptor γ) stimulate maintenance of a quiescent PSC phenotype. In the future, targeting regulators of the PSC activation process might become a promising approach for the treatment of pancreatic fibrosis.
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Affiliation(s)
- Robert Jaster
- Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, E,-Heydemann-Str, 6, 18057 Rostock, Germany.
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Saile B, DiRocco P, Dudas J, El-Armouche H, Sebb H, Eisenbach C, Neubauer K, Ramadori G. IGF-I induces DNA synthesis and apoptosis in rat liver hepatic stellate cells (HSC) but DNA synthesis and proliferation in rat liver myofibroblasts (rMF). J Transl Med 2004; 84:1037-49. [PMID: 15156158 DOI: 10.1038/labinvest.3700116] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Several lines of evidence suggest a role of insulin-like growth factor I (IGF-I) in the regulation of apoptosis. Up to now its impact on many specific cells is unknown. We therefore studied the effect of IGF-I on two similar mesenchymal matrix-producing cell types of the liver, the hepatic stellate cells (HSC) and the myofibroblasts (rMF). The present study aimed to reveal the influence of IGF-I on cell cycle and apoptosis of HSC and rMF and to elucidate responsible signaling. While IGF-I significantly increased DNA synthesis in HSC, cell number decreased and apoptosis increased. In rMF IGF-I also increased DNA synthesis, which is, however, followed by proliferation. Blocking extracellular signal regulating kinase (ERK) revealed that in HSC, bcl-2 upregulation and bax downregulation are effected downstream of ERK, whereas downregulation of NFkappaB and consecutive of bcl-xL is mediated upstream. In the rMF upregulation of both, the antiapoptotic bcl-2 and bcl-xL is mediated upstream of ERK. The expression of the proapoptotic bax is not regulated by IGF-I in rMF. The studies demonstrate a completely different effect and signaling of IGF-I in two morphologically and functionally similar matrix-producing cells of the liver.
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Affiliation(s)
- Bernhard Saile
- Department of Internal Medicine, Section of Gastroenterology and Endocrinology, University of Göttingen, Göttingen, Germany
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