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Sorour A, Aly RG, Ragab HM, Wahid A. Structure Modification Converts the Hepatotoxic Tacrine into Novel Hepatoprotective Analogs. ACS OMEGA 2024; 9:2491-2503. [PMID: 38250371 PMCID: PMC10795119 DOI: 10.1021/acsomega.3c07126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 12/02/2023] [Accepted: 12/11/2023] [Indexed: 01/23/2024]
Abstract
The liver is responsible for critical functions such as metabolism, secretion, storage, detoxification, and the excretion of various compounds. However, there is currently no approved drug treatment for liver fibrosis. Hence, this study aimed to explore the potential hepatoprotective effects of chlorinated and nonchlorinated 4-phenyl-tetrahydroquinoline derivatives. Originally developed as tacrine analogs with reduced hepatotoxicity, these compounds not only lacked hepatotoxicity but also displayed a remarkable hepatoprotective effect. Treatment with these derivatives notably prevented the chemically induced elevation of hepatic indicators associated with liver injury. Additionally, the compounds restored the activities of defense antioxidant enzymes as well as levels of inflammatory markers (TNF-α and IL-6), apoptotic proteins (Bax and Bcl2), and fibrogenic mediators (α-SMA and TGF-β) to normal levels. Histopathologic analysis confirmed the hepatoprotective activity of tetrahydroquinolines. Furthermore, computer-assisted simulation docking results were highly consistent with those of the observed in vivo activities. In conclusion, the designed tacrine analogs exhibited a hepatoprotective role in acute liver damage, possibly through their antioxidative, anti-inflammatory, and antifibrotic effects.
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Affiliation(s)
- Amani
A. Sorour
- Department
of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
| | - Rania G. Aly
- Department
of Pathology, Faculty of Medicine, Alexandria
University, Alexandria 21521, Egypt
| | - Hanan M. Ragab
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
| | - Ahmed Wahid
- Department
of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
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Yamaguchi T, Shibata K, Hasumi K, Nobe K. Potent Efficacy of 3-Amino-4-hydroxy Benzoic Acid, a Small Molecule Having Anti-fibrotic Activity, in a Mouse Model of Non-alcoholic Steatohepatitis. Biol Pharm Bull 2024; 47:434-442. [PMID: 38369342 DOI: 10.1248/bpb.b23-00771] [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] [Indexed: 02/20/2024]
Abstract
Non-alcoholic steatohepatitis (NASH), which is on the rise due to the increasing obese population and changing lifestyles, causes fibrosis over time and carries the risk of progression to cirrhosis and hepatocellular carcinoma. However, there are no approved effective treatments for NASH. Recent studies suggest that increased lipid metabolism and reduced nitric oxide content are responsible for NASH; 3-amino-4-hydroxy benzoic acid (AHBA) was identified as an inhibitor for the phosphatase activity of soluble epoxy hydrolase, which in turn inhibits lipid metabolism and endothelial nitric oxide synthase activity. The aim of this study was to assess the efficacy of AHBA in a mouse model of NASH. NASH was induced in mice by streptozotocin administration and a high-fat diet loading. The efficacy of AHBA was determined by measuring liver function using serum and liver samples and conducting a morphological assessment. AHBA considerably attenuated the increase in the liver weight and alkaline phosphatase content, which occurred due to the progression of NASH. Hepatocellular steatosis, inflammatory cell infiltration, and hepatocellular ballooning of hepatocytes remained unaltered. In contrast, AHBA treatment significantly ameliorated the fibrotic alterations within liver tissue that were induced by the onset of NASH. These results demonstrate the potential of AHBA as a therapeutic pharmaceutical compound that can treat NASH.
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Affiliation(s)
- Tomoaki Yamaguchi
- Department of Pharmacology, Showa University Graduate School of Pharmacy
- Pharmacological Research Center, Showa University
| | - Keita Shibata
- Department of Pharmacology, Showa University Graduate School of Pharmacy
- Pharmacological Research Center, Showa University
| | - Keiji Hasumi
- Department of Applied Biological Science, Tokyo University of Agriculture and Technology
| | - Koji Nobe
- Department of Pharmacology, Showa University Graduate School of Pharmacy
- Pharmacological Research Center, Showa University
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3
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Nady R, Ahmed RR, Moustafa N, Abdul-Hamid M. TNF-α blockage by etanercept restores spatial learning and reduces cellular degeneration in the hippocampus during liver cirrhosis. Tissue Cell 2023; 85:102249. [PMID: 37865039 DOI: 10.1016/j.tice.2023.102249] [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: 05/11/2023] [Revised: 09/29/2023] [Accepted: 10/16/2023] [Indexed: 10/23/2023]
Abstract
Hepatic encephalopathy (HE) is one of the most debilitating cerebral complications of liver cirrhosis. The one-year survival of patients with liver cirrhosis and severe encephalopathy is less than 50%. Recent studies have indicated that neuroinflammation is a new player in the pathogenesis of HE, which seems to be involved in the development of cognitive impairment. In this study, we demonstrated neurobehavioral and neuropathological consequences of liver cirrhosis and tested the therapeutic potential of the tumor necrosis factor-α (TNF-α) inhibitor, etanercept. Sixty male adult Wistar albino rats (120-190 g) were allocated into four groups, where groups I and IV served as controls. Thioacetamide (TAA; 300 mg/kg) was intraperitoneally injected twice a week for five months to induce liver cirrhosis in group II (n = 20). Both TAA and etanercept (2 mg/kg) were administered to group III (n = 20). At the end of the experiment, spatial learning was assessed using Morris water maze. TNF-α was detected in both serum and hippocampus. The excised brains were also immunohistochemically stained with glial fibrillary acidic protein (GFAP) to estimate both the number and integrity of hippocampal astrocytes. Ultrastructural changes in the hippocampus were characterized by transmission electron microscopy. The results showed that blocking TNF-α by etanercept was accompanied by a lower TNF-α expression and a higher number of GFAP-positive astrocytes in the hippocampus. Etanercept intervention alleviated the neuronal and glial degenerative changes and impeded the deterioration of spatial learning ability. In conclusion, TNF-α is strongly involved in the development of liver cirrhosis and the associated encephalopathy. TNF-α blockers may be a promising approach for management of hepatic cirrhosis and its cerebral complications.
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Affiliation(s)
- Rehab Nady
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef 62511, Egypt
| | - Rasha R Ahmed
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef 62511, Egypt
| | - Nadia Moustafa
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef 62511, Egypt
| | - Manal Abdul-Hamid
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef 62511, Egypt.
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Gong X, Han Z, Fan H, Wu Y, He Y, Fu Y, Zhu T, Li H. The interplay of inflammation and remodeling in the pathogenesis of chronic rhinosinusitis: current understanding and future directions. Front Immunol 2023; 14:1238673. [PMID: 37771597 PMCID: PMC10523020 DOI: 10.3389/fimmu.2023.1238673] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/28/2023] [Indexed: 09/30/2023] Open
Abstract
Chronic rhinosinusitis (CRS), a common clinical condition characterized by persistent mucosal inflammation and tissue remodeling, has a complex pathogenesis that is intricately linked to innate and adaptive immunity. A number of studies have demonstrated that a variety of immune cells and cytokines that play a vital role in mediating inflammation in CRS are also involved in remodeling of the nasal mucosa and the cells as well as different cytokines involved in remodeling in CRS are also able to exert some influence on inflammation, even though the exact relationship between inflammation and remodeling in CRS has not yet been fully elucidated. In this review, the potential role of immune cells and cytokines in regulating inflammation and remodeling of CRS mucosa has been described, starting with the immune cells and cytokines that act together in inflammation and remodeling. The goal is to aid researchers in understanding intimate connection between inflammation and remodeling of CRS and to offer novel ideas for future research.
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Affiliation(s)
- Xinru Gong
- Health and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zhoutong Han
- Health and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Hongli Fan
- Health and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yuqi Wu
- Health and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yuanqiong He
- Health and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yijie Fu
- School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Tianmin Zhu
- Health and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Hui Li
- School of Preclinical Medicine, Chengdu University, Chengdu, China
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Naringenin: A Promising Therapeutic Agent against Organ Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1210675. [PMID: 34804359 PMCID: PMC8601819 DOI: 10.1155/2021/1210675] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023]
Abstract
Fibrosis is the final common pathology of most chronic diseases as seen in the heart, liver, lung, kidney, and skin and contributes to nearly half of death in the developed countries. Fibrosis, or scarring, is mainly characterized by the transdifferentiation of fibroblasts into myofibroblasts and the excessive accumulation of extracellular matrix (ECM) secreted by myofibroblasts. Despite immense efforts made in the field of organ fibrosis over the past decades and considerable understanding of the occurrence and development of fibrosis gained, there is still lack of an effective treatment for fibrotic diseases. Therefore, identifying a new therapeutic strategy against organ fibrosis is an unmet clinical need. Naringenin, a flavonoid that occurs naturally in citrus fruits, has been found to confer a wide range of pharmacological effects including antioxidant, anti-inflammatory, and anticancer benefits and thus potentially exerting preventive and curative effects on numerous diseases. In addition, emerging evidence has revealed that naringenin can prevent the pathogenesis of fibrosis in vivo and in vitro via the regulation of various pathways that involved signaling molecules such as transforming growth factor-β1/small mother against decapentaplegic protein 3 (TGF-β1/Smad3), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), sirtuin1 (SIRT1), nuclear factor-kappa B (NF-κB), or reactive oxygen species (ROS). Targeting these profibrotic pathways by naringenin could potentially become a novel therapeutic approach for the management of fibrotic disorders. In this review, we present a comprehensive summary of the antifibrotic roles of naringenin in vivo and in vitro and their underlying mechanisms of action. As a food derived compound, naringenin may serve as a promising drug candidate for the treatment of fibrotic disorders.
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Li Q, Cheng F, Zhou K, Fang L, Wu J, Xia Q, Cen Y, Chen J, Qing Y. Increased sensitivity to TNF-α promotes keloid fibroblast hyperproliferation by activating the NF-κB, JNK and p38 MAPK pathways. Exp Ther Med 2021; 21:502. [PMID: 33791011 PMCID: PMC8005672 DOI: 10.3892/etm.2021.9933] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 01/18/2021] [Indexed: 02/05/2023] Open
Abstract
Hyperproliferation of fibroblasts is the main cause of keloid formation. However, the pathogenesis of keloids has yet to be fully elucidated. Tumor necrosis factor (TNF)-α may play an important role in the formation and proliferation of keloids, as it is implicated in the pathogenesis of various fibrous disorders. In the present study, the expression level of TNF-α and its receptors, soluble TNF receptor (sTNFR)1 and sTNFR2, in the peripheral blood and skin tissues was detected by ELISA, reverse transcription-quantitative PCR or immunohistochemistry. There was no statistically significant difference in the expression of TNF-α and sTNFR2 in the peripheral blood and skin tissues between patients with keloids and healthy participants (P>0.05), while the sTNFR1 mRNA level in fibroblasts cultured in vitro and its protein level in keloid skin samples were significantly higher compared with those in normal skin (P<0.05). Subsequently, TNF-α recombinant protein was used to treat keloid-derived and normal skin fibroblasts, and it was observed that TNF-α promoted the proliferation of keloid fibroblasts (KFs), but had little effect on normal skin fibroblasts. Furthermore, it was observed that TNF-α stimulation led to the activation of the nuclear factor (NF)-κB, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in KFs. In conclusion, KFs exhibited increased expression of sTNFR1, which may contribute to the increased sensitivity to TNF-α, resulting in low concentrations of TNF-α activating the NF-κB, JNK and p38 MAPK pathways, thereby promoting the sustained and excessive proliferation of KFs.
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Affiliation(s)
- Qijie Li
- Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Fengrui Cheng
- Department of Plastic and Burn Surgery, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Kai Zhou
- Department of Plastic and Burn Surgery, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lu Fang
- Department of Plastic and Burn Surgery, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Junliang Wu
- Department of Plastic and Burn Surgery, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qingjie Xia
- Department of Anesthesiology, Institute of Neurological Diseases, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ying Cen
- Department of Plastic and Burn Surgery, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Junjie Chen
- Department of Plastic and Burn Surgery, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yong Qing
- Department of Plastic and Burn Surgery, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Li Z, Bian X, Ma Y, Yang Q, Jia W, Liu J, Wang F, Liu M, Li YX, Shao X, Wang YL. Uterine Scarring Leads to Adverse Pregnant Consequences by Impairing the Endometrium Response to Steroids. Endocrinology 2020; 161:5911727. [PMID: 32976565 DOI: 10.1210/endocr/bqaa174] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 09/23/2020] [Indexed: 12/28/2022]
Abstract
Uterine surgical scarring is an increasing risk factor for adverse pregnant consequences that threaten fetal-maternal health. The detailed molecular features of scar implantation remain largely unknown. We aim to study the pathologic features of uterine surgical scarring and the mechanisms of compromised pregnancy outcomes of scar implantation. We generated a mouse model of uterine surgical scarring with a uterine incision penetrating the myometrium to endometrium to examine the pathologic changes and transcriptome profiles of uterine scarring at various postsurgery (PS) time points, as well as features of the feto-maternal interface during scar implantation. We found that uterine surgical scar recovery was consistently poor at PS3 until PS90, as shown by a reduced number of endometrial glands, inhibition of myometrial smooth muscle cell growth but excessive collagen fiber deposition, and massive leukocyte infiltration. Transcriptome annotation indicated significant chronic inflammation at the scarring site. At the peri-implantation and postimplantation stages, abnormal expression of various steroid-responsive genes at the scarring site was in parallel with lumen epithelial cell hyperplasia, inappropriate luminal closure, and disorientation of the implanted embryo, restricted stromal cell proliferation, and defective decidualization. High embryonic lethality (around 70%) before E10.5 was observed, and the small amount of survival embryos at E10.5 exhibited restricted growth and aberrant placenta defects including overinvasion of trophoblast cells into the decidua and insufficient fetal blood vessel branching in the labyrinth. The findings indicate that chronic inflammation and compromised responses to steroids in uterine scar tissues are the pivotal molecular basis for adverse pregnancy consequences of scar implantation.
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Affiliation(s)
- Zhilang Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiaotao Bian
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yeling Ma
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Qian Yang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Wentong Jia
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Juan Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Feiyang Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ming Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Yu-Xia Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Xuan Shao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yan-Ling Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
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8
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Abdelhamid YA, Elyamany MF, Al-Shorbagy MY, Badary OA. Effects of TNF-α antagonist infliximab on fructose-induced metabolic syndrome in rats. Hum Exp Toxicol 2020; 40:801-811. [PMID: 33118400 DOI: 10.1177/0960327120969960] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Public health issues have been raised regarding fructose toxicity and its serious metabolic disorders. Deleterious effects of high fructose intake on insulin sensitivity, body weight, lipid homeostasis have been identified. The new millennium has witnessed the emergence of a modern epidemic, the metabolic syndrome (MS), in approximately 25% of the world's adult population. The current study aimed to investigate the effect of the TNF-α antagonist infliximab on fructose-induced MS in rats. Rats were administered fructose (10%) in drinking water for 12 weeks to induce the experimental MS model. infliximab (5 mg/kg) was injected once weekly intraperitoneally starting on the 13th week for 4 weeks. Increase in body weight, blood glucose level, serum triglycerides (TGs), adiponectin level and blood pressure were present in MS rats. They also prompted increases in serum of leptin, TNF-α, and malondialdehyde (MDA) levels. Treatment with infliximab did not affect body weight, hyperglycemia or hypertension, but decreased serum TGs and increased serum HDL-c levels. Infliximab also decreased adiponectin levels. Surprisingly, infliximab increased MDA above its value in the MS group. These results reflect the fact that infliximab affects the manifestations of MS in rats. Though infliximab reduced TGs, increased HDL-c levels, reversed adiponectin resistance occurred by fructose, the drug failed to combat MS-mediated hyperglycemia, hypertension, and elevated MDA above the insult.
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Affiliation(s)
| | - Mohammed F Elyamany
- Pharmacology & Toxicology Department, 110154Faculty of Pharmacy, Cairo University, Giza, Egypt
| | - Muhammad Y Al-Shorbagy
- Pharmacology & Toxicology Department, 110154Faculty of Pharmacy, Cairo University, Giza, Egypt.,Pharmacology & Toxicology Department, School of Pharmacy, Newgiza University, Egypt
| | - Osama A Badary
- Clinical Pharmacy Department, Faculty of Pharmacy, British University in Egypt, Cairo, Egypt
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Salum KCR, Castro MCS, Moreira VB, Nani ASF, Kohlrausch FB. Interleukin 1α and 1β gene variations are associated with tuberculosis in silica exposed subjects. Am J Ind Med 2020; 63:74-84. [PMID: 31692000 DOI: 10.1002/ajim.23066] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 10/16/2019] [Accepted: 10/16/2019] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Silicosis is a fibrotic lung disease resulting from the inhalation of crystalline silica and can be classified as simple or complicated according to the International Labour Organization criteria. Furthermore, individuals exposed to crystalline silica also have a higher risk for the development of tuberculosis (Tb). The contribution of inflammatory cytokines to the risk of silicosis and Tb in different populations has previously been reported. Since genetic background might be related to susceptibility to silicosis and Tb, the study of polymorphisms within IL-1α, IL-1β, and tumor necrosis factor protein-coding genes may contribute to elucidating the genetic basis of these diseases. METHODS Single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction using restriction fragment length polymorphism or by Taqman methodology, in a sample of 102 silica-exposed patients from Brazil. RESULTS No significant associations were observed between the SNPs studied and the severity of silicosis. However, significant associations were found between Tb and the C allele (odds ratio [OR] = 1.93, 95% confidence interval [CI], 1.01-3.73) and the CC genotype (OR = 2.34, 95% CI, 1.04-5.31) of IL1A -899C>T. The IL1B +3954C>T polymorphism also showed an association with Tb (T allele dominant model OR = 2.38, 95% CI, 1.04-5.41). CONCLUSION These preliminary results demonstrate that the IL1A and IL1B gene variations may contribute to some extent to susceptibility to Tb, but not silicosis. However, additional studies are still needed to confirm these results.
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Affiliation(s)
| | - Marcos Cesar Santos Castro
- Departamento de Medicina Clínica, Hospital Universitário Antônio PedroUniversidade Federal FluminenseNiterói Brazil
- Ambulatório de Pneumologia, Hospital Universitário Pedro ErnestoUniversidade do Estado do Rio de JaneiroRio de Janeiro Brazil
| | - Valéria Barbosa Moreira
- Departamento de Medicina Clínica, Hospital Universitário Antônio PedroUniversidade Federal FluminenseNiterói Brazil
| | - Angela Santos Ferreira Nani
- Departamento de Medicina Clínica, Hospital Universitário Antônio PedroUniversidade Federal FluminenseNiterói Brazil
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10
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Xiao M, Liu Y, Wang L, Liang J, Wang T, Zhai Y, Wang Y, Liu S, Liu W, Luo X, Wang F, Sun X. Intraocular VEGF deprivation induces degeneration and fibrogenic response in retina. FASEB J 2019; 33:13920-13934. [DOI: 10.1096/fj.201901283rr] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Meichun Xiao
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang Liu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lingyu Wang
- GloriousMed Technology Company, Limited, Shanghai, China
| | - Jian Liang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
| | - Tianjun Wang
- School of Life Science, University of Liverpool, Liverpool, United Kingdom
| | - Yuanqi Zhai
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
| | - Yafang Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shu Liu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenjia Liu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueting Luo
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
| | - Fenghua Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
| | - Xiaodong Sun
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
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11
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Pergel A, Tümkaya L, Çolakoğlu MK, Demiral G, Kalcan S, Özdemir A, Mercantepe T, Yilmaz A. Effects of infliximab against carbon tetrachloride-induced intestinal injury via lipid peroxidation and apoptosis. Hum Exp Toxicol 2019; 38:1275-1282. [PMID: 31378095 DOI: 10.1177/0960327119867758] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Carbon tetrachloride (CCL4) is often employed in the production of chlorofluorocarbons, petroleum refining, oil and rubber processing, and laboratory applications. Oral, subcutaneous, and inhalation exposure to CCL4 in animal studies have been shown to be capable of leading to various types of cancer (benign and malignant, liver, breast, and adrenal gland tumors). The present study also evaluated the protective role of infliximab (INF) against the deleterious effects of CCL4 on the intestinal system. Twenty-four male Sprague-Dawley rats were randomly assigned into three groups, control (n = 8), CCL4 (n = 8), and CCL4 + INF (n = 8). The control group received 1 mL isotonic saline solution only via intraperitoneal (i.p.) injection. The CCL4 group received a single i.p. dose of 2 mL/kg CCL4. The CCL4 + INF group received a single i.p. dose of 7 mg/kg INF followed 24 h later by a single dose of 2 mL/kg CCL4. All rats were euthanized 2 days following drug administration. CCL4 group samples also exhibited diffuse loss of enterocytes, vascular congestion, neutrophil infiltration, an extension of the subepithelial space and significant epithelial lifting along the length of the villi with a few denuded villous tips. In addition, CCL4 treatment increased intestinal malondialdehyde (MDA) level and caspase-3 positivity. On the other hand, INF decreased MDA levels, caspase-3 positivity, and loss of villous. Our findings suggest that CCL4 appears to exert a highly deleterious effect on the intestinal mucosa. On the other hand, INF is effective in preventing this CCL4-induced intestinal injury by reducing oxidative stress and apoptosis.
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Affiliation(s)
- A Pergel
- Department of General Surgery, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - L Tümkaya
- Department of Histology and Embryology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - M K Çolakoğlu
- Department of General Surgery, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - G Demiral
- Department of General Surgery, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - S Kalcan
- Department of General Surgery, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - A Özdemir
- Department of General Surgery, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - T Mercantepe
- Department of Histology and Embryology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - A Yilmaz
- Department of Medical Biochemistry, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
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Strowitzki MJ, Ritter AS, Kimmer G, Schneider M. Hypoxia-adaptive pathways: A pharmacological target in fibrotic disease? Pharmacol Res 2019; 147:104364. [PMID: 31376431 DOI: 10.1016/j.phrs.2019.104364] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/19/2019] [Accepted: 07/19/2019] [Indexed: 02/07/2023]
Abstract
Wound healing responses are physiological reactions to injuries and share common characteristics and phases independently of the injured organ or tissue. A major hallmark of wound healing responses is the formation of extra-cellular matrix (ECM), mainly consisting of collagen fibers, to restore the initial organ architecture and function. Overshooting wound healing responses result in unphysiological accumulation of ECM and collagen deposition, a process called fibrosis. Importantly, hypoxia (oxygen demand exceeds supply) plays a significant role during wound healing responses and fibrotic diseases. Under hypoxic conditions, cells activate a gene program, including the stabilization of hypoxia-inducible factors (HIFs), which induces the expression of HIF target genes counteracting hypoxia. In contrast, in normoxia, so-called HIF-prolyl hydroxylases (PHDs) oxygen-dependently hydroxylate HIF-α, which marks it for proteasomal degradation. Importantly, PHDs can be pharmacologically inhibited (PHI) by so-called PHD inhibitors. There is mounting evidence that the HIF-pathway is continuously up-regulated during the development of tissue fibrosis, and that pharmacological (HIFI) or genetic inhibition of HIF can prevent organ fibrosis. By contrast, initial (short-term) activation of the HIF pathway via PHI during wound healing seems to be beneficial in several models of inflammation or acute organ injury. Thus, timing and duration of PHI and HIFI treatment seem to be crucial. In this review, we will highlight the role of hypoxia-adaptive pathways during wound healing responses and development of fibrotic disease. Moreover, we will discuss whether PHI and HIFI might be a promising treatment option in fibrotic disease, and consider putative pitfalls that might result from this approach.
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Affiliation(s)
- Moritz J Strowitzki
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Alina S Ritter
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Gwendolyn Kimmer
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
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Wang K, Fang S, Liu Q, Gao J, Wang X, Zhu H, Zhu Z, Ji F, Wu J, Ma Y, Hu L, Shen X, Gao D, Zhu J, Liu P, Zhou H. TGF-β1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM. EBioMedicine 2019; 42:458-469. [PMID: 30926424 PMCID: PMC6491716 DOI: 10.1016/j.ebiom.2019.03.058] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 03/13/2019] [Accepted: 03/19/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatic stellate cell (HSC) activation induced by transforming growth factor β1 (TGF-β1) plays a pivotal role in fibrogenesis, while the complex downstream mediators of TGF-β1 in such process are largely unknown. METHODS We performed pharmacoproteomic profiling of the mice liver tissues from control, carbon tetrachloride (CCl4)-induced fibrosis and NPLC0393 administrated groups. The target gene MAT2A was overexpressed or knocked down in vivo by tail vein injection of AAV vectors. We examined NF-κB transcriptional activity on MAT2A promoter via luciferase assay. Intracellular SAM contents were analyzed by LC-MS method. FINDINGS We found that methionine adenosyltransferase 2A (MAT2A) is significantly upregulated in the CCl4-induced fibrosis mice, and application of NPLC0393, a known small molecule inhibitor of TGF-β1 signaling pathway, inhibits the upregulation of MAT2A. Mechanistically, TGF-β1 induces phosphorylation of p65, i.e., activation of NF-κB, thereby promoting mRNA transcription and protein expression of MAT2A and reduces S-adenosylmethionine (SAM) concentration in HSCs. Consistently, in vivo and in vitro knockdown of MAT2A alleviates CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitates hepatic fibrosis and abolishes therapeutic effect of NPLC0393. INTERPRETATION This study identifies TGF-β1/p65/MAT2A pathway that is involved in the regulation of intracellular SAM concentration and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis. FUND: This work was supported by National Natural Science Foundation of China (No. 81500469, 81573873, 81774196 and 31800693), Zhejiang Provincial Natural Science Foundation of China (No. Y15H030004), the National Key Research and Development Program from the Ministry of Science and Technology of China (No. 2017YFC1700200) and the Key Program of National Natural Science Foundation of China (No. 8153000502).
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Affiliation(s)
- Kuifeng Wang
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, 150 Ximen Road of Linhai City, Taizhou 317000, China; Suzhou GenHouse Pharmaceutical Co., Ltd., 388 Ruoshui Road, Suzhou, Jiangsu 215123, China
| | - Shanhua Fang
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Qian Liu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
| | - Jing Gao
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Xiaoning Wang
- E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Hongwen Zhu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Zhenyun Zhu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Feihong Ji
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, 150 Ximen Road of Linhai City, Taizhou 317000, China; Suzhou GenHouse Pharmaceutical Co., Ltd., 388 Ruoshui Road, Suzhou, Jiangsu 215123, China
| | - Jiasheng Wu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Yueming Ma
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Lihong Hu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China
| | - Xu Shen
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China
| | - Daming Gao
- CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Jiansheng Zhu
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, 150 Ximen Road of Linhai City, Taizhou 317000, China.
| | - Ping Liu
- E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China.
| | - Hu Zhou
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
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Tumor necrosis factor gene polymorphisms are associated with silicosis: a systemic review and meta-analysis. Biosci Rep 2019; 39:BSR20181896. [PMID: 30643011 PMCID: PMC6361771 DOI: 10.1042/bsr20181896] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/18/2018] [Accepted: 01/13/2019] [Indexed: 01/11/2023] Open
Abstract
Studies investigating association between tumor necrosis factor (TNF) gene polymorphisms and silicosis susceptibility report conflicting results. The aim of this meta-analysis was to assess association between TNF gene polymorphisms and silicosis susceptibility. A systematic literature search was conducted to find relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. Finally, a total of 12 articles, involving 1990 silicosis patients and 1898 healthy controls were included in the meta-analysis. Overall, meta-analysis revealed a significant association between the TNF −308A allele and silicosis (OR = 1.348, 95%CI = 1.156–1.570, P<0.001). A significant association of AA+AG genotype of the TNF −308 A/G polymorphism with susceptibility to silicosis was also found (OR = 1.466, 95%CI = 1.226–1.753, P<0.001). After stratification by ethnicity, significant associations were detected under the genetic models (A allele and AA+AG genotype) for TNF −308A/G polymorphisms in the Asian population (P<0.05). Similarly, meta-analysis of the TNF −238A/G polymorphism revealed the same pattern as that shown by meta-analysis of TNF −308A/G. The meta-analysis suggests that the TNF −308A/G and −238A/G polymorphisms are associated with susceptibility to silicosis, especially in Asians.
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Yang LT, Liu X, Wu GH, Chen LF. Association between tumor necrosis factor-α -308 Gauss/A polymorphism and risk of silicosis and coal workers pneumoconiosis in Chinese population. Inhal Toxicol 2018; 30:213-217. [PMID: 30257124 DOI: 10.1080/08958378.2018.1494766] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Li-teng Yang
- Department of Respiratory Medicine, Shenzhen Luohu People's Hospital, The Third Affiliatied Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Xin Liu
- Zunyi Medicine-Pharmacology College, Zunyi, Guizhou, China
| | - Gao-hui Wu
- Department of Respiratory Medicine, Shenzhen Luohu People's Hospital, The Third Affiliatied Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Li-fang Chen
- Department of Respiratory Medicine, Shenzhen Luohu People's Hospital, The Third Affiliatied Hospital of Shenzhen University, Shenzhen, Guangdong, China
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Mack M. Inflammation and fibrosis. Matrix Biol 2018; 68-69:106-121. [DOI: 10.1016/j.matbio.2017.11.010] [Citation(s) in RCA: 179] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 11/24/2017] [Accepted: 11/25/2017] [Indexed: 02/07/2023]
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Sekkien A, Swilam N, Ebada SS, Esmat A, El-Khatib AH, Linscheid MW, Singab AN. Polyphenols from Tamarix nilotica: LC⁻ESI-MS n Profiling and In Vivo Antifibrotic Activity. Molecules 2018; 23:E1411. [PMID: 29891794 PMCID: PMC6100050 DOI: 10.3390/molecules23061411] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 05/30/2018] [Accepted: 06/03/2018] [Indexed: 02/07/2023] Open
Abstract
Tamarix nilotica (Ehrenb.) Bunge (Tamaricaceae), an indigenous plant to the Middle East region, is well-known as a medicinal plant for treating many human ailments. The current study aimed at exploring the polyphenol profile of the alcohol soluble fraction of aqueous T. nilotica extract, assessing its in vivo antifibrotic activity and the possible underlying mechanism, to unravel the impact of quantitative difference of sulphated polyphenols content on the antifibrotic activity of T. nilotca grown in two different habitats. Polyphenol profiling of T. nilotica extracts was performed using HPLC-HRESI-QTOF-MS-MS. The major polyphenol components included sulphated flavonoids, phenolic acids and free aglycones. The antifibrotic activity was evaluated through carbon tetrachloride-induced liver fibrosis in rats. Biochemical evaluations revealed that both fractions ameliorated the increased levels of hepatic aminotransferases, lipid peroxidation, hydroxyproline, α-smooth muscle actin (α-SMA), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB). Moreover, both fractions reduced catalase activity (CAT) and enhanced hepatic glutathione (GSH) content. Histopathological imaging undoubtedly confirmed such results. In conclusion, the T. nilotica polyphenol-rich fraction exhibited potential antifibrotic activity in rats. Significant alterations in GSH levels were recorded based on the sulphated polyphenol metabolite content.
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Affiliation(s)
- Ahmed Sekkien
- Department of Pharmacognosy, Faculty of Pharmacy, British University in Egypt (BUE), Cairo 11837, Egypt.
| | - Noha Swilam
- Department of Pharmacognosy, Faculty of Pharmacy, British University in Egypt (BUE), Cairo 11837, Egypt.
| | - Sherif S Ebada
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
| | - Ahmed Esmat
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
| | - Ahmed H El-Khatib
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
- Laboratory of Applied Analytical and Environmental Chemistry, Department of Chemistry, Humboldt-Universität zu Berlin, 10099 Berlin, Germany.
| | - Michael W Linscheid
- Laboratory of Applied Analytical and Environmental Chemistry, Department of Chemistry, Humboldt-Universität zu Berlin, 10099 Berlin, Germany.
| | - Abdel Nasser Singab
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
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Vega-Magaña N, Delgado-Rizo V, García-Benavides L, Del Toro-Arreola S, Segura-Ortega J, Morales ASMZ, Zepeda-Nuño JS, Escarra-Senmarti M, Gutiérrez-Franco J, Haramati J, Bueno-Topete MR. Bacterial Translocation Is Linked to Increased Intestinal IFN-γ, IL-4, IL-17, and mucin-2 in Cholestatic Rats. Ann Hepatol 2018; 17:318-329. [PMID: 29469038 DOI: 10.5604/01.3001.0010.8662] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
UNLABELLED Background and rationale for the study. Bacterial translocation is an important triggering factor of infection and mortality in cirrhosis. In a rat model using bile duct ligation (BDL), bacterial translocation appears within 24 h after ligation. The dynamic between TH1/TH2/TH17 cytokines and the integrity of the colonic mucosa in the context of cirrhosis is little known. This study aims to determine the link between bacterial translocation and intestinal inflammation in a cholestasis model. Additionally, alterations of the colonic mucus layer and the bacterial load were also addressed. RESULTS Bacterial translocation detected by microbiological cultures and MALDI-TOF showed that Escherichia coli predominates in mesenteric lymph nodes of BDL rats. Intestinal bacterial load analyzed by qPCR indicates a dramatic Escherichia/Shigella overgrowth at 8 and 30 days post-BDL. IFN-γ, IL-4, and IL-17 evaluated by Western blotting were increased at 8 and 30 days in the small intestine. In the colon, in contrast, only IFN-γ was significantly increased. The colonic mucus layer and mucin-2 expression determined by Alcian blue staining and immunohistochemistry surprisingly showed an increase in the mucus layer thickness related to increased mucin-2 expression during the entire process of liver damage. Hepatic enzymes, as well as collagen I, collagen III, TNF-α, and IL-6 liver gene expression were increased. In conclusion, bacterial overgrowth associated with bacterial translocation is linked to the over-expression of IFN-γ, IL-4, IL-17 and mucin-2. These molecules might facilitate the intestinal permeability through exacerbating the inflammatory process and disturbing tight junctions, leading to the perpetuation of the liver damage.
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Affiliation(s)
- Natali Vega-Magaña
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara. Guadalajara, Jalisco, México. Instituto de Investigación en Enfermedades Crónico-Degenerativas, Departamento de Biología Molecular y Genómica
| | - Vidal Delgado-Rizo
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara. Guadalajara, Jalisco, México. Laboratorio de Inmunología, Departamento de Fisiología
| | - Leonel García-Benavides
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara. Guadalajara, Jalisco, México. Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología
| | - Susana Del Toro-Arreola
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara. Guadalajara, Jalisco, México. Instituto de Investigación en Enfermedades Crónico-Degenerativas, Departamento de Biología Molecular y Genómica
| | - Jorge Segura-Ortega
- OPD Hospital Civil de Guadalajara "Juan I. Menchaca". Guadalajara, Jalisco, México. Servicio de Gastroenterología
| | - Adelaida Sara M Zepeda Morales
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara. Guadalajara, Jalisco, México. Instituto de Investigación en Enfermedades Crónico-Degenerativas, Departamento de Biología Molecular y Genómica
| | - José Sergio Zepeda-Nuño
- Centro Universitario de Ciencias de la Salud. Laboratorio de Patología, Departamento de Microbiología y Patología
| | - Marta Escarra-Senmarti
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara. Guadalajara, Jalisco, México. Instituto de Investigación en Enfermedades Crónico-Degenerativas, Departamento de Biología Molecular y Genómica
| | - Jorge Gutiérrez-Franco
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara. Guadalajara, Jalisco, México. Instituto de Investigación en Enfermedades Crónico-Degenerativas, Departamento de Biología Molecular y Genómica
| | - Jesse Haramati
- Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara. Guadalajara, Jalisco, México. Laboratorio de Inmunología, Departamento de Biología Celular y Molecular
| | - Miriam R Bueno-Topete
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara. Guadalajara, Jalisco, México. Instituto de Investigación en Enfermedades Crónico-Degenerativas, Departamento de Biología Molecular y Genómica
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Ahmad SB, Rehman MU, Fatima B, Ahmad B, Hussain I, Ahmad SP, Farooq A, Muzamil S, Razzaq R, Rashid SM, Ahmad Bhat S, Mir MUR. Antifibrotic effects of D-limonene (5(1-methyl-4-[1-methylethenyl]) cyclohexane) in CCl 4 induced liver toxicity in Wistar rats. ENVIRONMENTAL TOXICOLOGY 2018; 33:361-369. [PMID: 29251412 DOI: 10.1002/tox.22523] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/22/2017] [Accepted: 12/02/2017] [Indexed: 06/07/2023]
Abstract
This study was designed to assess the potential antifibrotic effect of D-Limonene-a component of volatile oils extracted from citrus plants. D-limonene is reported to have numerous therapeutic properties. CCl4 -intduced model of liver fibrosis in Wistar rats is most widely used model to study chemopreventive studies. CCl4 -intoxication significantly increased serum aminotransferases and total cholesterol these effects were prevented by cotreatment with D-Limonene. Also, CCl4 -intoxication caused depletion of glutathione and other antioxidant enzymes while D-Limonene preserved them within normal values. Hydroxyproline and malondialdehyde content was increased markedly by CCl4 treatment while D-Limonene prevented these alterations. Levels of TNF-α, TGF-β, and α-SMA were also assessed; CCl4 increased the expression of α-SMA, NF-κB and other downstream inflammatory cascade while D-Limonene co-treatment inhibited them. Collectively these findings indicate that D-Limonene possesses potent antifibrotic effect which may be attributed to its antioxidant and anti-inflammatory properties.
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Affiliation(s)
- Sheikh Bilal Ahmad
- Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K), Srinagar, Jammu and Kashmir, 190006, India
| | - Muneeb U Rehman
- Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K), Srinagar, Jammu and Kashmir, 190006, India
| | - Bilques Fatima
- Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K), Srinagar, Jammu and Kashmir, 190006, India
| | - Bilal Ahmad
- Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K), Srinagar, Jammu and Kashmir, 190006, India
| | - Ishraq Hussain
- Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K), Srinagar, Jammu and Kashmir, 190006, India
| | - Sheikh Pervaiz Ahmad
- Department of Statistics, University of Kashmir, Hazratbal Srinagar, Jammu and Kashmir, 190006, India
| | - Adil Farooq
- RAKCOPS, RAK Medical & Health Sciences University, Ras AL Khaimah, UAE-11172
| | - Showkeen Muzamil
- Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K), Srinagar, Jammu and Kashmir, 190006, India
| | - Rahil Razzaq
- Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K), Srinagar, Jammu and Kashmir, 190006, India
| | - Shahzada Mudasir Rashid
- Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K), Srinagar, Jammu and Kashmir, 190006, India
| | - Showkat Ahmad Bhat
- Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K), Srinagar, Jammu and Kashmir, 190006, India
| | - Manzoor Ur Rahman Mir
- Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K), Srinagar, Jammu and Kashmir, 190006, India
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Abdul-Hamid M, Ahmed RR, Moustafa N, Nady R. The antifibrogenic effect of etanercept on development of liver cirrhosis induced by thioacetamide in rats. Ultrastruct Pathol 2016; 41:23-35. [PMID: 27982723 DOI: 10.1080/01913123.2016.1256361] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Liver cirrhosis is an elevating cause of morbidity and mortality worldwide. TNF-α/TNF-R1 signal is implicated in progression of many liver diseases. This study provides histological and ultrastructural view that clarifies the effect of etanercept, a TNF-α inhibitor, on development of thioacetamide (TAA)-induced liver cirrhosis and the accompanied hemosiderosis in rats, highlighting the implication and distribution pattern of hepatic TNF-R1. Sixty male albino rats (Rattus norvegicus) were equally randomized into three groups. Group I served as the control. Liver cirrhosis was triggered in the other two groups by intraperitoneal injection of TAA twice a week for five months. Group II received TAA only, while group III subcutaneously injected with etanercept one hour before TAA, along five months. At the end of the experiment, blood was collected for biochemical analysis and livers were excised for histological, immunohistochemical, and electron microscopical preparations. Rats treated with TAA only developed hepatic cirrhosis accompanied by massive deposition of hemosiderin; strong and widespread expression of hepatic TNF-R1 in sinusoidal endothelial cells (SECs), Kupffer cells (KCs), and many hepatocytes; and frequent appearance of fibrogenic, plasma, and mast cells, at the ultrastructural level. By contrast, administration of etanercept diminished the expression of TNF-R1, attenuated the accumulation of collagen and hemosiderin, and preserved the hepatic histoarchitecture. In conclusion, TNF-α signal via TNF-R1 may be implicated in the mechanism of fibrogenesis and the associated hemosiderosis. Etanercept may provide a promising therapeutic approach not only for attenuating the progression of fibrogenesis, but also for hepatic iron overload-associated disorders.
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Affiliation(s)
- Manal Abdul-Hamid
- a Department of Zoology, Faculty of Science , Beni-Suef University , Beni-Suef , Egypt
| | - Rasha R Ahmed
- a Department of Zoology, Faculty of Science , Beni-Suef University , Beni-Suef , Egypt
| | - Nadia Moustafa
- a Department of Zoology, Faculty of Science , Beni-Suef University , Beni-Suef , Egypt
| | - Rehab Nady
- a Department of Zoology, Faculty of Science , Beni-Suef University , Beni-Suef , Egypt
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Dong J, Ma Q. Myofibroblasts and lung fibrosis induced by carbon nanotube exposure. Part Fibre Toxicol 2016; 13:60. [PMID: 27814727 PMCID: PMC5097370 DOI: 10.1186/s12989-016-0172-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 10/25/2016] [Indexed: 01/07/2023] Open
Abstract
Carbon nanotubes (CNTs) are newly developed materials with unique properties and a range of industrial and commercial applications. A rapid expansion in the production of CNT materials may increase the risk of human exposure to CNTs. Studies in rodents have shown that certain forms of CNTs are potent fibrogenic inducers in the lungs to cause interstitial, bronchial, and pleural fibrosis characterized by the excessive deposition of collagen fibers and the scarring of involved tissues. The cellular and molecular basis underlying the fibrotic response to CNT exposure remains poorly understood. Myofibroblasts are a major type of effector cells in organ fibrosis that secrete copious amounts of extracellular matrix proteins and signaling molecules to drive fibrosis. Myofibroblasts also mediate the mechano-regulation of fibrotic matrix remodeling via contraction of their stress fibers. Recent studies reveal that exposure to CNTs induces the differentiation of myofibroblasts from fibroblasts in vitro and stimulates pulmonary accumulation and activation of myofibroblasts in vivo. Moreover, mechanistic analyses provide insights into the molecular underpinnings of myofibroblast differentiation and function induced by CNTs in the lungs. In view of the apparent fibrogenic activity of CNTs and the emerging role of myofibroblasts in the development of organ fibrosis, we discuss recent findings on CNT-induced lung fibrosis with emphasis on the role of myofibroblasts in the pathologic development of lung fibrosis. Particular attention is given to the formation and activation of myofibroblasts upon CNT exposure and the possible mechanisms by which CNTs regulate the function and dynamics of myofibroblasts in the lungs. It is evident that a fundamental understanding of the myofibroblast and its function and regulation in lung fibrosis will have a major influence on the future research on the pulmonary response to nano exposure, particle and fiber-induced pneumoconiosis, and other human lung fibrosing diseases.
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Affiliation(s)
- Jie Dong
- Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Road, Morgantown, WV, USA
| | - Qiang Ma
- Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Road, Morgantown, WV, USA.
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Schmiedlin-Ren P, Reingold LJ, Broxson CS, Rittershaus AC, Brudi JS, Adler J, Owens SR, Zimmermann EM. Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease. Am J Physiol Gastrointest Liver Physiol 2016; 311:G688-G698. [PMID: 27562059 PMCID: PMC5142192 DOI: 10.1152/ajpgi.00216.2015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 08/16/2016] [Indexed: 02/06/2023]
Abstract
Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α in a treatment paradigm. PG-PS or human serum albumin (HSA; control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNF-α or vehicle treatment was begun day (d)1, d7, or d14 postlaparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the percent decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as %decrease; gross abdominal score: d1 = 75% (P = 0.003), d7 = 57% (P = 0.18), d14 = no change (P = 0.99); histologic inflammation: d1 = 57% (P = 0.006), d7 = 50% (P = 0.019), d14 = no change (P = 0.99)]. This was also reflected in changes in IL-1β, IL-6, TNF-α, IGF-I, TGF-β1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNF-α beginning d1 or d7 compared with vehicle-treated rats; there was no effect if anti-TNF-α was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNF-α therapy is initiated early in the course of CD.
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Affiliation(s)
- Phyllissa Schmiedlin-Ren
- 1Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan;
| | - Laura J. Reingold
- 1Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan;
| | - Christopher S. Broxson
- 4Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Florida Health System, Gainesville, Florida
| | - Ahren C. Rittershaus
- 2Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan;
| | - Josh S. Brudi
- 1Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan;
| | - Jeremy Adler
- 3Division of Gastroenterology, Department of Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, Michigan; and
| | - Scott R. Owens
- 2Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan;
| | - Ellen M. Zimmermann
- 1Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan; ,4Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Florida Health System, Gainesville, Florida
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Bader El Din NG, Farouk S, El-Shenawy R, Ibrahim MK, Dawood RM, Elhady MM, Salem AM, Zayed N, Khairy A, El Awady MK. Tumor necrosis factor-α -G308A polymorphism is associated with liver pathological changes in hepatitis C virus patients. World J Gastroenterol 2016; 22:7767-7777. [PMID: 27678360 PMCID: PMC5016377 DOI: 10.3748/wjg.v22.i34.7767] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 07/05/2016] [Accepted: 07/31/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association of tumor necrosis factor alpha (TNFα) -G308A polymorphism with different liver pathological changes in treatment-naïve Egyptian patients infected with hepatitis C virus (HCV) genotype 4. METHODS This study included 180 subjects, composed of 120 treatment-naïve chronic HCV patients with different fibrosis grades (F0-F4) and 60 healthy controls. The TNFα -G308A region was amplified by PCR and the different genotypes were detected by restriction fragment length polymorphism analysis. The TNFα protein was detected by enzyme-linked immunosorbent assay. The influence of different TNFα -G308A genotypes on TNFα expression and liver disease progression were statistically analyzed. The OR and 95%CI were calculated to assess the relative risk confidence. RESULTS Current data showed that the TNFα -G308A SNP frequency was significantly different between controls and HCV infected patients (P = 0.001). Both the AA genotype and A allele were significantly higher in late fibrosis patients (F2-F4, n = 60) than in early fibrosis patients (F0-F1, n = 60) (P = 0.05, 0.04 respectively). Moreover, the GA or AA genotypes increased the TNFα serum level greater than the GG genotype (P = 0.002). The results showed a clear association between severe liver pathological conditions (inflammation, steatosis and fibrosis) and (GA + AA) genotypes (P = 0.035, 0.03, 0.04 respectively). The stepwise logistic regression analysis showed that the TNFα genotypes (GA + AA) were significantly associated with liver inflammation (OR = 3.776, 95%CI: 1.399-10.194, P = 0.009), severe steatosis (OR = 4.49, 95%CI: 1.441-14.0, P = 0.010) and fibrosis progression (OR = 2.84, 95%CI: 1.080-7.472, P = 0.034). Also, the A allele was an independent risk factor for liver inflammation (P = 0.003), steatosis (P = 0.003) and fibrosis (P = 0.014). CONCLUSION TNFα SNP at nucleotide -308 represents an important genetic marker that can be used for the prognosis of different liver pathological changes in HCV infected patients.
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Antifibrotic effect of meloxicam in rat liver: role of nuclear factor kappa B, proinflammatory cytokines, and oxidative stress. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:971-83. [PMID: 27245167 DOI: 10.1007/s00210-016-1263-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 05/24/2016] [Indexed: 01/01/2023]
Abstract
This study was aimed at investigating the antifibrotic effect of meloxicam in CCl4-induced liver fibrosis and elucidating its underlying mechanism. Forty male rats were equally randomized for 8-week treatment with corn oil (negative control), CCl4 (to induce liver fibrosis), and/or meloxicam. Meloxicam effectively ameliorated the CCl4-induced alterations in liver histology, liver weight to body weight ratio, liver functions, and serum markers for liver fibrosis (hyaluronic acid, laminin, and PCIII). Meloxicam significantly abrogated CCl4-induced elevation of messenger RNA (mRNA) expressions for collagen I and alpha smooth muscle actin (α-SMA) and hepatic contents of hydroxyproline, transforming growth factor beta (TGF-β), and tissue inhibitor of matrix metalloproteases (TIMP-1). Meloxicam mitigated CCl4-induced elevation in hepatic levels of nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), total nitric oxide (NO), interleukin-l beta (IL 1β), and prostaglandin E2 (PGE2). Meloxicam modulated CCl4-induced disturbance of liver cytochrome P450 subfamily 2E1 (CYP2E1) and glutathione-S-transferase (GST). The attenuation of meloxicam to liver fibrosis was associated with suppression of oxidative stress via reduction of lipid peroxides along with induction of reduced glutathione content and enhancement of superoxide dismutase, glutathione peroxidase, and catalase activities. This study provides an evidence for antifibrotic effect of meloxicam against CCl4-induced liver fibrosis in rat. The antifibrotic mechanism of meloxicam could be through decreasing NF-κB level and subsequent proinflammatory cytokine production (TNF-α, NO, IL-1 beta, and PGE2) and, hence, collagen deposition through inhibition of TIMP-1 and TGF-β. Abrogation of oxidative stress and modulation of liver-metabolizing enzymes (CYP2E1 and GST) were also involved.
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25
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Kim HS, Kim HG, Lee HW, Lee SB, Lee JS, Im HJ, Kim WY, Lee DS, Son CG. A Herbal Formula, CGXII, Exerts Antihepatofibrotic Effect in Dimethylnitrosamine-Induced SD Rat Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2016; 2016:5093718. [PMID: 27340416 PMCID: PMC4907344 DOI: 10.1155/2016/5093718] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 02/20/2016] [Accepted: 04/11/2016] [Indexed: 01/20/2023]
Abstract
We aimed to evaluate the antihepatofibrotic effects of CGXII, an aqueous extract which is composed of A. iwayomogi, A. xanthioides, and S. miltiorrhiza, against dimethylnitrosamine- (DMN-) induced hepatofibrosis. Male Sprague Dawley rats were intraperitoneally injected with 10 mg/kg of DMN for 4 weeks (three consecutive days weekly). Rats were orally given distilled water, CGXII (50 or 100 mg/kg), or dimethyl dimethoxy biphenyl dicarboxylate (50 mg/kg) daily. DMN injection caused substantial alteration of total body weight and liver and spleen mass, whereas they were notably normalized by CGXII. CGXII treatment also markedly attenuated the elevation of serum aspartate aminotransferase and alanine aminotransferase levels, hepatic lipid peroxidation, and protein carbonyl contents. Collagen accumulation in hepatic tissue evidenced by histopathological analysis and quantitative assessment of hepatic hydroxyproline was ameliorated by CGXII. Immunohistochemistry analysis revealed decreased α-smooth muscle actin supporting the antihepatofibrotic effect of CGXII. The profibrogenic cytokines transforming growth factor-β, platelet-derived growth factor-β, and connective tissue growth factor were increased by DMN injection. Administration of CGXII normalized the protein and gene expression levels of these cytokines. Our findings suggest that CGXII lowers the levels of profibrogenic cytokines and thereby exerts antifibrotic effects.
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Affiliation(s)
- Hyo-Seon Kim
- Liver and Immunology Research Center, Daejeon Oriental Hospital, Oriental Medical College, Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 34929, Republic of Korea
| | - Hyeong-Geug Kim
- Liver and Immunology Research Center, Daejeon Oriental Hospital, Oriental Medical College, Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 34929, Republic of Korea
| | - Hye-Won Lee
- TKM-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea
| | - Sung-Bae Lee
- Liver and Immunology Research Center, Daejeon Oriental Hospital, Oriental Medical College, Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 34929, Republic of Korea
| | - Jin-Seok Lee
- Liver and Immunology Research Center, Daejeon Oriental Hospital, Oriental Medical College, Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 34929, Republic of Korea
| | - Hwi-Jin Im
- Liver and Immunology Research Center, Daejeon Oriental Hospital, Oriental Medical College, Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 34929, Republic of Korea
| | - Won-Yong Kim
- Liver and Immunology Research Center, Daejeon Oriental Hospital, Oriental Medical College, Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 34929, Republic of Korea
| | - Dong-Soo Lee
- Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea, 64 Daeheung-ro, Jung-gu, Daejeon 34943, Republic of Korea
| | - Chang-Gue Son
- Liver and Immunology Research Center, Daejeon Oriental Hospital, Oriental Medical College, Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 34929, Republic of Korea
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Jacob N, Targan SR, Shih DQ. Cytokine and anti-cytokine therapies in prevention or treatment of fibrosis in IBD. United European Gastroenterol J 2016; 4:531-40. [PMID: 27536363 DOI: 10.1177/2050640616649356] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 04/19/2016] [Indexed: 12/18/2022] Open
Abstract
The frequency of fibrosing Crohn's disease (CD) is significant, with approximately 40% of CD patients with ileal disease developing clinically apparent strictures throughout their lifetime. Although strictures may be subdivided into fibrotic, inflammatory, or mixed forms, despite immunosuppressive therapy in CD patients in the form of steroids or immunomodulators, the frequency of fibrostenosing complications has still remained significant. A vast number of genetic and epigenetic variables are thought to contribute to fibrostenosing disease, including those that affect cytokine biology, and therefore highlight the complexity of disease, but also shed light on targetable pathways. Exclusively targeting fibrosis may be difficult, however, because of the relatively slow evolution of fibrosis in CD, and the potential adverse effects of inhibiting pathways involved in tissue repair and mucosal healing. Acknowledging these caveats, cytokine-targeted therapy has become the mainstay of treatment for many inflammatory conditions and is being evaluated for fibrotic disorders. The question of whether anti-cytokine therapy will prove useful for intestinal fibrosis is, therefore, acutely relevant. This review will highlight some of the current therapeutics targeting cytokines involved in fibrosis.
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Affiliation(s)
- Noam Jacob
- F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Digestive Diseases, Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Stephan R Targan
- F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - David Q Shih
- F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Siegmund B, Feakins RM, Barmias G, Ludvig JC, Teixeira FV, Rogler G, Scharl M. Results of the Fifth Scientific Workshop of the ECCO (II): Pathophysiology of Perianal Fistulizing Disease. J Crohns Colitis 2016; 10:377-386. [PMID: 26681764 PMCID: PMC4946764 DOI: 10.1093/ecco-jcc/jjv228] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 12/08/2015] [Indexed: 12/19/2022]
Abstract
The fifth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of fistulas to the disease course of patients with Crohn's disease (CD). The objectives were to reach a better understanding of the pathophysiological mechanisms underlying the formation of CD fistulas; to identify future topics in fistula research that could provide insights into pathogenesis; to develop novel therapeutic approaches; and to review current therapeutic strategies (with clarification of existing approaches to prevention, diagnosis and treatment). The results of the workshop are presented in two separate manuscripts. This manuscript describes current state-of-the-art knowledge about fistula pathogenesis, including the roles of epithelial-to-mesenchymal transition and cytokine matrix remodelling enzymes, and highlights the common association between fistulas and stenosis in CD. The review also considers the possible roles that genetic predisposition and intestinal microbiota play in fistula development. Finally, it proposes future directions and needs for fistula research that might substantially increase our understanding of this complex condition and help unravel novel therapeutic strategies and specific targets for treatment. Overall, it aims to highlight unanswered questions in fistula research and to provide a framework for future research work.
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Affiliation(s)
- Britta Siegmund
- Department of Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Roger M Feakins
- Department of Histopathology, Royal London Hospital, London, UK
| | - Giorgos Barmias
- Academic Department of Gastroenterology, Ethnikon and Kapodistriakon University of Athens, Laikon Hospital, Athens, Greece
| | - Juliano Coelho Ludvig
- ESADI Clinic and Gastroenterology Unit, Santa Isabel Hospital, Blumenau, Santa Catarina, Brazil
| | - Fabio Vieira Teixeira
- Colorectal Unit, Gastrosaude Clinic, Marilia, Sao Paulo, Brazil Department of Surgery, UNESP Botucatu, Sao Paulo, Brazil
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Abstract
Introduction The present review serves to provide a concise overview of the current knowledge on therapeutic strategies with regard to fibrostenotic lesions in Crohn's disease. Methods A literature search was performed focusing on the last 5 years, and current concepts of pathophysiology, epidemiology, and treatment have been summarized. Results Fibrostenotic lesions in Crohn's disease are currently considered to be a consequence of the chronic inflammatory nature of the disease. Hence, therapeutic strategies are limited to the concept that early treatment of the inflammatory lesions can prevent structural changes, and to various endoscopic and surgical approaches. Direct targeting of the fibrostenotic lesion itself has not been the focus until now. This review will provide an overview of the pathophysiology and epidemiology of fibrostenotic lesions including current therapeutic approaches. Since research with regard to other organ systems and fibrosis is far more advanced, current strategies from available studies in these areas will be discussed. The results and the potential impact for Crohn's disease will be considered. Conclusion The vision of these approaches is to reverse structural changes and restore normal function.
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Affiliation(s)
- Britta Siegmund
- Medical Department (Gastroenterology, Infectious Diseases, Rheumatology), Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
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Vairappan B. Endothelial dysfunction in cirrhosis: Role of inflammation and oxidative stress. World J Hepatol 2015; 7:443-459. [PMID: 25848469 PMCID: PMC4381168 DOI: 10.4254/wjh.v7.i3.443] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/08/2014] [Accepted: 11/27/2014] [Indexed: 02/06/2023] Open
Abstract
This review describes the recent developments in the pathobiology of endothelial dysfunction (ED) in the context of cirrhosis with portal hypertension and defines novel strategies and potential targets for therapy. ED has prognostic implications by predicting unfavourable early hepatic events and mortality in patients with portal hypertension and advanced liver diseases. ED characterised by an impaired bioactivity of nitric oxide (NO) within the hepatic circulation and is mainly due to decreased bioavailability of NO and accelerated degradation of NO with reactive oxygen species. Furthermore, elevated inflammatory markers also inhibit NO synthesis and causes ED in cirrhotic liver. Therefore, improvement of NO availability in the hepatic circulation can be beneficial for the improvement of endothelial dysfunction and associated portal hypertension in patients with cirrhosis. Furthermore, therapeutic agents that are identified in increasing NO bioavailability through improvement of hepatic endothelial nitric oxide synthase (eNOS) activity and reduction in hepatic asymmetric dimethylarginine, an endogenous modulator of eNOS and a key mediator of elevated intrahepatic vascular tone in cirrhosis would be interesting therapeutic approaches in patients with endothelial dysfunction and portal hypertension in advanced liver diseases.
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Affiliation(s)
- Balasubramaniyan Vairappan
- Balasubramaniyan Vairappan, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
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Aslan A, Can Mİ. Milk thistle impedes the development of carbontetrachloride-induced liver damage in rats through suppression of bcl-2 and regulating caspase pathway. Life Sci 2014; 117:13-8. [PMID: 25305509 DOI: 10.1016/j.lfs.2014.09.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 08/21/2014] [Accepted: 09/08/2014] [Indexed: 01/07/2023]
Abstract
AIM The objective of this study was to examine whether MT plays a protective role against the damage in the liver by administering carbontetrachloride (CCl4) to rats. MAIN METHOD 28 male Wistar albino (n=28, 8weeks old) rats have been used in the study. The rats were distributed into 4 groups according to their live weights. The groups were: (i) negative control (NC): normal water consuming group to which no CCl4 and milk thistle (MT) is administered; (ii) positive control (PC): normal water consuming group to which no CCl4 is administered but MT is administered; (iii) CCl4 group: normal water consuming and group to which CCl4 is administered (2ml/kg live weight, ip); and (iv) CCl4+MT group: CCl4 and MT administered group (2ml/kg live weight, ip). Caspase-3, caspase-9, bax, and bcl-2 protein syntheses were examined via western blotting. MDA determination in liver tissue was made using spectrophotometer. KEY FINDINGS MDA amount has decreased in the CCl4+MT group in comparison to CCl4 group whereas caspase-3 and caspase-9 has increased and bax and bcl-2 has decreased. SIGNIFICANCE These results show that MT protects the liver against oxidative damage.
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Affiliation(s)
- Abdullah Aslan
- Firat University, Faculty of Science, Department of Biology, Elazığ, Turkey.
| | - Muhammed İsmail Can
- Aksaray University, Department of Biotechnology and Molecular Biology, Aksaray, Turkey.
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Dutta-Moscato J, Solovyev A, Mi Q, Nishikawa T, Soto-Gutierrez A, Fox IJ, Vodovotz Y. A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression. Front Bioeng Biotechnol 2014; 2:18. [PMID: 25152891 PMCID: PMC4126446 DOI: 10.3389/fbioe.2014.00018] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 05/14/2014] [Indexed: 01/06/2023] Open
Abstract
Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl4). An in silico “tension test” for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl4-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl4-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into liver fibrosis.
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Affiliation(s)
- Joyeeta Dutta-Moscato
- Department of Biomedical Informatics, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA
| | - Alexey Solovyev
- Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Mathematics, University of Pittsburgh , Pittsburgh, PA , USA
| | - Qi Mi
- Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Sports Medicine and Nutrition, University of Pittsburgh , Pittsburgh, PA , USA
| | - Taichiro Nishikawa
- McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Surgery, Children's Hospital of Pittsburgh , Pittsburgh, PA , USA
| | - Alejandro Soto-Gutierrez
- McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Pathology, University of Pittsburgh , Pittsburgh, PA , USA ; Thomas E. Starzl Transplantation Institute, University of Pittsburgh , Pittsburgh, PA , USA
| | - Ira J Fox
- McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Surgery, Children's Hospital of Pittsburgh , Pittsburgh, PA , USA ; Thomas E. Starzl Transplantation Institute, University of Pittsburgh , Pittsburgh, PA , USA
| | - Yoram Vodovotz
- Department of Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA
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Bettenworth D, Rieder F. Medical therapy of stricturing Crohn's disease: what the gut can learn from other organs - a systematic review. FIBROGENESIS & TISSUE REPAIR 2014; 7:5. [PMID: 24678903 PMCID: PMC4230721 DOI: 10.1186/1755-1536-7-5] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 03/06/2014] [Indexed: 12/11/2022]
Abstract
Crohn’s disease (CD) is a chronic remitting and relapsing disease. Fibrostenosing complications such as intestinal strictures, stenosis and ultimately obstruction are some of its most common long-term complications. Despite recent advances in the pathophysiological understanding of CD and a significant improvement of anti-inflammatory therapeutics, medical therapy for stricturing CD is still inadequate. No specific anti-fibrotic therapy exists and the incidence rate of strictures has essentially remained unchanged. Therefore, the current therapy of established fibrotic strictures comprises mainly endoscopic dilation as well as surgical approaches. However, these treatment options are associated with major complications as well as high recurrence rates. Thus, a specific anti-fibrotic therapy for CD is urgently needed. Importantly, there is now a growing body of evidence for prevention as well as effective medical treatment of fibrotic diseases of other organs such as the skin, lung, kidney and liver. In face of the similarity of molecular mechanisms of fibrogenesis across these organs, translation of therapeutic approaches from other fibrotic diseases to the intestine appears to be a promising treatment strategy. In particular transforming growth factor beta (TGF-β) neutralization, selective tyrosine kinase inhibitors, blockade of components of the renin-angiotensin system, IL-13 inhibitors and mammalian target of rapamycin (mTOR) inhibitors have emerged as potential drug candidates for anti-fibrotic therapy and may retard progression or even reverse established intestinal fibrosis. However, major challenges have to be overcome in the translation of novel anti-fibrotics into intestinal fibrosis therapy, such as the development of appropriate biomarkers that predict the development and accurately monitor therapeutic responses. Future clinical studies are a prerequisite to evaluate the optimal timing for anti-fibrotic treatment approaches, to elucidate the best routes of application, and to evaluate the potential of drug candidates to reach the ultimate goal: the prevention or reversal of established fibrosis and strictures in CD patients.
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Affiliation(s)
| | - Florian Rieder
- Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.,Department of Pathobiology, Lerner Research Institute, NC22, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
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Demiroren K, Dogan Y, Kocamaz H, Ozercan IH, Ilhan S, Ustundag B, Bahcecioglu IH. Protective effects of L-carnitine, N-acetylcysteine and genistein in an experimental model of liver fibrosis. Clin Res Hepatol Gastroenterol 2014; 38:63-72. [PMID: 24239319 DOI: 10.1016/j.clinre.2013.08.014] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 08/27/2013] [Accepted: 08/28/2013] [Indexed: 02/04/2023]
Abstract
AIM Liver fibrosis is a reversible wound-healing response that occurs following liver injury. In this study, we aimed to investigate the possible protective effects of L-carnitine, N-acetylcysteine and genistein in liver fibrosis induced by carbon tetrachloride (CCl4). In addition, the effects of these agents were compared in the same study. METHODS In this study, rats were randomly allocated into 8 groups, consisting of 10 rats each, as follows: a control group, CCl4, L-carnitine, N-acetylcysteine, genistein, CCl4 and L-carnitine, CCl4 and N-acetylcysteine, and CCl4 and genistein. At the end of 6 weeks, blood and liver tissue specimens were collected. Alanine aminotransferase (ALT); aspartate aminotransferase (AST); complete blood count, tumor necrosis factor-α (TNF-α); platelet-derived growth factor-BB (PDGF-BB); interleukin-6 (IL-6); liver glutathione level; oxidant/antioxidant status; scores of hepatic steatosis, necrosis, inflammation, and fibrosis; and the expression of α-smooth muscle actin were studied. RESULTS Although the ALT and AST values in the group administered CCl4 were significantly higher than in all the other groups (P<0.05), there was no significant difference between the control group and the groups administered CCl4 combined with L-carnitine, N-acetylcysteine and genistein (P>0.05). There were significant differences in the levels of TNF-α, PDGF-BB and IL-6 (P<0.05) between the CCl4 group and the groups with L-carnitine, N-acetylcysteine and genistein added to CCl4. N-acetylcysteine and genistein had positive effects on the oxidant/antioxidant status and on liver necrosis and fibrosis scores. CONCLUSIONS In our study, L-carnitine, N-acetylcysteine and genistein showed significant protective effects in liver fibrosis induced by CCl4.
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Affiliation(s)
- Kaan Demiroren
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey.
| | - Yasar Dogan
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey
| | - Halil Kocamaz
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey
| | - Ibrahim Hanifi Ozercan
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey
| | - Selcuk Ilhan
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey
| | - Bilal Ustundag
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey
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Luo XY, Takahara T, Kawai K, Fujino M, Sugiyama T, Tsuneyama K, Tsukada K, Nakae S, Zhong L, Li XK. IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet. Am J Physiol Gastrointest Liver Physiol 2013; 305:G891-9. [PMID: 24136786 DOI: 10.1152/ajpgi.00193.2013] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cytokines play important roles in all stages of steatohepatitis, including hepatocyte injury, the inflammatory response, and the altered function of sinusoidal cells. This study examined the involvement of a major inflammatory cytokine, interferon-γ (IFN-γ), in the progression of steatohepatitis. In a steatohepatitis model by feeding a methionine- and choline-deficient high-fat (MCDHF) diet to both wild-type and IFN-γ-deficient mice, the liver histology, expression of genes encoding inflammatory cytokines, and fibrosis-related markers were examined. To analyze the effects of IFN-γ on Kupffer cells in vitro, we examined the tumor necrosis factor-α (TNF-α) production by a mouse macrophage cell line. Forty two days of MCDHF diet resulted in weight loss, elevated aminotransferases, liver steatosis, and inflammation in wild-type mice. However, the IFN-γ-deficient mice exhibited less extensive changes. RT-PCR revealed that the expression of tumor necrosis factor-α (TNF-α), transforming growth factor-β, inducible nitric oxide synthase, interleukin-4 and osteopontin were increased in wild-type mice, although they were suppressed in IFN-γ-deficient mice. Seventy days of MCDHF diet induced much more liver fibrosis in wild-type mice than in IFN-γ-deficient mice. The expression levels of fibrosis-related genes, α-smooth muscle actin, type I collagen, tissue inhibitor of matrix metalloproteinase-1, and matrix metalloproteinase-2, were dramatically increased in wild-type mice, whereas they were significantly suppressed in IFN-γ-deficient mice. Moreover, in vitro experiments showed that, when RAW 264.7 macrophages were treated with IFN-γ, they produced TNF-α in a dose-dependent manner. The present study showed that IFN-γ deficiency might inhibit the inflammatory response of macrophages cells and subsequently suppress stellate cell activation and liver fibrosis. These findings highlight the critical role of IFN-γ in the progression of steatohepatitis.
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Affiliation(s)
- Xiao-Yu Luo
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535 Japan.
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Li Z, Xue J, Yan S, Chen P, Chen L. Association between tumor necrosis factor-α 308G/A gene polymorphism and silicosis susceptibility: a meta-analysis. PLoS One 2013; 8:e76614. [PMID: 24124578 PMCID: PMC3790741 DOI: 10.1371/journal.pone.0076614] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 08/25/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Tumor necrosis factor-α (TNF-α) 308 G/A gene polymorphism has been reported to be associated with susceptibility to silicosis. However, the relevant study results are still inconsistent. OBJECTIVE AND METHODS A meta-analysis was performed in order to drive a more precise estimation of the relationship between TNF-α-308 G/A gene polymorphism and susceptibility to silicosis. Electronic databases were searched and nine separate studies were included. The pooled odds ratios (ORs) and the corresponding 95% confidence internal (CI) were calculated by a fixed effect model. RESULTS A total of 1267 cases and 1214 controls were included. In the overall analysis, significantly increased silicosis risk was found (for GA+AA vs. GG OR=1.45, 95%CI: 1.20-1.760, P=1.58E4; for GA vs. GG: OR=1.53, 95%CI=1.25-1.86, P=3.11E5; for A allele vs. G allele: OR=1.27, 95%CI=1.08-1.50, P= 0.004). In the subgroup analysis, significantly increased silicosis risk was also found among Asians (for GA+AA vs. GG: OR=1.63, 95%CI=1.27-2.08, P=1.01E4), for GA vs. GG: OR=1.71, 95%CI=1.33-2.20, P=3.44E5), for A allele vs. G allele: OR=1.45, 95%CI=1.17-1.80, P=0.001). However, no significantly increased risk was found among non-Asians for all genetic models. CONCLUSIONS TNF-α-308 G/A polymorphism might lead to an increased risk of silicosis susceptibility, especially for Asians. However, further studies with large sample sizes should be conducted to confirm the association.
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Affiliation(s)
- Zhanzhan Li
- Department of Epidemiology and Health Statistics, School of Public Health, Central South University, Changsha, Hunan Province, China
| | - Jing Xue
- Department of Epidemiology and Health Statistics, School of Public Health, Central South University, Changsha, Hunan Province, China
| | - Shipeng Yan
- Department of Epidemiology and Health Statistics, School of Public Health, Central South University, Changsha, Hunan Province, China
| | - Peng Chen
- Xiangya Medical School, Central South University, Changsha, Hunan Province, China
| | - Lizhang Chen
- Department of Epidemiology and Health Statistics, School of Public Health, Central South University, Changsha, Hunan Province, China
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Nishikawa Y, Sone M, Nagahama Y, Kumagai E, Doi Y, Omori Y, Yoshioka T, Tokairin T, Yoshida M, Yamamoto Y, Ito A, Sugiyama T, Enomoto K. Tumor necrosis factor-α promotes bile ductular transdifferentiation of mature rat hepatocytes in vitro. J Cell Biochem 2013; 114:831-43. [PMID: 23097189 DOI: 10.1002/jcb.24424] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 10/08/2012] [Indexed: 12/27/2022]
Abstract
We previously showed that mature hepatocytes could transdifferentiate into bile ductular cells when placed in a collagen-rich microenvironment. To explore the mechanism of transdifferentiation, we examined whether inflammatory cytokines affected the phenotype of hepatocytes in a three-dimensional culture system. Spheroidal aggregates of rat hepatocytes were embedded within a type I collagen gel matrix and cultured in the presence of various cytokines. In the control, hepatocytes gradually lost expression of albumin, tyrosine aminotransferase, and hepatocyte nuclear factor (HNF)-4α, while aberrantly expressed bile ductular markers, including cytokeratin 19 (CK 19) and spermatogenic immunoglobulin superfamily (SgIGSF). Among the cytokines examined, tumor necrosis factor (TNF)-α inhibited expression of albumin and HNF-4α, both at mRNA and protein levels. After culturing for 2 weeks with TNF-α, hepatocytic spheroids were transformed into extensively branching tubular structures composed of CK 19- and SgIGSF-positive small cuboidal cells. These cells responded to secretin with an increase in secretion and expressed functional bile duct markers. TNF-α also induced the phosphorylation of Jun N-terminal kinase (JNK) and c-Jun, and the morphogenesis was inhibited by SP600125, a specific JNK inhibitor. Furthermore, in chronic rat liver injury induced by CCl(4) , ductular reaction in the centrilobular area demonstrated strong nuclear staining of phosphorylated c-Jun. Our results demonstrate that TNF-α promotes the ductular transdifferentiation of hepatocytes and suggest a role of TNF-α in the pathogenesis of ductular reaction.
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Affiliation(s)
- Yuji Nishikawa
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Higashi 2-1-1-1 Midorigaoka, Asahikawa, Hokkaido 078-8510, Japan.
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Borthwick LA, Wynn TA, Fisher AJ. Cytokine mediated tissue fibrosis. BIOCHIMICA ET BIOPHYSICA ACTA 2013; 1832:1049-60. [PMID: 23046809 PMCID: PMC3787896 DOI: 10.1016/j.bbadis.2012.09.014] [Citation(s) in RCA: 288] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 09/28/2012] [Accepted: 09/29/2012] [Indexed: 12/20/2022]
Abstract
Acute inflammation is a recognised part of normal wound healing. However, when inflammation fails to resolve and a chronic inflammatory response is established this process can become dysregulated resulting in pathological wound repair, accumulation of permanent fibrotic scar tissue at the site of injury and the failure to return the tissue to normal function. Fibrosis can affect any organ including the lung, skin, heart, kidney and liver and it is estimated that 45% of deaths in the western world can now be attributed to diseases where fibrosis plays a major aetiological role. In this review we examine the evidence that cytokines play a vital role in the acute and chronic inflammatory responses that drive fibrosis in injured tissues. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
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Affiliation(s)
- Lee A Borthwick
- Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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Sharma M, Mohapatra J, Malik U, Wagh A, Singh A, Patel HM, Pandey D, Kadam S, Shah GB, Chatterjee A, Jain MR. Selective inhibition of tumor necrosis factor-α converting enzyme attenuates liver toxicity in a murine model of concanavalin A induced auto-immune hepatitis. Int Immunopharmacol 2013; 17:229-36. [PMID: 23816535 DOI: 10.1016/j.intimp.2013.06.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 05/17/2013] [Accepted: 06/09/2013] [Indexed: 01/24/2023]
Abstract
Emerging evidence suggest that tumor necrosis factor (TNF)-α plays a major role in pathogenesis of auto-immune hepatitis (AIH) induced liver injury. Blockade of TNF-α synthesis or bio-activity protects against experimental AIH. TNF-α converting enzyme (TACE) is a member of the ADAM (a disintegrin and metalloproteinase) family which processes precursor TNF-α to release soluble TNF-α. We hypothesized that selective inhibition of TACE might protect AIH. To investigate this, we studied the effects of a selective TACE inhibitor DPC-333 on murine model of liver injury and fibrosis induced with concanavalin A (Con A). Pre-treatment with DPC-333 significantly suppressed plasma alanine transaminase, aspartate transaminase and cytokines such as TNF-α, interferon (IFN)-γ, interleukin (IL)-2 and IL-6 levels due to acute Con A challenge. Interestingly; DPC-333 inhibited liver poly (ADP-ribose) polymerase (PARP)-1 activity which was associated with reduced number of necrotic hepatocytes in histological examination and mortality associated with Con A. In fibrosis study, repeated Con A administration significantly up-regulated liver collagen deposition as assessed by measurement of hydroxyproline content which was further confirmed in liver histology with Masson's trichrome staining. Treatment with 30mg/kg of DPC-333 was able to suppress liver hydroxyproline and fibrous tissue proliferation which corroborated well with inhibition in expression of pro-fibrotic genes such as tissue inhibitor of metalloproteinase (TIMP)-1 and transforming growth factor (TGF)-β1. These observations suggest that selective TACE inhibition is an effective approach for the treatment of both immune mediated hepatic inflammation and fibrosis.
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Affiliation(s)
- Manoranjan Sharma
- Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India
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Liaskou E, Zimmermann HW, Li KK, Oo YH, Suresh S, Stamataki Z, Qureshi O, Lalor PF, Shaw J, Syn WK, Curbishley SM, Adams DH. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 2013; 57:385-98. [PMID: 22911542 PMCID: PMC4194426 DOI: 10.1002/hep.26016] [Citation(s) in RCA: 192] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 08/01/2012] [Indexed: 12/11/2022]
Abstract
UNLABELLED Liver fibrosis is a wound healing response to chronic liver injury and inflammation in which macrophages and infiltrating monocytes participate in both the development and resolution phase. In humans, three monocyte subsets have been identified: the classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes. We studied the phenotype and function of these monocyte subsets in peripheral blood and liver tissue from patients with chronic inflammatory and fibrotic liver diseases. The frequency of intrahepatic monocytes increased in disease compared with control liver tissue, and in both nondiseased and diseased livers there was a higher frequency of CD14++CD16+ cells with blood. Our data suggest two nonexclusive mechanisms of CD14++CD16+ accumulation in the inflamed liver: (1) recruitment from blood, because more than twice as many CD14++CD16+ monocytes underwent transendothelial migration through hepatic endothelial cells compared with CD14++CD16- cells; and (2) local differentiation from CD14++CD16- classical monocytes in response to transforming growth factor β and interleukin (IL)-10. Intrahepatic CD14++CD16+ cells expressed both macrophage and dendritic cell markers but showed high levels of phagocytic activity, antigen presentation, and T cell proliferation and secreted proinflammatory (tumor necrosis factor α, IL-6, IL-8, IL-1β) and profibrogenic cytokines (IL-13), chemokines (CCL1, CCL2, CCL3, CCL5), and growth factors (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor), consistent with a role in the wound healing response. CONCLUSION Intermediate CD14++CD16+ monocytes preferentially accumulate in chronically inflamed human liver as a consequence of enhanced recruitment from blood and local differentiation from classical CD14++CD16- monocytes. Their phagocytic potential and ability to secrete inflammatory and profibrogenic cytokines suggests they play an important role in hepatic fibrogenesis.
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Affiliation(s)
- Evaggelia Liaskou
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Henning W. Zimmermann
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
- Medical Department III, University Hospital of Aachen, Germany
| | - Ka-Kit Li
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Ye H. Oo
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Shankar Suresh
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Zania Stamataki
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Omar Qureshi
- Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom
| | - Patricia F. Lalor
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Jean Shaw
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Wing-kin Syn
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
- The Institute of Hepatology, Regeneration and Repair Group, London, United Kingdom
- Department of Physiology, University of the Basque Country, Bilbao, Spain
| | - Stuart M. Curbishley
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - David H. Adams
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
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Duffield JS, Lupher M, Thannickal VJ, Wynn TA. Host responses in tissue repair and fibrosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2012; 8:241-76. [PMID: 23092186 DOI: 10.1146/annurev-pathol-020712-163930] [Citation(s) in RCA: 463] [Impact Index Per Article: 35.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Myofibroblasts accumulate in the spaces between organ structures and produce extracellular matrix (ECM) proteins, including collagen I. They are the primary "effector" cells in tissue remodeling and fibrosis. Previously, leukocyte progenitors termed fibrocytes and myofibroblasts generated from epithelial cells through epithelial-to-mesenchymal transition (EMT) were considered the primary sources of ECM-producing myofibroblasts in injured tissues. However, genetic fate mapping experiments suggest that mesenchyme-derived cells, known as resident fibroblasts, and pericytes are the primary precursors of scar-forming myofibroblasts, whereas epithelial cells, endothelial cells, and myeloid leukocytes contribute to fibrogenesis predominantly by producing key fibrogenic cytokines and by promoting cell-to-cell communication. Numerous cytokines derived from T cells, macrophages, and other myeloid cell populations are important drivers of myofibroblast differentiation. Monocyte-derived cell populations are key regulators of the fibrotic process: They act as a brake on the processes driving fibrogenesis, and they dismantle and degrade established fibrosis. We discuss the origins, modes of activation, and fate of myofibroblasts in various important fibrotic diseases and describe how manipulation of macrophage activation could help ameliorate fibrosis.
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Affiliation(s)
- Jeremy S Duffield
- Division of Nephrology, Center for Lung Biology, and the Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98019, USA
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Abstract
Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix-producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases.
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Abstract
Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix-producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases.
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Affiliation(s)
- Thomas A Wynn
- Immunopathogenesis Section, Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
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Abdelmagid SM, Barr AE, Rico M, Amin M, Litvin J, Popoff SN, Safadi FF, Barbe MF. Performance of repetitive tasks induces decreased grip strength and increased fibrogenic proteins in skeletal muscle: role of force and inflammation. PLoS One 2012; 7:e38359. [PMID: 22675458 PMCID: PMC3364991 DOI: 10.1371/journal.pone.0038359] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2012] [Accepted: 05/04/2012] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND This study elucidates exposure-response relationships between performance of repetitive tasks, grip strength declines, and fibrogenic-related protein changes in muscles, and their link to inflammation. Specifically, we examined forearm flexor digitorum muscles for changes in connective tissue growth factor (CTGF; a matrix protein associated with fibrosis), collagen type I (Col1; a matrix component), and transforming growth factor beta 1 (TGFB1; an upstream modulator of CTGF and collagen), in rats performing one of two repetitive tasks, with or without anti-inflammatory drugs. METHODOLOGY/RESULTS To examine the roles of force versus repetition, rats performed either a high repetition negligible force food retrieval task (HRNF), or a high repetition high force handle-pulling task (HRHF), for up to 9 weeks, with results compared to trained only (TR-NF or TR-HF) and normal control rats. Grip strength declined with both tasks, with the greatest declines in 9-week HRHF rats. Quantitative PCR (qPCR) analyses of HRNF muscles showed increased expression of Col1 in weeks 3-9, and CTGF in weeks 6 and 9. Immunohistochemistry confirmed PCR results, and also showed greater increases of CTGF and collagen matrix in 9-week HRHF rats than 9-week HRNF rats. ELISA, and immunohistochemistry revealed greater increases of TGFB1 in TR-HF and 6-week HRHF, compared to 6-week HRNF rats. To examine the role of inflammation, results from 6-week HRHF rats were compared to rats receiving ibuprofen or anti-TNF-α treatment in HRHF weeks 4-6. Both treatments attenuated HRHF-induced increases in CTGF and fibrosis by 6 weeks of task performance. Ibuprofen attenuated TGFB1 increases and grip strength declines, matching our prior results with anti-TNFα. CONCLUSIONS/SIGNIFICANCE Performance of highly repetitive tasks was associated with force-dependent declines in grip strength and increased fibrogenic-related proteins in flexor digitorum muscles. These changes were attenuated, at least short-term, by anti-inflammatory treatments.
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Affiliation(s)
- Samir M. Abdelmagid
- Department of Surgery, Plastic and Reconstructive Division, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Ann E. Barr
- College of Health Professions, Pacific University, Hillsboro, Oregon, United States of America
| | - Mario Rico
- Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Mamta Amin
- Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Judith Litvin
- Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
- Musculoskeletal Research Group, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Steven N. Popoff
- Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
- Musculoskeletal Research Group, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Fayez F. Safadi
- Musculoskeletal Research Group, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, Ohio, United States of America
| | - Mary F. Barbe
- Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
- Musculoskeletal Research Group, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
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Gao HY, Li GY, Lou MM, Li XY, Wei XY, Wang JH. Hepatoprotective effect of Matrine salvianolic acid B salt on Carbon Tetrachloride-Induced Hepatic Fibrosis. JOURNAL OF INFLAMMATION-LONDON 2012; 9:16. [PMID: 22559721 PMCID: PMC3404020 DOI: 10.1186/1476-9255-9-16] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2011] [Accepted: 05/04/2012] [Indexed: 01/17/2023]
Abstract
The aim of this study was to investigate the hepatoprotective effect of Matrine salvianolic acid B salt on carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats. Salvianolic acid B and Matrine has long been used to treat liver fibrosis. Matrine salvianolic acid B salt is a new compound containing Salvianolic acid B and Matrine. Hepatic fibrosis induced by CCl4 was studied in animal models using Wistar rats. Organ coefficient, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), hexadecenoic acid (HA), laminin (LN), hydroxyproline (Hyp), and glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) in liver tissues were measured, respectively. Histopathological changes in the livers were studied by hematoxylin-eosin (H&E) staining and Masson Trichrome (MT) examination. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) was observed by immunohistochemical analysis. A significant reduction in serum levels of AST, ALT, HA, LN and Hyp was observed in the Matrine salvianolic acid B salt treated groups, suggesting that the salt had hepatoprotective effects. The depletion of GSH and SOD, as well as MDA accumulation in liver tissues was suppressed by Matrine salvianolic acid B salt too. The expression of TGF-β1 and α-SMA measured by immunohistology was significantly reduced by Matrine salvianolic acid B salt in a dose-dependent manner. Matrine salvianolic acid B salt treatment attenuated the necro-inflammation and fibrogenesis induced by CCl4 injection, and thus it is promising as a therapeutic anti-fibrotic agent against hepatic fibrosis.
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Affiliation(s)
- Hong-Ying Gao
- School of Pharmacy, Shihezi University, Shihezi 832002, P, R, China.
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Li J, Gong YM, Wu J, Wu WJ, Cai W. Anti-tumor necrosis factor-α monoclonal antibody alleviates parenteral nutrition-associated liver disease in mice. JPEN J Parenter Enteral Nutr 2012; 36:219-25. [PMID: 22275328 DOI: 10.1177/0148607111424412] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The authors aimed to investigate the role of anti-tumor necrosis factor (TNF)-α monoclonal antibody treatment in a mouse model of parenteral nutrition-associated liver disease (PNALD). METHODS C57BL/6J male mice (aged 6-8 weeks) were randomly assigned to 3 groups: parenteral nutrition (PN), PN with anti-TNF-α monoclonal antibody treatment (PN + mAb), and controls. A central venous catheter was inserted for intravenous infusion of a PN solution (PN and PN + mAb groups) or saline (controls) for 7 days. Liver pathology, hepatic biochemical indicators, and serum TNF-α concentrations were analyzed. Levels of hepatic bsep, mdr1a/mdr1b, mdr2, and mrp2 mRNA were also evaluated in each group. RESULTS The PN group showed significant increases in serum transaminase, direct bilirubin, and bile acids relative to the control group (P < .05). Histopathological changes in this group were consistent with early stage cholestasis. The pathological score and serum alanine aminotransferase, total bilirubin, and direct bilirubin levels were improved in the PN + mAb group relative to the PN group (P < .05). The PN group showed significantly lower hepatic bsep, mdr1a/mdr1b, mdr2, and mrp2 mRNA expression than the controls (P < .05), but these were significantly increased compared to the PN group (P < .05). CONCLUSIONS Infliximab administered at a single dose of 5 mg/kg body weight ameliorated the progression of PNALD and improved the expression of hepatic ABC transporter genes. Therefore, anti-TNF-α monoclonal antibody may be a beneficial therapy for patients with PNALD.
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Affiliation(s)
- Jing Li
- Clinical Nutrition Center, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Mantawy EM, Tadros MG, Awad AS, Hassan DAA, El-Demerdash E. Insights antifibrotic mechanism of methyl palmitate: impact on nuclear factor kappa B and proinflammatory cytokines. Toxicol Appl Pharmacol 2012; 258:134-144. [PMID: 22079257 DOI: 10.1016/j.taap.2011.10.016] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2011] [Revised: 10/24/2011] [Accepted: 10/25/2011] [Indexed: 12/16/2022]
Abstract
Fibrosis accompanies most chronic liver disorders and is a major factor contributing to hepatic failure. Therefore, the need for an effective treatment is evident. The present study was designed to assess the potential antifibrotic effect of MP and whether MP can attenuate the severity of oxidative stress and inflammatory response in chronic liver injury. Male albino rats were treated with either CCl(4) (1 ml/kg, twice a week) and/or MP (300 mg/kg, three times a week) for six weeks. CCl(4)-intoxication significantly increased liver weight, serum aminotransferases, total cholesterol and triglycerides while decreased albumin level and these effects were prevented by co-treatment with MP. As indicators of oxidative stress, CCl(4)-intoxication caused significant glutathione depletion and lipid peroxidation while MP co-treatment preserved them within normal values. As markers of fibrosis, hydroxyproline content and α-SMA expression increased markedly in the CCl(4) group and MP prevented these alterations. Histopathological examination by both light and electron microscope further confirmed the protective efficacy of MP. To elucidate the antifibrotic mechanisms of MP, the expression of NF-κB, iNOS and COX-2 and the tissue levels of TNF-α and nitric oxide were assessed; CCl(4) increased the expression of NF-κB and all downstream inflammatory cascade while MP co-treatment inhibited them. Collectively these findings indicate that MP possesses a potent antifibrotic effect which may be partly a consequence of its antioxidant and anti-inflammatory properties.
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Affiliation(s)
- Eman M Mantawy
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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Cohen-Naftaly M, Friedman SL. Current status of novel antifibrotic therapies in patients with chronic liver disease. Therap Adv Gastroenterol 2011; 4:391-417. [PMID: 22043231 PMCID: PMC3187682 DOI: 10.1177/1756283x11413002] [Citation(s) in RCA: 150] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Fibrosis accumulation is a dynamic process resulting from a wound-healing response to acute or chronic liver injury of all causes. The cascade starts with hepatocyte necrosis and apoptosis, which instigate inflammatory signaling by chemokines and cytokines, recruitment of immune cell populations, and activation of fibrogenic cells, culminating in the deposition of extracellular matrix. These key elements, along with pathways of transcriptional and epigenetic regulation, represent fertile therapeutic targets. New therapies include drugs specifically designed as antifibrotics, as well as drugs already available with well-established safety profiles, whose mechanism of action may also be antifibrotic. At the same time, the development of noninvasive fibrogenic markers, and techniques (e.g. fibroscan), as well as combined scoring systems incorporating serum and clinical features will allow improved assessment of therapy response. In aggregate, the advances in the elucidation of the biology of fibrosis, combined with improved technologies for assessment will provide a comprehensive framework for design of antifibrotics and their analysis in well-designed clinical trials. These efforts may ultimately yield success in halting the progression of, or reversing, liver fibrosis.
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Affiliation(s)
| | - Scott L. Friedman
- Fishberg Professor of Medicine, Division of Liver Diseases, Box 1123, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70C, New York, NY 10029-6574, USA
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TNFR1-mediated signaling is important to induce the improvement of liver fibrosis by bone marrow cell infusion. Cell Tissue Res 2011; 346:79-88. [PMID: 21987217 PMCID: PMC3204000 DOI: 10.1007/s00441-011-1236-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Accepted: 08/30/2011] [Indexed: 12/17/2022]
Abstract
The importance of TNF-α signals mediated by tumor necrosis factor receptor type 1 (TNFR1) in inflammation and fibrosis induced by carbon tetrachloride (CCl4), and in post-injury liver regeneration including a GFP/CCl4 model developed as a liver repair model by bone marrow cell (BMC) infusion, was investigated. In mice in which TNFR1 was suppressed by antagonist administration or by knockout, liver fibrosis induced by CCl4 was significantly decreased. In these mice, intrahepatic macrophage infiltration and TGF-β1 expression were reduced and stellate cell activity was decreased; however, expression of MMP-9 was also decreased. With GFP-positive BMC (TNFR1 wild-type, WT) infusion in these mice, fibrosis proliferation, including host endogenous intrahepatic macrophage infiltration, TGF-β1 expression and stellate cell activity, increased significantly. There was no significant increase of MMP-9 expression. In this study, TNFR1 in hosts had a promoting effect on CCl4-induced hepatotoxicity and fibrosis, whereas BMC infusion in TNFR1 knockout mice enhanced host-derived intrahepatic inflammation and fibrosis proliferation. These findings differed from those in WT recipient mice, in which improvement in inflammation and fibrosis with BMC infusion had previously been reported. TNFR1-mediated signaling might be important to induce the improvement of liver fibrosis by bone marrow cell infusion.
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Dagdeviren S, Kandilci HB, Uysal B, Zeybek ND, Korkusuz P, Gümüsel B, Korkusuz F. Tumor necrosis factor-alpha antagonist administration recovers skeletal muscle dysfunction in ovariectomized rats. J Orthop Res 2011; 29:275-80. [PMID: 20690186 DOI: 10.1002/jor.21226] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Skeletal muscles deteriorate after ovariectomy. Molecular pathway of this deterioration has not been defined. Tumor necrosis factor (TNF)-alpha activation is assumed to trigger muscle atrophy and administration of its antagonist is hypothesized to recover this atrophy in rats. Slow-twitch soleus and fast-twitch extensor digitorum longus muscle functions were investigated in intact, ovariectomized (OVX), and OVX plus 10 µg/g/week TNF-alpha antagonist administered female rats. Maximum isometric twitch and tetanic contraction responses were lower in the OVX groups. Maximum isometric twitch amplitudes recovered in the extensor digitorum longus but not in the soleus muscles after TNF-alpha antagonist administration. The decrease in responses to tetanic stimulations recovered in the OVX-TNF group at frequencies higher than 20 Hz in both muscle types. OVX animals body weight was 21% higher than intact animals. Muscle weight to body weight ratios of the OVX groups were higher than the control group which recovered after TNF-alpha antagonist administration. Findings suggest that the functional loss in OVX rat muscles is TNF-alpha pathway dependent. Skeletal muscle atrophy and function after OVX recovered by TNF-alpha antagonist administration.
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Affiliation(s)
- Sezin Dagdeviren
- Medical Center, Department of Biotechnology, Middle East Technical University, İnönü Bulvarı, Ankara 06531, Turkey
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Qiao H, Han H, Hong D, Ren Z, Chen Y, Zhou C. Protective effects of baicalin on carbon tetrachloride induced liver injury by activating PPARγ and inhibiting TGFβ1. PHARMACEUTICAL BIOLOGY 2011; 49:38-45. [PMID: 20687787 DOI: 10.3109/13880209.2010.493179] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
CONTEXT Traditional Chinese herbal medicines have attracted considerable attention in many countries with treatment of several end-stage liver diseases. OBJECTIVE The present study investigated the protective effects of baicalin on hepatotoxicity and hepatic fibrosis and explored the role of transforming growth factor β1 (TGFβ1) and peroxisome proliferator activated receptors γ (PPARγ) on the rat liver injury model. MATERIALS AND METHODS The rat liver injury model was introduced by subcutaneous injection of carbon tetrachloride (CCl(4)) for 8 weeks. At week 5, rats were treated with baicalin of different doses or silymarin. Detection of biochemical indicators, histological analysis, and enzyme-linked immunosorbent assays were employed to evaluate severity of liver inflammation, and western blotting and RT-PCR assay were performed to evaluate TGFβ1 and PPARγ pathway related proteins and gene expression. RESULTS The administration of baicalin could significantly improve histological changes of CCl(4) treated rat livers and return biochemical indicators for liver injury to nearly baseline level. In addition, the increased expression of TGFβ1 was markedly suppressed by baicalin, and decreased expression of PPARγ was also dramatically elevated by baicalin as well. The hepatoprotective effects of baicalin may be conferred by elevating the level of PPARγ contributing to down-regulation of TGFβ1 signaling pathway and suppression of hepatic stellate cell activation. CONCLUSIONS The studies demonstrated that baicalin is a potent and promising antifibrotic drug in the treatment of hepatic fibrosis.
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Affiliation(s)
- Hongxiang Qiao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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