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Zhang X, Zhang X, Huang W, Ge X. The role of heat shock proteins in the regulation of fibrotic diseases. Biomed Pharmacother 2020; 135:111067. [PMID: 33383375 DOI: 10.1016/j.biopha.2020.111067] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 11/08/2020] [Accepted: 11/20/2020] [Indexed: 12/29/2022] Open
Abstract
Heat shock proteins (HSPs) are key players to restore cell homeostasis and act as chaperones by assisting the folding and assembly of newly synthesized proteins and preventing protein aggregation. Recently, evidence has been accumulating that HSPs have been proven to have other functions except for the classical molecular chaperoning in that they play an important role in a wider range of fibrotic diseases via modulating cytokine induction and inflammation response, including lung fibrosis, liver fibrosis, and idiopathic pulmonary fibrosis. The recruitment of inflammatory cells, a large number of secretion of pro-fibrotic cytokines such as transforming growth factor-β1 (TGF-β1) and increased apoptosis, oxidative stress, and proteasomal system degradation are all events occurring during fibrogenesis, which might be associated with HSPs. However, their role on fibrotic process is not yet fully understood. In this review, we discuss new discoveries regarding the involvement of HSPs in the regulation of organ and tissue fibrosis, and note recent findings suggesting that HSPs may be a promising therapeutic target for improving the current frustrating outcome of fibrotic disorders.
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Affiliation(s)
- Xiaoling Zhang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, 226019, PR China.
| | - Xiaoyan Zhang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China
| | - Wenmin Huang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China
| | - Xiaoqun Ge
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, PR China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.
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Shi B, Wang W, Korman B, Kai L, Wang Q, Wei J, Bale S, Marangoni RG, Bhattacharyya S, Miller S, Xu D, Akbarpour M, Cheresh P, Proccissi D, Gursel D, Espindola-Netto JM, Chini CCS, de Oliveira GC, Gudjonsson JE, Chini EN, Varga J. Targeting CD38-dependent NAD + metabolism to mitigate multiple organ fibrosis. iScience 2020; 24:101902. [PMID: 33385109 PMCID: PMC7770554 DOI: 10.1016/j.isci.2020.101902] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 09/20/2020] [Accepted: 12/03/2020] [Indexed: 11/26/2022] Open
Abstract
The processes underlying synchronous multiple organ fibrosis in systemic sclerosis (SSc) remain poorly understood. Age-related pathologies are associated with organismal decline in nicotinamide adenine dinucleotide (NAD+) that is due to dysregulation of NAD+ homeostasis and involves the NADase CD38. We now show that CD38 is upregulated in patients with diffuse cutaneous SSc, and CD38 levels in the skin associate with molecular fibrosis signatures, as well as clinical fibrosis scores, while expression of key NAD+-synthesizing enzymes is unaltered. Boosting NAD+ via genetic or pharmacological CD38 targeting or NAD+ precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. In mechanistic experiments, CD38 was found to reduce NAD+ levels and sirtuin activity to augment cellular fibrotic responses, while inhibiting CD38 had the opposite effect. Thus, we identify CD38 upregulation and resulting disrupted NAD+ homeostasis as a fundamental mechanism driving fibrosis in SSc, suggesting that CD38 might represent a novel therapeutic target.
CD38 shows elevated expression in skin biopsies of patients with systemic sclerosis Elevated CD38 is associated with reduced NAD+ and augmented fibrotic responses Genetic loss of CD38 is associated with increased NAD+ levels and attenuated fibrosis NAD+ boosting via CD38 inhibition or NR supplementation prevents multi-organ fibrosis
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Affiliation(s)
- Bo Shi
- Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Wenxia Wang
- Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Benjamin Korman
- Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Li Kai
- Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Qianqian Wang
- Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Jun Wei
- Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Swarna Bale
- Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Roberta Goncalves Marangoni
- Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Swati Bhattacharyya
- Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Stephen Miller
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Dan Xu
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Mahzad Akbarpour
- Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Paul Cheresh
- Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Daniele Proccissi
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Demirkan Gursel
- Pathology Core Facility, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | | | - Claudia C S Chini
- Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Rochester 55905 MN, USA
| | - Guilherme C de Oliveira
- Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Rochester 55905 MN, USA
| | | | - Eduardo N Chini
- Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Rochester 55905 MN, USA
| | - John Varga
- Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.,Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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Application of Traditional Chinese Medicines in Postoperative Abdominal Adhesion. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:8073467. [PMID: 32419827 PMCID: PMC7199640 DOI: 10.1155/2020/8073467] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 03/05/2020] [Accepted: 03/17/2020] [Indexed: 12/16/2022]
Abstract
Adhesion is a frequent complication after abdominal surgery. Although various methods have been applied to prevent and treat postoperative abdominal adhesion (PAA), few modern drugs designed for clinical applications have reached the expected preventive or therapeutic effect so far. There is an imperative to develop some new strategies for the treatment of PAA. Traditional Chinese medicine (TCM) has been widely practiced for thousands of years and played an indispensable role in the prevention and treatment of diseases. Modern medicine researchers have accepted the therapeutic effects of many active components derived from Chinese medicinal herbs. The review stresses the most commonly used TCM treatment, including Chinese medicinal herbals and monomers, TCM formulas, and acupuncture treatment.
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Jiang C, Lin W, Wang L, Lv Y, Song Y, Chen X, Yang H. Fushen Granule, A Traditional Chinese Medicine, ameliorates intestinal mucosal dysfunction in peritoneal dialysis rat model by regulating p38MAPK signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2020; 251:112501. [PMID: 31877365 DOI: 10.1016/j.jep.2019.112501] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 11/12/2019] [Accepted: 12/22/2019] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fushen Granule (FSG) is a Chinese medicinal formular prepared in hospital to treat intestinal mucosal dysfunction induced by peritoneal dialysis (PD). However, the mechanisms of this formular has not been studied yet. AIM OF THE STUDY The present study was designed to investigate the effect of FSG against intestinal dysfunction during PD treatment and explore the potential mechanisms using a rat PD model. METHODS AND METHODS In the present study, the effect of FSG on improving intestinal mucosal architecture injury was intuitively shown by hematoxylin-eosin staining, the serum levels of DAO and D-lactate were measured to evaluate the intestinal permeability by the DAO Assay Kit and D-Lactic Acid ELISA Kit. The expression of the intestinal mucosal barrier related inflammation factor by real-time PCR. The main effective constituents of FSG were characterized by UPLC/Q-TOF analysis, and the targets and pathways of the constituents were predicted via TCMSP database and IPA. the activation of p38MAPK signaling pathway by western blotting. RESULTS HE staining results showed that FSG protected against intestinal mucosal injury in pathology in PD rats. FSG decreased the intestinal mucosal permeability by increasing the transepithelial electrical resistance (TER) level and decreasing the intestinal clearance of fluorescein-isothiocyanate dextran (FD4) and the level of D-lactate and diamine oxidase (DAO). FSG significantly decreased the expression of ICAM-1, IL-1β, iNOS and TNF-α, and further inhibited the activation of p38MAPK signaling pathway via down-regulating the expression of P-p38MAPK and up-regulating the expression of DUSP1, occludin, and ZO-1. CONCLUSION This study demonstrates that FSG ameliorated intestinal mucosal dysfunction in PD by decreasing expression of pro-inflammatory cytokines and inhibiting the activation of p38MAPK signaling pathway. The results provide a promising basis for the alternative medicine treatment of intestinal mucosal dysfunction in PD.
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Affiliation(s)
- Chen Jiang
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
| | - Wei Lin
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
| | - Lingyun Wang
- Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Yang Lv
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
| | - Yu Song
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
| | - Xin Chen
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
| | - Hongtao Yang
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
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Wu S, Uyama N, Itou RA, Hatano E, Tsutsui H, Fujimoto J. The Effect of Daikenchuto, Japanese Herbal Medicine, on Adhesion Formation Induced by Cecum Cauterization and Cecum Abrasion in Mice. Biol Pharm Bull 2019; 42:179-186. [PMID: 30713250 DOI: 10.1248/bpb.b18-00543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Daikenchuto (DKT) has been widely used for the treatment of postsurgical ileus in Japan. However, its effect on postsurgical adhesion formation has been obscure. In this study, the effect of DKT on postsurgical adhesion formation induced by cecum cauterization or cecum abrasion in mice was investigated. First, the expression of adhesion-related molecules in damaged ceca was investigated by quantitative (q)RT-PCR. During 24 h after surgery, mRNA expressions of interferon-γ (IFN-γ), plasminogen activator inhibitor-1 (PAI-1), interleukin-17 (IL-17), and Substance P (SP) in cauterized ceca and those of PAI-1 and IL-17 in abraded ceca were significantly up-regulated. Next, the effect of DKT on adhesion formation macroscopically evaluated with adhesion scoring standards. DKT (22.5-67.5 mg/d) was administered orally for 7 d during the perioperative period, and DKT did not reduce adhesion scores in either the cauterization model (control : DKT 67.5 mg/d, 4.8 ± 0.2 : 4.8 ± 0.2) or in the abrasion model (control : DKT 67.5 mg/d, 4.9 ± 0.1 : 4.5 ± 0.3). Histologically, collagen deposition and leukocyte accumulation were found at the adhesion areas of control mice in both models, and DKT supplementation did not alleviate them. Last, effect of DKT on expression of proadhesion moleculs was evaluated. DKT also failed to down-regulate mRNA expression levels of them in damaged ceca of both models. In conclusion, PAI-1 and IL-17 may be key molecules of postsurgical adhesion formation. Collagen deposition and leukocytes accumulation are histological characteristic feature of post-surgical adhesion formation. DKT may not have any preventive effect on postsurgical adhesion formation in mice.
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Affiliation(s)
- Songtao Wu
- Department of Surgery, Division of Hepatobiliary Pancreas Surgery, Hyogo College of Medicine
| | - Naoki Uyama
- Department of Surgery, Division of Hepatobiliary Pancreas Surgery, Hyogo College of Medicine
| | - Rei Atono Itou
- Department of Surgery, Division of Hepatobiliary Pancreas Surgery, Hyogo College of Medicine
| | - Etsuro Hatano
- Department of Surgery, Division of Hepatobiliary Pancreas Surgery, Hyogo College of Medicine
| | - Hiroko Tsutsui
- Department of Surgery, Division of Hepatobiliary Pancreas Surgery, Hyogo College of Medicine
| | - Jiro Fujimoto
- Department of Surgery, Division of Hepatobiliary Pancreas Surgery, Hyogo College of Medicine
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Hiraishi K, Kurahara LH, Sumiyoshi M, Hu YP, Koga K, Onitsuka M, Kojima D, Yue L, Takedatsu H, Jian YW, Inoue R. Daikenchuto (Da-Jian-Zhong-Tang) ameliorates intestinal fibrosis by activating myofibroblast transient receptor potential ankyrin 1 channel. World J Gastroenterol 2018; 24:4036-4053. [PMID: 30254408 PMCID: PMC6148431 DOI: 10.3748/wjg.v24.i35.4036] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/06/2018] [Accepted: 07/21/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the anti-fibrotic effects of the traditional oriental herbal medicine Daikenchuto (DKT) associated with transient receptor potential ankyrin 1 (TRPA1) channels in intestinal myofibroblasts.
METHODS Inflammatory and fibrotic changes were detected in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) chronic colitis model of wild-type and TRPA1-knockout (TRPA1-KO) mice via pathological staining and immunoblotting analysis. Ca2+ imaging experiments examined the effects of DKT and its components/ingredients on intestinal myofibroblast (InMyoFib) cell TRPA1 channel function. Pro-fibrotic factors and transforming growth factor (TGF)-β1-associated signaling were tested in an InMyoFib cell line by qPCR and immunoblotting experiments. Samples from non-stenotic and stenotic regions of the intestines of patients with Crohn’s disease (CD) were used for pathological analysis.
RESULTS Chronic treatment with TNBS caused more severe inflammation and fibrotic changes in TRPA1-KO than in wild-type mice. A one-week enema administration of DKT reduced fibrotic lesions in wild-type but not in TRPA1-KO mice. The active ingredients of DKT, i.e., hydroxy α-sanshool and 6-shogaol, induced Ca2+ influxes in InMyoFib, and this was antagonized by co-treatment with a selective TRPA1 channel blocker, HC-030031. DKT counteracted TGF-β1-induced expression of Type I collagen and α-smooth muscle actin (α-SMA), which were accompanied by a reduction in the phosphorylation of Smad-2 and p38-mitogen-activated protein kinase (p38-MAPK) and the expression of myocardin. Importantly, 24-h incubation with a DKT active component Japanese Pepper increased the mRNA and protein expression levels of TRPA1 in InMyoFibs, which in turn negatively regulated collagen synthesis. In the stenotic regions of the intestines of CD patients, TRPA1 expression was significantly enhanced.
CONCLUSION The effects of DKT on the expression and activation of the TRPA1 channel could be advantageous for suppressing intestinal fibrosis, and benefit inflammatory bowel disease treatment.
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Affiliation(s)
- Keizo Hiraishi
- Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Fukuoka 8140180, Japan
| | - Lin-Hai Kurahara
- Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Fukuoka 8140180, Japan
| | - Miho Sumiyoshi
- Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Fukuoka 8140180, Japan
| | - Yao-Peng Hu
- Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Fukuoka 8140180, Japan
| | - Kaori Koga
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka 8140180, Japan
| | - Miki Onitsuka
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka 8140180, Japan
| | - Daibo Kojima
- Department of Gastroenterological Surgery, Faculty of Medicine, Fukuoka University, Fukuoka 8140180, Japan
| | - Lixia Yue
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, United States
| | - Hidetoshi Takedatsu
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, Fukuoka 8140180, Japan
| | - Yu-Wen Jian
- College of Letters and Science, University of California, Davis, CA 95616, United States
| | - Ryuji Inoue
- Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Fukuoka 8140180, Japan
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Preventive Effects of the Intestine Function Recovery Decoction, a Traditional Chinese Medicine, on Postoperative Intra-Abdominal Adhesion Formation in a Rat Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:1621894. [PMID: 28105058 PMCID: PMC5220493 DOI: 10.1155/2016/1621894] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 11/18/2016] [Accepted: 12/05/2016] [Indexed: 12/20/2022]
Abstract
The intestine function recovery decoction (IFRD) is a traditional Chinese medicine that has been used for the treatment of adhesive intestinal obstruction. In this study, the preventative effects and probable mechanism of the IFRD were investigated in a rat model. We randomly assigned rats to five groups: normal, model, control, low dose IFRD, and high dose IFRD. In the animal model, the caecum wall and parietal peritoneum were abraded to induce intra-abdominal adhesion formation. Seven days after surgery, adhesion scores were assessed using a visual scoring system, and histopathological samples were examined. The levels of serum interleukin-6 (IL-6) and transforming growth factor beta-1 (TGF-β1) were analysed by an enzyme-linked immunosorbent assay (ELISA). The results showed that a high dose of IFRD reduced the grade of intra-abdominal adhesion in rats. Furthermore, the grades of inflammation, fibrosis, and neovascularization in the high dose IFRD group were significantly lower than those in the control group. The results indicate that the IFRD can prevent intra-abdominal adhesion formation in a rat model. These data suggest that the IFRD may be an effective antiadhesion agent.
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