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Yao Q, Wei T, Qiu H, Cai Y, Yuan L, Liu X, Li X. Epigenetic Effects of Natural Products in Inflammatory Diseases: Recent Findings. Phytother Res 2025; 39:90-137. [PMID: 39513382 DOI: 10.1002/ptr.8364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/17/2024] [Accepted: 07/12/2024] [Indexed: 11/15/2024]
Abstract
Inflammation is an essential step for the etiology of multiple diseases. Clinically, due to the limitations of current drugs for the treatment of inflammatory diseases, such as serious side effects and expensive costs, it is urgent to explore novel mechanisms and medicines. Natural products have received extensive attention recently because of their multi-component and multi-target characteristics. Epigenetic modifications are crucial pathophysiological targets for developing innovative therapies for pharmacological interventions. Investigations examining how natural products improving inflammation through epigenetic modifications are emerging. This review state that natural products relieve inflammation via regulating the gene transcription levels through chromosome structure regulated by histone acetylation levels and the addition or deletion of methyl groups on DNA duplex. They could also exert anti-inflammatory effects by modulating the proteins in typical inflammatory signaling pathways by ubiquitin-related degradation and the effect of glycolysis derived free glycosyls. Studies on epigenetic modifications have the potential to facilitate the development of natural products as therapeutic agents. Future research directed at better understanding of how natural products modulate inflammatory processes through less studied epigenetic modifications including neddylation, SUMOylation, palmitoylation and lactylation, may provide new implications. Meanwhile, higher quality preclinical studies and more powerful clinical evidence are still needed to firmly establish the clinical efficacy of the natural products. Trial Registration: ClinicalTrials.gov Identifier: NCT01764204; ClinicalTrials.gov Identifier: NCT05845931; ClinicalTrials.gov Identifier: NCT04657926; ClinicalTrials.gov Identifier: NCT02330276.
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Affiliation(s)
- Qianyi Yao
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, China
| | - Tanjun Wei
- Department of Pharmacy, Dazhou Integrated TCM & Western Medical Hospital, Sichuan, China
| | - Hongmei Qiu
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, China
| | - Yongqing Cai
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Lie Yuan
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, China
| | - Xin Liu
- Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xiaoli Li
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, China
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2
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Liang L, Mi Y, Zhou S, Yang A, Wei C, Dai E. Advances in the study of key cells and signaling pathways in renal fibrosis and the interventional role of Chinese medicines. Front Pharmacol 2024; 15:1403227. [PMID: 39687302 PMCID: PMC11647084 DOI: 10.3389/fphar.2024.1403227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 10/21/2024] [Indexed: 12/18/2024] Open
Abstract
Renal fibrosis (RF) is a pathological process characterized by the excessive accumulation of extracellular matrix (ECM), which triggers a repair cascade in response to stimuli and pathogenic factors, leading to the activation of molecular signaling pathways involved in fibrosis. This article discusses the key cells, molecules, and signaling pathways implicated in the pathogenesis of RF, with a particular focus on tubular epithelial cells (TECs), cellular senescence, ferroptosis, autophagy, epithelial-mesenchymal transition (EMT), and transforming growth factor-β(TGF-β)/Smad signaling. These factors drive the core and regulatory pathways that significantly influence RF. A comprehensive understanding of their roles is essential. Through a literature review, we explore recent advancements in traditional Chinese medicine (TCM) aimed at reducing RF and inhibiting chronic kidney disease (CKD). We summarize, analyze, and elaborate on the important role of Chinese herbs in RF, aiming to provide new directions for their application in prevention and treatment, as well as scientific guidance for clinical practices.
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Affiliation(s)
- Lijuan Liang
- Gansu University of Chinese Medicine, Lanzhou, China
- Key Laboratory of Dunhuang Medicine and Translation, Ministry of Education, Lanzhou, China
| | - Youjun Mi
- Institute of pathophysiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Shihan Zhou
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Aojian Yang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Chaoyu Wei
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Enlai Dai
- Gansu University of Chinese Medicine, Lanzhou, China
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Shen S, Zhong H, Zhou X, Li G, Zhang C, Zhu Y, Yang Y. Advances in Traditional Chinese Medicine research in diabetic kidney disease treatment. PHARMACEUTICAL BIOLOGY 2024; 62:222-232. [PMID: 38357845 PMCID: PMC10877659 DOI: 10.1080/13880209.2024.2314705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 01/31/2024] [Indexed: 02/16/2024]
Abstract
CONTEXT Diabetic kidney disease (DKD) is a prominent complication arising from diabetic microangiopathy, and its prevalence and renal impact have placed it as the primary cause of end-stage renal disease. Traditional Chinese Medicine (TCM) has the distinct advantage of multifaceted and multilevel therapeutic attributes that show efficacy in improving clinical symptoms, reducing proteinuria, protecting renal function, and slowing DKD progression. Over recent decades, extensive research has explored the mechanisms of TCM for preventing and managing DKD, with substantial studies that endorse the therapeutic benefits of TCM compounds and single agents in the medical intervention of DKD. OBJECTIVE This review lays the foundation for future evidence-based research efforts and provide a reference point for DKD investigation. METHODS The relevant literature published in Chinese and English up to 30 June 2023, was sourced from PubMed, Cochrane Library, VIP Database for Chinese Technical Periodicals (VIP), Wanfang Data, CNKI, and China Biology Medicine disc (CBM). The process involved examining and summarizing research on TCM laboratory tests and clinical randomized controlled trials for DKD treatment. RESULTS AND CONCLUSIONS The TCM intervention has shown the potential to inhibit the expression of inflammatory cytokines and various growth factors, lower blood glucose levels, and significantly affect insulin resistance, lipid metabolism, and improved renal function. Furthermore, the efficacy of TCM can be optimized by tailoring personalized treatment regimens based on the unique profiles of individual patients. We anticipate further rigorous and comprehensive clinical and foundational investigations into the mechanisms underlying the role of TCM in treating DKD.
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Affiliation(s)
- Shiyi Shen
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, China
| | - Huiyun Zhong
- School of Medicine and Food, Sichuan Vocational College of Health and Rehabilitation, Zigong, China
| | - Xiaoshi Zhou
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, China
| | - Guolin Li
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Changji Zhang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yulian Zhu
- Department of Pharmacy, Ziyang People’s Hospital, Ziyang, China
| | - Yong Yang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, China
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Li X, Ma G, Liu J, Zhang G, Ma K, Ding B, Liang W, Gao W. The regulatory effect and mechanism of traditional Chinese medicine on the renal inflammatory signal transduction pathways in diabetic kidney disease: A review. Medicine (Baltimore) 2024; 103:e39746. [PMID: 39312356 PMCID: PMC11419508 DOI: 10.1097/md.0000000000039746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 08/28/2024] [Indexed: 09/25/2024] Open
Abstract
Inflammatory injury is a critical factor in the occurrence and development of diabetic kidney disease (DKD). Signal transduction pathways such as the nuclear factor kappa beta (NF-κB), mitogen-activated protein kinase (MAPK), NOD-like receptor protein 3, and Smads are important mechanisms of inflammatory kidney injury in DKD, and the NF-κB pathway plays a key role. The inflammatory factor network formed after activation of the NF-κB pathway connects different signaling pathways and exacerbates renal inflammatory damage. Many traditional Chinese medicine compounds, single agents, effective components and active ingredients can regulate the expression of key molecules in the signaling pathways associated with inflammatory injury, such as transforming growth factor-β activated kinase 1, NF-κB, p38MAPK, NOD-like receptor protein 3, and Smad7. These treatments have the characteristics of multiple targets and have multiple and overlapping effects, which can treat DKD kidney inflammation and injury through multiple mechanisms and apply the "holistic concept" of traditional Chinese medicine.
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Affiliation(s)
- Xiaoxia Li
- College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Guoping Ma
- The First Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jin Liu
- College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Guoqiang Zhang
- Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, Hebei, China
| | - Kexin Ma
- The First Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Baozhu Ding
- Rural Physician College, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Wenjie Liang
- Hebei Key Laboratory of Integrative Medicine of Liver-Kidney Patterns, Institute of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Weifang Gao
- College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
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Xiao L, Ye G. RUNX3 alleviates mitochondrial dysfunction and tubular damage by inhibiting TLR4/NF-κB signalling pathway in diabetic kidney disease. Nephrology (Carlton) 2024; 29:470-481. [PMID: 38735649 DOI: 10.1111/nep.14307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/16/2024] [Accepted: 04/05/2024] [Indexed: 05/14/2024]
Abstract
AIM The impaired function of tubular mitochondria is critical in diabetic kidney disease (DKD) progression. RUNX3 is down-regulated in DKD models. We intend to explore the effects of RUNX3 on mitochondrial dysfunction and renal tubule injury in DKD and related mechanisms. METHODS The development of diabetes models involved injecting mice with streptozotocin while treating HK-2 cells with high glucose (HG). By using immunohistochemical techniques, the renal localizations of RUNX3 were identified. Levels of adenosine triphosphate (ATP), mitochondrial membrane potential, and biochemical index were detected by appropriate kits. Reactive oxygen species (ROS) generation was assessed with dihydroethidium and MitoSOX Red staining. Apoptosis was assessed by flow cytometry and TUNEL. RUNX3 ubiquitination was measured. RESULTS RUNX3 was mainly present in renal tubules. Overexpressing RUNX3 increased Mfn2, Mfn1, ATP levels, and mitochondrial membrane potential, reduced Drp1 and ROS levels and cell apoptosis, as well as Cyt-C release into the cytoplasm. RUNX3 overexpression displayed a reduction in urinary albumin to creatinine ratio, Hemoglobin A1c, serum creatinine, and blood urea nitrogen. Overexpressing TLR4 attenuated the inhibitory effect of RUNX3 overexpression on mitochondrial dysfunction and cell apoptosis. HG promoted RUNX3 ubiquitination and SMURF2 expression. RUNX3 knockdown cancelled the inhibitory effect of SMURF2 on mitochondrial dysfunction and cell apoptosis. CONCLUSION SMURF2 interference inhibits RUNX3 ubiquitination and TLR4/NF-κB signalling pathway, thereby alleviating renal tubule injury.
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Affiliation(s)
- Ling Xiao
- Department of Nephrology, Wuhan Third Hospital, Wuhan, China
| | - Gang Ye
- Department of Nephrology, Wuhan Third Hospital, Wuhan, China
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Chen X, Li X, Cao B, Chen X, Zhang K, Han F, Kan C, Zhang J, Sun X, Guo Z. Mechanisms and efficacy of traditional Chinese herb monomers in diabetic kidney disease. Int Urol Nephrol 2024; 56:571-582. [PMID: 37552392 DOI: 10.1007/s11255-023-03703-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 07/04/2023] [Indexed: 08/09/2023]
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes and is the primary cause of end-stage renal disease. Current treatment strategies primarily focus on the inhibition of the renin-angiotensin-aldosterone system and the attainment of blood glucose control. Although current medical therapies for DKD have been shown to delay disease progression and improve long-term outcomes, their efficacy is limited and they may be restricted in certain cases, particularly when hyperkalemia is present. Traditional Chinese medicine (TCM) treatment has emerged as a significant complementary approach for DKD. TCM monomers, derived from various Chinese herbs, have been found to modulate multiple therapeutic targets and exhibit a broad range of therapeutic effects in patients with DKD. This review aims to summarize the mechanisms of action of TCM monomers in the treatment of DKD, based on findings from clinical trials, as well as cell and animal studies. The results of these investigations demonstrate the potential effective use of TCM monomers in treating or preventing DKD, offering a promising new direction for future research in the field. By providing a comprehensive overview of the mechanisms and efficacy of TCM monomers in DKD, this review highlights the potential of these natural compounds as alternative therapeutic options for improving outcomes in patients with DKD.
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Affiliation(s)
- Xuexun Chen
- Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Xuan Li
- Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Bo Cao
- Department of Emergency, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Xinping Chen
- Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Kexin Zhang
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Chengxia Kan
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
| | - Jingwen Zhang
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
| | - Xiaodong Sun
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China.
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China.
| | - Zhentao Guo
- Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China.
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Qi M, Hu X, Zhu W, Ren Y, Dai C. Study on effects and relevant mechanisms of Mudan granules on renal fibrosis in streptozotocin-induced diabetes rats. Ren Fail 2024; 46:2310733. [PMID: 38357745 PMCID: PMC10877650 DOI: 10.1080/0886022x.2024.2310733] [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: 10/25/2023] [Accepted: 01/23/2024] [Indexed: 02/16/2024] Open
Abstract
AIMS The effects and relevant mechanisms of Mudan granules in the renal fibrosis of diabetic rats were explored through in vivo experiments, which provided a scientific basis for expanding their clinical indications. METHODS Male SD rats were given a single intraperitoneal injection of STZ (65 mg/kg) to induce diabetes rat models. After treatment with Mudan granules, the general condition of rats was recorded. Blood glucose, blood lipids, and renal function-related indicators were detected, renal tissue morphological changes and fibrosis-related indicators were observed, and the expression of pathway-related proteins were examined. RESULTS The general condition of diabetes rats was improved after the treatment of Mudan granules, the 24-h urinary protein and urinary albumin to creatinine ratio were reduced, and the renal function and lipid results were modified. The tissue damage to the rat kidney has been repaired. Expression of TGF-β1/Smad-related pathway proteins was suppressed in kidney tissues, and the fibrosis factor CO-IV, FN, and LN were reduced in serum. CONCLUSION Mudan granules may inhibit of TGF-β1/Smad pathway, inhibit the production of ECM, reduce the levels of fibrosis factors CO-IV, FN, and LN, to have a protective effect on kidney in diabetes rats.
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Affiliation(s)
- Mushuang Qi
- Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Xiangka Hu
- Institute of Materia Medica, Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Wanjun Zhu
- Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Ying Ren
- Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Chunmei Dai
- Institute of Materia Medica, Jinzhou Medical University, Jinzhou, Liaoning, China
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Yang X, Zhao J, Li H, Pan L, Guo J, Li J, Zhang Y, Chen P, Li P. Effect of Tangshen formula on the remodeling of small intestine and colon in Zucker diabetic fatty rats. Heliyon 2023; 9:e21007. [PMID: 37886764 PMCID: PMC10597860 DOI: 10.1016/j.heliyon.2023.e21007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/28/2023] [Accepted: 10/12/2023] [Indexed: 10/28/2023] Open
Abstract
Background and aim Previous study have demonstrated that Tangshen Formula (TSF) could attenuate colonic histomorphological remodeling in the diabetic rat model induced by high fat diet plus low dosage streptozotocin (STZ). However, it is not clear whether TSF has same effect on small intestine and the effect on biomechanical properties of bowel. The aim of this study is to investigate the effect of TSF on histomorphological and biomechanical remodeling of small intestine and colon by using Zucker Diabetic Fatty (ZDF) Rat model. Materials and methods ZDF rats (obese fa/fa) with blood glucose higher than 11.7 mmol/L were divided into ZDF group (diabetic control group) and ZDF + TSF group (TSF treatment group), the later were intragastrically administered TSF. The ZDF rats (lean fa/+) were served as normal control (ZL) group. The rats in the ZL and ZDF groups were administered with saline. The experimental period covered from 8 weeks to 24 weeks. At the end of experiment, the ileal and colonic segments were studied in vitro. The histomorphometry and biomechanical parameters were measured. Results Compared with ZL group histomorphologically, the wet weight per unit length, wall thickness, wall area and fractions of total and type I and type III collagen in different layers for both ileum and colon increased in ZDF group. Those increasing parameters were partially inhibited in ZDF + TSF group. Compared with ZL group biomechanically, ZDF and ZDF + TSF groups had smaller opening angle and residual strain in ileum, and bigger opening angle and residual strain in colon. Whereas the wall became softer in circumferential direction and stiffer in longitudinal direction for both ileum and colon. However, no difference of biomechanical parameters was found between ZDF and ZDF + TSF groups. Conclusion The histomorphological and biomechanical remodeling of ileum and colon were happened in ZDF rats （obese fa/fa）. TSF could partly attenuate ileal and colonic histomorphological remodeling rather than biomechanical remodeling.
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Affiliation(s)
- Xin Yang
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Jingbo Zhao
- Anbiping (Chongqing) Pathological Diagnosis Center, Chongqing, China
| | - Hong Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Lin Pan
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Jing Guo
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Jing Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Yuting Zhang
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Pengmin Chen
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Ping Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
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Wang S, Qin S, Cai B, Zhan J, Chen Q. Promising therapeutic mechanism for Chinese herbal medicine in ameliorating renal fibrosis in diabetic nephropathy. Front Endocrinol (Lausanne) 2023; 14:932649. [PMID: 37522131 PMCID: PMC10376707 DOI: 10.3389/fendo.2023.932649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 06/22/2023] [Indexed: 08/01/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the most serious chronic microvascular abnormalities of diabetes mellitus and the major cause of uremia. Accumulating evidence has confirmed that fibrosis is a significant pathological feature that contributes to the development of chronic kidney disease in DN. However, the exact mechanism of renal fibrosis in DN is still unclear, which greatly hinders the treatment of DN. Chinese herbal medicine (CHM) has shown efficacy and safety in ameliorating inflammation and albuminuria in diabetic patients. In this review, we outline the underlying mechanisms of renal fibrosis in DN, including oxidative stress (OS) generation and OS-elicited ASK1-p38/JNK activation. Also, we briefly summarize the current status of CHM treating DN by improving renal fibrosis. The treatment of DN by inhibiting ASK1 activation to alleviate renal fibrosis in DN with CHM will promote the discovery of novel therapeutic targets for DN and provide a beneficial therapeutic method for DN.
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Affiliation(s)
- Shengju Wang
- Department of Nephrology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Shuai Qin
- Department of Nephrology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Baochao Cai
- Diabetes Department, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, Zhejiang, China
| | - Jihong Zhan
- Department of Nephrology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Qiu Y, Tang J, Zhao Q, Jiang Y, Liu YN, Liu WJ. From Diabetic Nephropathy to End-Stage Renal Disease: The Effect of Chemokines on the Immune System. J Diabetes Res 2023; 2023:3931043. [PMID: 37287620 PMCID: PMC10243947 DOI: 10.1155/2023/3931043] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/08/2023] [Accepted: 05/11/2023] [Indexed: 06/09/2023] Open
Abstract
Background Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), and there is growing evidence to support the role of immunity in the progression of DN to ESRD. Chemokines and chemokine receptors (CCRs) can recruit immune cells to sites of inflammation or injury. Currently, no studies have reported the effect of CCRs on the immune environment during the progression of DN to ESRD. Methods Differentially expressed genes (DEGs) from the GEO database were identified in DN patients versus ESRD patients. GO and KEGG enrichment analyses were performed using DEGs. A protein-protein interaction (PPI) network was constructed to identify hub CCRs. Differentially expressed immune cells were screened by immune infiltration analysis, and the correlation between immune cells and hub CCRs was also calculated. Result In this study, a total of 181 DEGs were identified. Enrichment analysis showed that chemokines, cytokines, and inflammation-related pathways were significantly enriched. Combining the PPI network and CCRs, four hub CCRs (CXCL2, CXCL8, CXCL10, and CCL20) were identified. These hub CCRs showed an upregulation trend in DN patients and a downregulation trend in ESRD patients. Immune infiltration analysis identified a variety of immune cells that underwent significant changes during disease progression. Among them, CD56bright natural killer cell, effector memory CD8 T cell, memory B cell, monocyte, regulatory T cell, and T follicular helper cell were significantly associated with all hub CCR correlation. Conclusion The effect of CCRs on the immune environment may contribute to the progression of DN to ESRD.
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Affiliation(s)
- Yuheng Qiu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Jingyi Tang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Qihan Zhao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yuhua Jiang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yu Ning Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Wei Jing Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
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Akhouri V, Majumder S, Gaikwad AB. The emerging insight into E3 ligases as the potential therapeutic target for diabetic kidney disease. Life Sci 2023; 321:121643. [PMID: 36997061 DOI: 10.1016/j.lfs.2023.121643] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/25/2023] [Accepted: 03/25/2023] [Indexed: 03/30/2023]
Abstract
Diabetic kidney disease (DKD) is a major diabetic complication and global health concern, occurring in nearly 30 % to 40 % of people with diabetes. Importantly, several therapeutic strategies are being used against DKD; however, available treatments are not uniformly effective and the continuous rise in the prevalence of DKD demands more potential therapeutic approaches or targets. Epigenetic modifiers are regarded for their potential therapeutic effects against DKD. E3 ligases are such epigenetic modifier that regulates the target gene expression by attaching ubiquitin to the histone protein. In recent years, the E3 ligases came up as a potential therapeutic target as it selectively attaches ubiquitin to the substrate proteins in the ubiquitination cascade and modulates cellular homeostasis. The E3 ligases are also actively involved in DKD by regulating the expression of several proteins involved in the proinflammatory and profibrotic pathways. Burgeoning reports suggest that several E3 ligases such as TRIM18 (tripartite motif 18), Smurf1 (Smad ubiquitination regulatory factor 1), and NEDD4-2 (neural precursor cell-expressed developmentally downregulated gene 4-2) are involved in kidney epithelial-mesenchymal transition, inflammation, and fibrosis by regulating respective signaling pathways. However, the various signaling pathways that are regulated by different E3 ligases in the progression of DKD are poorly understood. In this review, we have discussed E3 ligases as potential therapeutic target for DKD. Moreover, different signaling pathways regulated by E3 ligases in the progression of DKD have also been discussed.
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Affiliation(s)
- Vivek Akhouri
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India
| | - Syamantak Majumder
- Department of Biological Sciences, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
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Chen HH, Zhang YX, Lv JL, Liu YY, Guo JY, Zhao L, Nan YX, Wu QJ, Zhao YH. Role of sirtuins in metabolic disease-related renal injury. Biomed Pharmacother 2023; 161:114417. [PMID: 36812714 DOI: 10.1016/j.biopha.2023.114417] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 02/08/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Poor control of metabolic diseases induces kidney injury, resulting in microalbuminuria, renal insufficiency and, ultimately, chronic kidney disease. The potential pathogenetic mechanisms of renal injury caused by metabolic diseases remain unclear. Tubular cells and podocytes of the kidney show high expression of histone deacetylases known as sirtuins (SIRT1-7). Available evidence has shown that SIRTs participate in pathogenic processes of renal disorders caused by metabolic diseases. The present review addresses the regulatory roles of SIRTs and their implications for the initiation and development of kidney damage due to metabolic diseases. SIRTs are commonly dysregulated in renal disorders induced by metabolic diseases such as hypertensive nephropathy and diabetic nephropathy. This dysregulation is associated with disease progression. Previous literature has also suggested that abnormal expression of SIRTs affects cellular biology, such as oxidative stress, metabolism, inflammation, and apoptosis of renal cells, resulting in the promotion of invasive diseases. This literature reviews the research progress made in understanding the roles of dysregulated SIRTs in the pathogenesis of metabolic disease-related kidney disorders and describes the potential of SIRTs serve as biomarkers for early screening and diagnosis of these diseases and as therapeutic targets for their treatment.
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Affiliation(s)
- Huan-Huan Chen
- Department of Oncology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Yi-Xiao Zhang
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Urology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Jia-Le Lv
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Yu-Yang Liu
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Jing-Yi Guo
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Lu Zhao
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Yu-Xin Nan
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Qi-Jun Wu
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Yu-Hong Zhao
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
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Yao Y, Yu YC, Cai MR, Zhang ZQ, Bai J, Wu HM, Li P, Zhao TT, Ni J, Yin XB. UPLC-MS/MS method for the determination of the herb composition of Tangshen formula and the in vivo pharmacokinetics of its metabolites in rat plasma. PHYTOCHEMICAL ANALYSIS : PCA 2022; 33:402-426. [PMID: 34907611 DOI: 10.1002/pca.3098] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/08/2021] [Accepted: 10/04/2021] [Indexed: 06/14/2023]
Abstract
INTRODUCTION Tangshen formula (TSF) is a traditional Chinese medicine composed of seven medicinal herbs including Astragalus membranaceus, Rehmannia glutinosa Libosch, Citrus aurantium L., etc. which is used to treat diabetic nephropathy III, IV qi and yin deficiency and stasis syndrome. Most of the studies on TSF are pharmacological and pharmacodynamic experiments. There are few basic studies on its chemical substances, and the effective constituents are not clear. OBJECTIVE To analyse the main chemical components of TSF and the absorbed components in rat plasma following oral administration based on liquid chromatography tandem mass spectrometry (LC-MS/MS). Moreover, providing a rapid and valid analytical strategy for simultaneous determination of six components in rat plasma and use it in pharmacokinetic studies. RESULTS A total of 132 components were identified in TSF, and 44 components were identified in rat plasma after oral TSF, 35 of which were prototype components and nine were metabolic components. A sensitive and reliable LC-MS/MS method was developed for simultaneous determination of six components in rat plasma. The intra-day and inter-day precision relative standard deviation (RSD) was lower than 15%; the accuracy of low, medium and high concentrations ranged from 80% to 120%. The recovery met the requirements and the RSD of the recoveries was less than 15%. CONCLUSION A total of 132 components were identified in TSF. The LC-MS/MS quantitative method for the simultaneous determination of morroniside, loganin, notoginsenoside R1 , ginsenoside Re, ginsenoside Rb1 and astragaloside IV in rat plasma was established for the first time. The pharmacokinetic parameters are clarified, which can guide the clinical medication of TSF.
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Affiliation(s)
- Yu Yao
- School of Chinese Material Medical, Beijing University of Chinese Medicine, Beijing, China
| | - Ying-Chao Yu
- Medical Department, Yujiawu Community Healthcare Center, Beijing, China
| | - Meng-Ru Cai
- School of Chinese Material Medical, Beijing University of Chinese Medicine, Beijing, China
| | - Zhi-Qin Zhang
- School of Chinese Material Medical, Beijing University of Chinese Medicine, Beijing, China
| | - Jie Bai
- School of Chinese Material Medical, Beijing University of Chinese Medicine, Beijing, China
| | - Hui-Min Wu
- School of Chinese Material Medical, Beijing University of Chinese Medicine, Beijing, China
| | - Ping Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Ting-Ting Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Jian Ni
- School of Chinese Material Medical, Beijing University of Chinese Medicine, Beijing, China
| | - Xing-Bin Yin
- School of Chinese Material Medical, Beijing University of Chinese Medicine, Beijing, China
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Hu L, Wang Y, Wan Y, Ma L, Zhao T, Li P. Tangshen Formula Improves Diabetes-Associated Myocardial Fibrosis by Inhibiting TGF-β/Smads and Wnt/β-Catenin Pathways. Front Med (Lausanne) 2021; 8:732042. [PMID: 34938743 PMCID: PMC8687440 DOI: 10.3389/fmed.2021.732042] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/05/2021] [Indexed: 01/10/2023] Open
Abstract
Cardiovascular disease has become the main cause of death among complications of diabetes. Myocardial fibrosis is a crucial pathological change of cardiovascular disease. Tangshen Formula (TSF) shows a good clinical effect in the treatment of diabetic kidney disease (DKD). However, whether TSF alleviates diabetes-associated myocardial fibrosis is still unknown. In the present research, we studied the effect and mechanism of TSF in the treatment of myocardial fibrosis in vivo and in vitro. We found that TSF treatment significantly downregulates myocardial fibrosis-related markers, including collagens I and III, and α-SMA. TSF also protects primary mouse cardiac fibroblast (CF) from transforming growth factor-β1- (TGF-β1-) induced damage. Moreover, TSF decreased the expression levels of TGF-β/Smad-related genes (α-SMA, collagens I and III, TGF-β1, and pSmad2/3), and increased Smad7 gene expression. Finally, TSF decreased the expressions of wnt1, active-β-catenin, FN, and MMP7 to regulate the Wnt/β-catenin pathway. Taken together, TSF seems to attenuate myocardial fibrosis in KKAy mice by inhibiting TGF-β/Smad2/3 and Wnt/β-catenin signaling pathways.
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Affiliation(s)
- Lin Hu
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,National Energy R&D Center for Biorefinery, Beijing University of Chemical Technology, Beijing, China
| | - Yuyang Wang
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Yuzhou Wan
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,College of Pharmacy, Weifang Medical University, Weifang, China
| | - Liang Ma
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Tingting Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Ping Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
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Type 2 Diabetes Mellitus Mediation by the Disruptive Activity of Environmental Toxicants on Sex Hormone Receptors: In Silico Evaluation. TOXICS 2021; 9:toxics9100255. [PMID: 34678951 PMCID: PMC8538912 DOI: 10.3390/toxics9100255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 11/16/2022]
Abstract
This study investigates the disruptive activity of environmental toxicants on sex hormone receptors mediating type 2 diabetes mellitus (T2DM). Toxicokinetics, gene target prediction, molecular docking, molecular dynamics, and gene network analysis were applied in silico techniques. From the results, permethrin, perfluorooctanoic acid, dichlorodiphenyltrichloroethane, O-phenylphenol, bisphenol A, and diethylstilbestrol were the active toxic compounds that could modulate androgen (AR) and estrogen-α and -β receptors (ER) to induce T2DM. Early growth response 1 (EGR1), estrogen receptor 1 (ESR1), and tumour protein 63 (TP63) were the major transcription factors, while mitogen-activated protein kinases (MAPK) and cyclin-dependent kinases (CDK) were the major kinases upregulated by these toxicants via interactions with intermediary proteins such as PTEN, AKT1, NfKβ1, SMAD3 and others in the gene network analysis to mediate T2DM. These toxicants pose a major challenge to public health; hence, monitoring their manufacture, use, and disposal should be enforced. This would ensure reduced interaction between people and these toxic chemicals, thereby reducing the incidence and prevalence of T2DM.
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Protective Effect of Tangshen Formula () on Interstitial Cells of Cajal in Colon of Diabetic Rats. Chin J Integr Med 2021; 28:43-51. [PMID: 34581938 DOI: 10.1007/s11655-021-3297-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2020] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To explore the effect of Tangshen Formula (, TSF), a Chinese herbal medicine, on interstitial cells of Cajal (ICC) in the colon of diabetic rats. METHODS Fifty-four male Wistar rats were randomly divided into normal control (NC, n=14) and high-fat diet (HFD) groups (n=40). After 6 weeks, the rats in the HFD group were injected intraperitoneally streptozotocin once (30 mg/kg). Thirty rats with fasting blood glucose higher than 11.7 mmol/L were randomly divided into diabetes (DM) and TSF groups, 15 rats in each group. Rats in the NC and DM groups were intragastrically administered with saline, and those in the TSF group were given with TSF (2.4 g/kg) once daily for 20 weeks. Expression levels of Bax, Bcl-2, and caspase-3 in colonic smooth muscle layer were measured by Western blotting and immunohistochemical staining. The number of ICC was determined by immunohistochemical staining. Immunofluorescence was used for analyzing the ratio of classically activated macrophages (M1) and alternatively activated macrophages (M2) to total macrophages. Electron microscopy was used to observe the epithelial ultrastructure and junctions. RESULTS TSF appeared to partially prevented loss of ICC in DM rats (P<0.05). Compared with the NC group, expression levels of Bcl-2, Bax, caspase-3, and TNF-α as well as the ratio of M1 to total macrophages increased in DM rats (all P<0.05), and the ratio of M2 to total macrophages decreased (P<0.05 or P<0.01). Compared with the DM group, TSF decreased the expression levels of abovementioned proteins and restore M2 to total macrophages ratio (P<0.05 or P<0.01). TSF appeared to attenuate the ultrastructural changes of epithelia and improve the tight and desmosome junctions between epithelia reduced in the DM rats. CONCLUSION Reduced number of ICC in DM rats may be associated with damage of the intestinal barrier. The protective effects of TSF on ICC may be through repair of the epithelial junctions, which attenuates inflammation and inflammation-initiated apoptosis in colon of DM rats.
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Tang G, Li S, Zhang C, Chen H, Wang N, Feng Y. Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management. Acta Pharm Sin B 2021; 11:2749-2767. [PMID: 34589395 PMCID: PMC8463270 DOI: 10.1016/j.apsb.2020.12.020] [Citation(s) in RCA: 156] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/17/2020] [Accepted: 12/25/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetic nephropathy (DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease, which causes serious health problems and great financial burden to human society worldwide. Conventional strategies, such as renin-angiotensin-aldosterone system blockade, blood glucose level control, and bodyweight reduction, may not achieve satisfactory outcomes in many clinical practices for DN management. Notably, due to the multi-target function, Chinese medicine possesses promising clinical benefits as primary or alternative therapies for DN treatment. Increasing studies have emphasized identifying bioactive compounds and molecular mechanisms of reno-protective effects of Chinese medicines. Signaling pathways involved in glucose/lipid metabolism regulation, antioxidation, anti-inflammation, anti-fibrosis, and podocyte protection have been identified as crucial mechanisms of action. Herein, we summarize the clinical efficacies of Chinese medicines and their bioactive components in treating and managing DN after reviewing the results demonstrated in clinical trials, systematic reviews, and meta-analyses, with a thorough discussion on the relative underlying mechanisms and molecular targets reported in animal and cellular experiments. We aim to provide comprehensive insights into the protective effects of Chinese medicines against DN.
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Key Words
- ACEI, angiotensin-converting enzyme inhibitor
- ADE, adverse event
- AGEs, advanced glycation end-products
- AM, mesangial area
- AMPKα, adenosine monophosphate-activated protein kinase α
- ARB, angiotensin receptor blocker
- AREs, antioxidant response elements
- ATK, protein kinase B
- BAX, BCL-2-associated X protein
- BCL-2, B-cell lymphoma 2
- BCL-XL, B-cell lymphoma-extra large
- BMP-7, bone morphogenetic protein-7
- BUN, blood urea nitrogen
- BW, body weight
- C, control group
- CCR, creatinine clearance rate
- CD2AP, CD2-associated protein
- CHOP, C/EBP homologous protein
- CI, confidence interval
- COL-I/IV, collagen I/IV
- CRP, C-reactive protein
- CTGF, connective tissue growth factor
- Chinese medicine
- D, duration
- DAG, diacylglycerol
- DG, glomerular diameter
- DKD, diabetic kidney disease
- DM, diabetes mellitus
- DN, diabetic nephropathy
- Diabetic kidney disease
- Diabetic nephropathy
- EMT, epithelial-to-mesenchymal transition
- EP, E-prostanoid receptor
- ER, endoplasmic reticulum
- ESRD, end-stage renal disease
- ET-1, endothelin-1
- ETAR, endothelium A receptor
- FBG, fasting blood glucose
- FN, fibronectin
- GCK, glucokinase
- GCLC, glutamate-cysteine ligase catalytic subunit
- GFR, glomerular filtration rate
- GLUT4, glucose transporter type 4
- GPX, glutathione peroxidase
- GRB 10, growth factor receptor-bound protein 10
- GRP78, glucose-regulated protein 78
- GSK-3, glycogen synthase kinase 3
- Gαq, Gq protein alpha subunit
- HDL-C, high density lipoprotein-cholesterol
- HO-1, heme oxygenase-1
- HbA1c, glycosylated hemoglobin
- Herbal medicine
- ICAM-1, intercellular adhesion molecule-1
- IGF-1, insulin-like growth factor 1
- IGF-1R, insulin-like growth factor 1 receptor
- IKK-β, IκB kinase β
- IL-1β/6, interleukin 1β/6
- IR, insulin receptor
- IRE-1α, inositol-requiring enzyme-1α
- IRS, insulin receptor substrate
- IκB-α, inhibitory protein α
- JAK, Janus kinase
- JNK, c-Jun N-terminal kinase
- LC3, microtubule-associated protein light chain 3
- LDL, low-density lipoprotein
- LDL-C, low density lipoprotein-cholesterol
- LOX1, lectin-like oxidized LDL receptor 1
- MAPK, mitogen-activated protein kinase
- MCP-1, monocyte chemotactic protein-1
- MD, mean difference
- MDA, malondialdehyde
- MMP-2, matrix metallopeptidase 2
- MYD88, myeloid differentiation primary response 88
- Molecular target
- N/A, not applicable
- N/O, not observed
- N/R, not reported
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NOX-4, nicotinamide adenine dinucleotide phosphate-oxidase-4
- NQO1, NAD(P)H:quinone oxidoreductase 1
- NRF2, nuclear factor erythroid 2-related factor 2
- OCP, oxidative carbonyl protein
- ORP150, 150-kDa oxygen-regulated protein
- P70S6K, 70-kDa ribosomal protein S6 kinase
- PAI-1, plasminogen activator inhibitor-1
- PARP, poly(ADP-Ribose) polymerase
- PBG, postprandial blood glucose
- PERK, protein kinase RNA-like eukaryotic initiation factor 2A kinase
- PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α
- PGE2, prostaglandin E2
- PI3K, phosphatidylinositol 3 kinases
- PINK1, PTEN-induced putative kinase 1
- PKC, protein kinase C
- PTEN, phosphatase and tensin homolog
- RAGE, receptors of AGE
- RASI, renin-angiotensin system inhibitor
- RCT, randomized clinical trial
- ROS, reactive oxygen species
- SCr, serum creatinine
- SD, standard deviation
- SD-rat, Sprague–Dawley rat
- SIRT1, sirtuin 1
- SMAD, small mothers against decapentaplegic
- SMD, standard mean difference
- SMURF-2, SMAD ubiquitination regulatory factor 2
- SOCS, suppressor of cytokine signaling proteins
- SOD, superoxide dismutase
- STAT, signal transducers and activators of transcription
- STZ, streptozotocin
- Signaling pathway
- T, treatment group
- TBARS, thiobarbituric acid-reactive substance
- TC, total cholesterol
- TCM, traditional Chinese medicine
- TFEB, transcription factor EB
- TG, triglyceride
- TGBM, thickness of glomerular basement membrane
- TGF-β, tumor growth factor β
- TGFβR-I/II, TGF-β receptor I/II
- TII, tubulointerstitial injury index
- TLR-2/4, toll-like receptor 2/4
- TNF-α, tumor necrosis factor α
- TRAF5, tumor-necrosis factor receptor-associated factor 5
- UACR, urinary albumin to creatinine ratio
- UAER, urinary albumin excretion rate
- UMA, urinary microalbumin
- UP, urinary protein
- VCAM-1, vascular cell adhesion molecule-1
- VEGF, vascular endothelial growth factor
- WMD, weight mean difference
- XBP-1, spliced X box-binding protein 1
- cAMP, cyclic adenosine monophosphate
- eGFR, estimated GFR
- eIF2α, eukaryotic initiation factor 2α
- mTOR, mammalian target of rapamycin
- p-IRS1, phospho-IRS1
- p62, sequestosome 1 protein
- α-SMA, α smooth muscle actin
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Affiliation(s)
- Guoyi Tang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR 999077, China
| | - Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR 999077, China
| | - Cheng Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR 999077, China
| | - Haiyong Chen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR 999077, China
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR 999077, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR 999077, China
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Wang L, Wang HL, Liu TT, Lan HY. TGF-Beta as a Master Regulator of Diabetic Nephropathy. Int J Mol Sci 2021; 22:7881. [PMID: 34360646 PMCID: PMC8345981 DOI: 10.3390/ijms22157881] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/13/2021] [Accepted: 07/13/2021] [Indexed: 12/26/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the most common complications in diabetes mellitus and the leading cause of end-stage renal disease. TGF-β is a pleiotropic cytokine and has been recognized as a key mediator of DN. However, anti-TGF-β treatment for DN remains controversial due to the diverse role of TGF-β1 in DN. Thus, understanding the regulatory role and mechanisms of TGF-β in the pathogenesis of DN is the initial step towards the development of anti-TGF-β treatment for DN. In this review, we first discuss the diverse roles and signaling mechanisms of TGF-β in DN by focusing on the latent versus active TGF-β1, the TGF-β receptors, and the downstream individual Smad signaling molecules including Smad2, Smad3, Smad4, and Smad7. Then, we dissect the regulatory mechanisms of TGF-β/Smad signaling in the development of DN by emphasizing Smad-dependent non-coding RNAs including microRNAs and long-non-coding RNAs. Finally, the potential therapeutic strategies for DN by targeting TGF-β signaling with various therapeutic approaches are discussed.
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Affiliation(s)
- Li Wang
- Research Center for Integrative Medicine, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China; (L.W.); (H.-L.W.); (T.-T.L.)
| | - Hong-Lian Wang
- Research Center for Integrative Medicine, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China; (L.W.); (H.-L.W.); (T.-T.L.)
| | - Tong-Tong Liu
- Research Center for Integrative Medicine, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China; (L.W.); (H.-L.W.); (T.-T.L.)
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong 999077, China
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Li L, Lee J, Cho A, Kim JH, Ju W, An JN, Park JH, Zhu SM, Lee J, Yu SS, Lim CS, Kim DK, Kim YS, Yang SH, Lee JP. cMet agonistic antibody prevents acute kidney injury to chronic kidney disease transition by suppressing Smurf1 and activating Smad7. Clin Sci (Lond) 2021; 135:1427-1444. [PMID: 34061176 DOI: 10.1042/cs20210013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 05/19/2021] [Accepted: 06/01/2021] [Indexed: 11/17/2022]
Abstract
We aimed to investigate the role of cMet agonistic antibody (cMet Ab) in preventing kidney fibrosis during acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Additionally, we explored the effect of cMet Ab on TGF-β1/Smad pathway during the pathogenesis of kidney fibrosis. A unilateral ischemia-reperfusion injury (UIRI) mouse model was established to induce AKI-to-CKD transition. Furthermore, we incubated human proximal tubular epithelial cells (hPTECs) under hypoxic conditions as in vitro model of kidney fibrosis. We analyzed the soluble plasma cMet level in patients with AKI requiring dialysis. Patients who did not recover kidney function and progressed to CKD presented a higher increase in the cMet level. The kidneys of mice treated with cMet Ab showed fewer contractions and weighed more than the controls. The mice in the cMet Ab-treated group showed reduced fibrosis and significantly decreased expression of fibronectin and α-smooth muscle actin. cMet Ab treatment decreased inflammatory markers (MCP-1, TNF-α, and IL-1β) expression, reduced Smurf1 and Smad2/3 level, and increased Smad7 expressions. cMet Ab treatment increased cMet expression and reduced the hypoxia-induced increase in collagen-1 and ICAM-1 expression, thereby reducing apoptosis in the in vitro cell model. After cMet Ab treatment, hypoxia-induced expression of Smurf1, Smad2/3, and TGF-β1 was reduced, and suppressed Smad7 was activated. Down-regulation of Smurf1 resulted in suppression of hypoxia-induced fibronectin expression, whereas treatment with cMet Ab showed synergistic effects. cMet Ab can successfully prevent fibrosis response in UIRI models of kidney fibrosis by decreasing inflammatory response and inhibiting the TGF-β1/Smad pathway.
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Affiliation(s)
- Lilin Li
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Intensive Care Unit, Yanbian University Hospital, Yanji, Jilin, China
| | - Jeonghwan Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Ara Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Jin Hyuk Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Wonmin Ju
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jung Nam An
- Department of Internal Medicine, Hallym Sacred Heart Hospital, Anyang, Gyeonggi-do, Republic of Korea
| | - Jeong Hwan Park
- Department of Pathology, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Shi Mao Zhu
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Junghun Lee
- R&D Center of Innovative Medicines, Helixmith Co., Ltd., Seoul, Republic of Korea
| | - Seung-Shin Yu
- R&D Center of Innovative Medicines, Helixmith Co., Ltd., Seoul, Republic of Korea
| | - Chun Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seung Hee Yang
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
- Seoul National University Kidney Research Institute, Seoul, Republic of Korea
| | - Jung Pyo Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
- Seoul National University Kidney Research Institute, Seoul, Republic of Korea
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20
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Gu YY, Dou JY, Huang XR, Liu XS, Lan HY. Transforming Growth Factor-β and Long Non-coding RNA in Renal Inflammation and Fibrosis. Front Physiol 2021; 12:684236. [PMID: 34054586 PMCID: PMC8155637 DOI: 10.3389/fphys.2021.684236] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/06/2021] [Indexed: 12/17/2022] Open
Abstract
Renal fibrosis is one of the most characterized pathological features in chronic kidney disease (CKD). Progressive fibrosis eventually leads to renal failure, leaving dialysis or allograft transplantation the only clinical option for CKD patients. Transforming growth factor-β (TGF-β) is the key mediator in renal fibrosis and is an essential regulator for renal inflammation. Therefore, the general blockade of the pro-fibrotic TGF-β may reduce fibrosis but may risk promoting renal inflammation and other side effects due to the diverse role of TGF-β in kidney diseases. Long non-coding RNAs (lncRNAs) are RNA transcripts with more than 200 nucleotides and have been regarded as promising therapeutic targets for many diseases. This review focuses on the importance of TGF-β and lncRNAs in renal inflammation, fibrogenesis, and the potential applications of TGF-β and lncRNAs as the therapeutic targets and biomarkers in renal fibrosis and CKD are highlighted.
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Affiliation(s)
- Yue-Yu Gu
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jing-Yun Dou
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Nephrology, Weihai Hospital of Traditional Chinese Medicine, Weihai, China
| | - Xiao-Ru Huang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Xu-Sheng Liu
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, The Chinese University of Hong Kong, Hong Kong, China
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21
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Lin HL, Lin MY, Tsai CH, Wang YH, Chen CJ, Hwang SJ, Yen MH, Chiu YW. Harmonizing Formula Prescription Patterns in Patients With Chronic Kidney Disease: A Population-Based Cross-Sectional Study. Front Pharmacol 2021; 12:573145. [PMID: 33995002 PMCID: PMC8117089 DOI: 10.3389/fphar.2021.573145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 03/22/2021] [Indexed: 11/13/2022] Open
Abstract
Objective: Harmonizing formulas are associated with beneficial renal outcomes in chronic kidney disease (CKD), but the therapeutic mechanisms are unclear. The study aims to explore the associations of intentions and independent factors with harmonizing formulas prescriptions for patients with CKD. Methods: We conducted a population-based cross-sectional study to explore factors associated with harmonizing formulas prescription. Patients who had been prescribed harmonizing formulas after CKD diagnosis was defined as the using harmonizing formulas group. Disease diagnoses when having harmonizing formula prescriptions and patient characteristics related to these prescriptions were collected. Results: In total, 24,971 patients were enrolled in this analysis, and 5,237 (21%) patients were prescribed harmonizing formulas after CKD diagnosis. The three most frequent systematic diseases and related health problems for which harmonizing formula prescriptions were issued in CKD were symptoms, signs, and ill-defined conditions (24.5%), diseases of the digestive system (20.67%), and diseases of the musculoskeletal system (12.9%). Higher likelihoods of harmonizing formula prescriptions were associated with young age (adjusted odds ratio: 0.98, 95% confidence interval: 0.97-0.98), female sex (1.79, 1.68-1.91), no diabetes (1.20, 1.06-1.36), no hypertension (1.38, 1.27-1.50), no cerebrovascular disease (1.34, 1.14-1.56), less disease severity (0.85, 0.83-0.88), using nonsteroidal anti-inflammatory drugs (NSAIDs) (1.65, 1.54-1.78), and using analgesic drugs other than NSAIDs (1.47, 1.35-1.59). Conclusion: Harmonizing formulas are commonly used for treating symptoms of the digestive and musculoskeletal systems in CKD cases. Further research on harmonizing formula effectiveness with regard to particular characteristics of CKD patients is warranted.
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Affiliation(s)
- Hung-Lung Lin
- Department of Chinese Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Yen Lin
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Master of Public Health Degree Program, College of Public Health, National Taiwan University, Taipei, Taiwan
- Department of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Hsun Tsai
- Department of Chinese Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hsiu Wang
- Department of Chinese Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Jen Chen
- Department of Chinese Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shang-Jyh Hwang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
| | - Ming-Hong Yen
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Wen Chiu
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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22
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Li N, Zhao T, Cao Y, Zhang H, Peng L, Wang Y, Zhou X, Wang Q, Li J, Yan M, Dong X, Zhao H, Li P. Tangshen Formula Attenuates Diabetic Kidney Injury by Imparting Anti-pyroptotic Effects via the TXNIP-NLRP3-GSDMD Axis. Front Pharmacol 2021; 11:623489. [PMID: 33584307 PMCID: PMC7880163 DOI: 10.3389/fphar.2020.623489] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/29/2020] [Indexed: 01/04/2023] Open
Abstract
We previously reported that Tangshen formula (TSF), a Chinese herbal medicine for diabetic kidney disease (DKD) therapy, imparts renal protective effects. However, the underlying mechanisms of these effects remain unclear. Pyroptosis is a form of programmed cell death that can be triggered by the NLRP3 inflammasome. Recently, the association between the pyroptosis of renal resident cells and DKD was established, but with limited evidence. This study aimed to investigate whether the renal protective effects of TSF are related to its anti-pyroptotic effect. DKD rats established by right uninephrectomy plus a single intraperitoneal injection of STZ and HK-2 cells stimulated by AGEs were used. In vivo, TSF reduced the 24 h urine protein (24 h UP) of DKD rats and alleviated renal pathological changes. Meanwhile, the increased expression of pyroptotic executor (GSDMD) and NLRP3 inflammasome pathway molecules (NLRP3, caspase-1, and IL-1β) located in the tubules of DKD rats were downregulated with TSF treatment. In vitro, we confirmed the existence of pyroptosis in AGE-stimulated HK-2 cells and the activation of the NLRP3 inflammasome. TSF reduced pyroptosis and NLRP3 inflammasome activation in a dosage-dependent manner. Then, we used nigericin to determine that TSF imparts anti-pyroptotic effects by inhibiting the NLRP3 inflammasome. Finally, we found that TSF reduces reactive oxygen species (ROS) production and thioredoxin-interacting protein (TXNIP) expression in AGE-stimulated HK-2 cells. More importantly, TSF decreased the colocalization of TXNIP and NLRP3, indicating that ROS-TXNIP may be the target of TSF. In summary, the anti-pyroptotic effect via the TXNIP-NLRP3-GSDMD axis may be an important mechanism of TSF for DKD therapy.
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Affiliation(s)
- Nan Li
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.,Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,Clinical Laboratory, China-Japan Friendship Hospital, Beijing, China
| | - Tingting Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Yongtong Cao
- Clinical Laboratory, China-Japan Friendship Hospital, Beijing, China
| | - Haojun Zhang
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Liang Peng
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Yan Wang
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Xuefeng Zhou
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Qian Wang
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Jialin Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Meihua Yan
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Xi Dong
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Hailing Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Ping Li
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.,Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
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23
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de Ceuninck van Capelle C, Spit M, Ten Dijke P. Current perspectives on inhibitory SMAD7 in health and disease. Crit Rev Biochem Mol Biol 2020; 55:691-715. [PMID: 33081543 DOI: 10.1080/10409238.2020.1828260] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Transforming growth factor β (TGF-β) family members play an extensive role in cellular communication that orchestrates both early development and adult tissue homeostasis. Aberrant TGF-β family signaling is associated with a pathological outcome in numerous diseases, and in-depth understanding of molecular and cellular processes could result in therapeutic benefit for patients. Canonical TGF-β signaling is mediated by receptor-regulated SMADs (R-SMADs), a single co-mediator SMAD (Co-SMAD), and inhibitory SMADs (I-SMADs). SMAD7, one of the I-SMADs, is an essential negative regulator of the pleiotropic TGF-β and bone morphogenetic protein (BMP) signaling pathways. In a negative feedback loop, SMAD7 inhibits TGF-β signaling by providing competition for TGF-β type-1 receptor (TβRI), blocking phosphorylation and activation of SMAD2. Moreover, SMAD7 recruits E3 ubiquitin SMURF ligases to the type I receptor to promote ubiquitin-mediated proteasomal degradation. In addition to its role in TGF-β and BMP signaling, SMAD7 is regulated by and implicated in a variety of other signaling pathways and functions as a mediator of crosstalk. This review is focused on SMAD7, its function in TGF-β and BMP signaling, and its role as a downstream integrator and crosstalk mediator. This crucial signaling molecule is tightly regulated by various mechanisms. We provide an overview of the ways by which SMAD7 is regulated, including noncoding RNAs (ncRNAs) and post-translational modifications (PTMs). Finally, we discuss its role in diseases, such as cancer, fibrosis, and inflammatory bowel disease (IBD).
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Affiliation(s)
| | - Maureen Spit
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
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24
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Wang Q, Tian X, Zhou W, Wang Y, Zhao H, Li J, Zhou X, Zhang H, Zhao T, Li P. Protective Role of Tangshen Formula on the Progression of Renal Damage in db/db Mice by TRPC6/Talin1 Pathway in Podocytes. J Diabetes Res 2020; 2020:3634974. [PMID: 33015191 PMCID: PMC7519445 DOI: 10.1155/2020/3634974] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 08/11/2020] [Accepted: 08/29/2020] [Indexed: 12/16/2022] Open
Abstract
Tangshen Formula (TSF) is a Chinese Medicine formula that has been reported to alleviate proteinuria and protect renal function in humans and animals with diabetic kidney disease (DKD). However, little is known about its mechanism in improving proteinuria. The dysregulation of podocyte cell-matrix adhesion has been demonstrated to play an important role in the pathogenesis and progression of proteinuric kidney diseases including DKD. In the present study, the underlying protective mechanism of TSF on podocytes was investigated using the murine model of type 2 DKD db/db mice in vivo and advanced glycation end products (AGEs)-stimulated primary mice podocytes in vitro. Results revealed that TSF treatment could significantly mitigate reduction of podocyte numbers and foot process effacement, reduce proteinuria, and protect renal function in db/db mice. There was a significant increase in expression of transient receptor potential canonical channel 6 (TRPC6) and a decrease in expression of talin1 in podocytes of db/db mice. The results of AGEs-stimulated primary mice podocytes showed increased cell migration and actin-cytoskeleton rearrangement. Moreover, primary mice podocytes stimulated by AGEs displayed an increase in TRPC6-dependent Ca2+ influx, a loss of talin1, and translocation of nuclear factor of activated T cell (NFATC) 2. These dysregulations in mice primary podocytes stimulated by AGEs could be significantly attenuated after TSF treatment. 1-Oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC6 agonist, blocked the protective role of TSF on podocyte cell-matrix adherence. In conclusion, TSF could protect podocytes from injury and reduce proteinuria in DKD, which may be mediated by the regulation of the TRPC6/Talin1 pathway in podocytes.
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Affiliation(s)
- Qian Wang
- Beijing University of Chinese Medicine, Beijing 100029, China
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xuefei Tian
- Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Wei'e Zhou
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yan Wang
- Beijing Key Laboratory of Diabetes Research and Care, Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing 101149, China
| | - Hailing Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jialin Li
- Beijing University of Chinese Medicine, Beijing 100029, China
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xuefeng Zhou
- Beijing University of Chinese Medicine, Beijing 100029, China
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Haojun Zhang
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Tingting Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Ping Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
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25
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The Role of Chemokines and Chemokine Receptors in Diabetic Nephropathy. Int J Mol Sci 2020; 21:ijms21093172. [PMID: 32365893 PMCID: PMC7246426 DOI: 10.3390/ijms21093172] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/12/2022] Open
Abstract
Kidney function decline is one of the complications of diabetes mellitus and may be indicated as diabetic nephropathy (DN). DN is a chronic inflammatory disease featuring proteinuria and a decreasing glomerular filtration rate. Despite several therapeutic options being currently available, DN is still the major cause of end-stage renal disease. Accordingly, widespread innovation is needed to improve outcomes in patients with DN. Chemokines and their receptors are critically involved in the inflammatory progression in the development of DN. Although recent studies have shown multiple pathways related to the chemokine system, the specific and direct effects of chemokines and their receptors remain unclear. In this review, we provide an overview of the potential role and mechanism of chemokine systems in DN proposed in recent years. Chemokine system-related mechanisms may provide potential therapeutic targets in DN.
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26
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Abstract
Renal fibrosis is a hallmark of chronic kidney disease. Although considerable achievements in the pathogenesis of renal fibrosis have been made, the underlying mechanisms of renal fibrosis remain largely to be explored. Now we have reached the consensus that TGF-β is a master regulator of renal fibrosis. Indeed, TGF-β regulates renal fibrosis via both canonical and noncanonical TGF-β signaling. Moreover, ongoing renal inflammation promotes fibrosis as inflammatory cells such as macrophages, conventional T cells and mucosal-associated invariant T cells may directly or indirectly contribute to renal fibrosis, which is also tightly regulated by TGF-β. However, anti-TGF-β treatment for renal fibrosis remains ineffective and nonspecific. Thus, research into mechanisms and treatment of renal fibrosis remains highly challenging.
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27
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Gu YY, Liu XS, Huang XR, Yu XQ, Lan HY. Diverse Role of TGF-β in Kidney Disease. Front Cell Dev Biol 2020; 8:123. [PMID: 32258028 PMCID: PMC7093020 DOI: 10.3389/fcell.2020.00123] [Citation(s) in RCA: 153] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 02/12/2020] [Indexed: 12/13/2022] Open
Abstract
Inflammation and fibrosis are two pathological features of chronic kidney disease (CKD). Transforming growth factor-β (TGF-β) has been long considered as a key mediator of renal fibrosis. In addition, TGF-β also acts as a potent anti-inflammatory cytokine that negatively regulates renal inflammation. Thus, blockade of TGF-β inhibits renal fibrosis while promoting inflammation, revealing a diverse role for TGF-β in CKD. It is now well documented that TGF-β1 activates its downstream signaling molecules such as Smad3 and Smad3-dependent non-coding RNAs to transcriptionally and differentially regulate renal inflammation and fibrosis, which is negatively regulated by Smad7. Therefore, treatments by rebalancing Smad3/Smad7 signaling or by specifically targeting Smad3-dependent non-coding RNAs that regulate renal fibrosis or inflammation could be a better therapeutic approach. In this review, the paradoxical functions and underlying mechanisms by which TGF-β1 regulates in renal inflammation and fibrosis are discussed and novel therapeutic strategies for kidney disease by targeting downstream TGF-β/Smad signaling and transcriptomes are highlighted.
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Affiliation(s)
- Yue-Yu Gu
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Xu-Sheng Liu
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiao-Ru Huang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Xue-Qing Yu
- Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
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28
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Jin D, Huang WJ, Meng X, Yang F, Bao Q, Zhang MZ, Yang YN, Ni Q, Lian FM, Tong XL. Chinese herbal medicine Tangshen Formula treatment for type 2 diabetic kidney disease in the early stage: study protocol for a randomized controlled trial. Trials 2019; 20:756. [PMID: 31864393 PMCID: PMC6925411 DOI: 10.1186/s13063-019-3821-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 10/22/2019] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) is the main cause of end-stage kidney disease and has become a heavy economic and social burden due to its high prevalence and morbidity. The most effective strategy is that patients with DKD should be diagnosed and treated early. Preliminary studies showed that the Chinese herbal Tangshen Formula (TSF) may delay the progression of DKD, reducing microalbuminuria and macroalbuminuria and improving renal function. We designed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of TSF in patients with DKD. METHODS/DESIGN This trial is a 13-center, randomized, double-blind, placebo-controlled study. A total of 632 participants will be randomized in a 1:1 ratio to an experiment group (TSF plus losartan) and a control group (placebo plus losartan). The trial cycle will last 24 weeks. The primary outcome will be the change in the urine microalbumin-creatinine ratio from baseline to week 24. The secondary outcome will be the change in the rate of progression to the clinical proteinuria period after intervention, the rate of urine microalbumin negative conversion, the rate of normal urinary microalbumin, the doubling rate of the baseline creatinine value and the glomerular filtration rate between the two groups. Safety in medication will also be evaluated. DISCUSSION We hypothesize that patients with type 2 diabetes in the early stage of DKD will benefit from TSF. If successful, this study will provide evidence-based recommendations for clinicians. TRIAL REGISTRATION ClinicalTrials.gov, NCT03009864. Registered January 2017.
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Affiliation(s)
- De Jin
- Guang’anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053 China
| | - Wen-Jing Huang
- Guang’anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053 China
| | - Xiang Meng
- Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Fan Yang
- Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Qi Bao
- Guang’anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053 China
| | - Mei-zhen Zhang
- Guang’anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053 China
| | - Ya-nan Yang
- Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Qing Ni
- Guang’anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053 China
| | - Feng-Mei Lian
- Guang’anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053 China
| | - Xiao-Lin Tong
- Guang’anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053 China
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Yu J, Qiu LX, Qing GP, Zhao BW, Wang H. Modified Cortex Mori Capsules improving the successful rate of functional filtering blebs after reclinical glaucoma filtering surgery. World J Clin Cases 2019; 7:3436-3445. [PMID: 31750327 PMCID: PMC6854417 DOI: 10.12998/wjcc.v7.i21.3436] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/27/2019] [Accepted: 10/05/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The major reason for filtering bleb failure or scarring of the bleb site is due to excessive scarring after glaucoma filtration surgery in the clinic. Traditional Chinese medicine has preeminence in the prevention of fibrosis formation through the regulation of systemic circulation and improvement of the properties of the inflammatory cells in the blood.
AIM To examine the clinical efficacy of using the Modified Cortex Mori Capsules (MCMC; Chinese name: Jiawei Sangbaipi Capsules) in the success rate of functional filtering blebs after glaucoma filtering surgery in clinical patients.
METHODS Sixty resurgery glaucoma patients were randomly divided into two groups: 30 patients in surgery with the placebo group and 30 patients in surgery with the MCMC group. Patients took either the placebo or the MCMC 2 wk before and after surgery. Postoperative morphology and function filtering bleb, visual acuity, intraocular pressure, postoperative complications, the success rate of filtration surgery and clinical efficacy were observed.
RESULTS Fifty patients completed the study. The percentage of functional filtering blebs in the surgery plus MCMC group was 84% at 6 mo after surgery, which was higher than surgery plus placebo group (64%, P < 0.05). The surgical success rate in the MCMC and placebo groups were 79% ± 8.3% and 57% ± 10.6% respectively (P < 0.05). The visual acuity, intraocular pressure and the postoperative complications in the two groups had no significant differences.
CONCLUSION Glaucoma filtering surgery while taking MCMC not only reduced excessive scar formation and increased the success rate of functional filtering blebs but also improved the success of glaucoma filtration operations.
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Affiliation(s)
- Jing Yu
- Beijing Tongren Eye Center, Laboratory of Ophthalmology and Visual Science in Beijing, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Li-Xin Qiu
- Beijing Tongren Eye Center, Laboratory of Ophthalmology and Visual Science in Beijing, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Guo-Ping Qing
- Beijing Tongren Eye Center, Laboratory of Ophthalmology and Visual Science in Beijing, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Bo-Wen Zhao
- Beijing Tongren Eye Center, Laboratory of Ophthalmology and Visual Science in Beijing, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Hui Wang
- Beijing Tongren Eye Center, Laboratory of Ophthalmology and Visual Science in Beijing, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
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Zhang YY, Tan RZ, Zhang XQ, Yu Y, Yu C. Calycosin Ameliorates Diabetes-Induced Renal Inflammation via the NF-κB Pathway In Vitro and In Vivo. Med Sci Monit 2019; 25:1671-1678. [PMID: 30830898 PMCID: PMC6413560 DOI: 10.12659/msm.915242] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Diabetic nephropathy (DN), which is one of the primary causes of end-stage renal disease (ESRD), is increasingly diagnosed in patients due to the continuous increase in the prevalence of diabetic mellitus (DM). Astragali Radix, a traditional Chinese herb, is widely administrated to ameliorate the symptoms of diabetes and diabetic nephropathy, but its mechanism is still not yet fully defined. Calycosin (C₁₆H₁₂O₅) is the major active component of Astragali Radix. In this study, we analyzed the role of calycosin in diabetic nephropathy and explored its underlying mechanism. MATERIAL AND METHODS Cell activation, inflammatory cytokines expression and secretion, and protein levels were analyzed in cultured mouse tubular epithelial cells (mTEC). db/db mice were intraperitoneally injected with 10 mg/(kg·d) calycosin or control saline for 4 weeks, followed by analysis of structure injury, inflammation, and NF-κB signaling activity. RESULTS Our results indicated that TNF-α and IL-1β were significantly induced by advanced glycation end-products (AGEs), but calycosin remarkably reduced the expression of TNF-α and IL-1β in the cultured mouse tubular epithelial cells (mTEC). Calycosin effectively alleviated kidney injury in diabetic kidneys of db/db mice during the progression of diabetic renal injury, indicated by the reduction of histological injury and immunohistochemical of inflammatory cytokines. Mechanistically, we identified calycosin inhibited diabetes-induced inflammation in kidneys by suppressing the phosphorylation of IKBa and NF-κB p65 in vitro and in vivo. CONCLUSIONS Calycosin significantly ameliorated diabetes-induced renal inflammation in diabetic renal injury by inhibition of the NF-κB-dependent signaling pathway in vivo and in vitro.
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Affiliation(s)
- Ying-Ying Zhang
- Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China (mainland)
| | - Rui-Zhi Tan
- Research Center of Combined Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China (mainland)
| | - Xiao-Qin Zhang
- Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China (mainland)
| | - Ying Yu
- Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China (mainland)
| | - Chen Yu
- Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China (mainland)
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Wang Y, Zhao H, Wang Q, Zhou X, Lu X, Liu T, Zhan Y, Li P. Chinese Herbal Medicine in Ameliorating Diabetic Kidney Disease via Activating Autophagy. J Diabetes Res 2019; 2019:9030893. [PMID: 31828168 PMCID: PMC6885296 DOI: 10.1155/2019/9030893] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 10/29/2019] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease (DKD), a leading cause of end-stage renal disease (ESRD), has become a serious public health problem worldwide and lacks effective therapies due to its complex pathogenesis. Recent studies suggested defective autophagy involved in the pathogenesis and progression of DKD. Chinese herbal medicine, as an emerging option for the treatment of DKD, could improve diabetic kidney injury by activating autophagy. In this review, we briefly summarize underlying mechanisms of autophagy dysregulation in DKD, including AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), and the sirtuin (Sirt) pathways, and we particularly concentrate on the current status of Chinese herbal medicine treating DKD by regulating autophagy. The advances in our understanding regarding the treatment of DKD via regulating autophagy with Chinese herbal medicine will enhance the clinical application of Chinese medicine as well as discovery of novel therapeutic agents for diabetic patients.
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Affiliation(s)
- Yuyang Wang
- Department of Nephrology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hailing Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Qian Wang
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
- Beijing University of Chinese Medicine, Beijing 10029, China
| | - Xuefeng Zhou
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
- Beijing University of Chinese Medicine, Beijing 10029, China
| | - Xiaoguang Lu
- Department of Nephrology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Tongtong Liu
- Department of Nephrology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Yongli Zhan
- Department of Nephrology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ping Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
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Wang FL, Wang YH, Han L, An HY, Zhang JH, Zhang XY, Chen ZQ, Qin JG. Renoprotective Effect of Yiqi Yangyin Huayu Tongluo Formula against Diabetic Nephropathy in Diabetic Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2018; 2018:4276052. [PMID: 30622601 PMCID: PMC6304536 DOI: 10.1155/2018/4276052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 10/30/2018] [Accepted: 11/15/2018] [Indexed: 01/15/2023]
Abstract
Diabetic nephropathy is developed in 20-40% of patients with diabetes mellitus, and patients with diabetic nephropathy require dialysis and renal transplantation. Traditional Chinese medicine has been widely used in treating patients with diabetic nephropathy in China. However, the detailed mechanisms of traditional Chinese medicine remain unclear. Yiqi Yangyin Huayu Tongluo formula (ZY formula) is a traditional Chinese medicinal formula. Here, we demonstrated kidney protective effect of ZY formula on the rats with diabetic nephropathy. The therapeutic effect of ZY formula on the diabetic nephropathy was almost the same as that of Irbesartan, which proved to have excellent curative effects on diabetic nephropathy. We also demonstrated the mechanism of ZY formula effect on the diabetic nephropathy. First, we validated that the activation of ROS-JNK signaling pathway in diabetic rats could be reduced by ZY. Furthermore, collagen I expression could be downregulated by ZY formula treatment. Meanwhile, cell apoptosis in the kidney of diabetic rats could be alleviated by ZY formula.
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Affiliation(s)
- Feng-li Wang
- Central Laboratory, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
| | - Yue-hua Wang
- Department of Nephropathy, Hebei Medical University Third Hospital, Shijiazhuang, Hebei 050081, China
| | - Lin Han
- School of Basic Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Hai-yan An
- Department of Nephropathy, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
| | - Jiang-hua Zhang
- School of Integrated Traditional Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - Xue-yun Zhang
- School of Integrated Traditional Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - Zhi-qiang Chen
- Department of Nephropathy, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang, Hebei 050017, China
| | - Jian-guo Qin
- Department of Nephropathy, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
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Wang X, Zhao H, Wu X, Xi G, Zhou S. Tangshen Formula Treatment for Diabetic Kidney Disease by Inhibiting Racgap1-stata5-Mediated Cell Proliferation and Restoring miR-669j-Arntl-Related Circadian Rhythm. Med Sci Monit 2018; 24:7914-7928. [PMID: 30394366 PMCID: PMC6232920 DOI: 10.12659/msm.907412] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Background The aim of this study was to investigate the underlying mechanisms of Tangshen formula (TSF) for treatment of diabetic kidney disease (DKD). Material/Methods Microarray dataset GSE90842 was collected from the Gene Expression Omnibus database, including renal cortical tissues from normal control (NC), DKD, and DKD mice given TSF for 12 weeks (TSF) (n=3). Differentially-expressed genes (DEGs) were identified using LIMMA method. A protein-protein interaction (PPI) network was constructed using data from the STRING database followed by module analysis. The Mirwalk2 database was used to predict the underlying miRNAs of DEGs. Function enrichment analysis was performed using the DAVID tool. Results A total of 2277 and 2182 genes were identified as DEGs between DKD and NC or TSF groups, respectively. After overlap, 373 DEGs were considered as common in 2 comparison groups. Function enrichment indicated common DEGs were related to cell proliferation (Asf1b, anti-silencing function 1B histone chaperone; Anln, anillin, actin-binding protein; Racgap1, Rac GTPase activating protein 1; and Stat5, signal transducer and activator of transcription 5) and circadian rhythm (Arntl, aryl hydrocarbon receptor nuclear translocator-like). Racgap1 was considered as a hub gene in the PPI network because it could interact with Asf1b, Anln, and Stat5. Arntl was regulated by miR-669j in the miRNA-DEGs network and this miRNA was also a DEG in 2 comparisons. Conclusions TSF may be effective for DKD by inhibiting Racgap1-stata5-mediated cell proliferation and restoring miR-669j-Arntl-related circadian rhythm.
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Affiliation(s)
- Xiuying Wang
- College of Chinese Medicine, Jilin Agricultural Science and Technology College, Jilin City, Jilin, China (mainland)
| | - Hai Zhao
- Department of Reconstructive and Plastic Surgery, The General Hospital of Shenyang Military, Shenyang, Liaoning, China (mainland)
| | - Xingquan Wu
- Zang-fu Massage, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China (mainland)
| | - Guangsheng Xi
- College of Chinese Medicine, Jilin Agricultural Science and Technology College, Jilin City, Jilin, China (mainland)
| | - Shengxue Zhou
- College of Chinese Medicine, Jilin Agricultural Science and Technology College, Jilin City, Jilin, China (mainland)
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Wang Z, Huang W, Li H, Tang L, Sun H, Liu Q, Zhang L. Synergistic action of inflammation and lipid dysmetabolism on kidney damage in rats. Ren Fail 2018; 40:175-182. [PMID: 29569980 PMCID: PMC6014339 DOI: 10.1080/0886022x.2018.1450763] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
In kidney disease, inflammation and lipid dysmetabolism are often associated together, however, the effect and mechanism of inflammatory mediators and lipid dysmetabolism on kidney damage is still unclear. In this study, Wistar rats were randomized into four groups: normal diet + saline (Group N), high-fat diet (HF)+ saline (Group HF), normal diet + adriamycin (Group ADR), HF + adriamycin (Group ADR + HF). After 10 weeks of feeding, rats in each group were randomly sacrificed. We found that the protein content of urine in ADR and ADR + HF groups were significantly higher than that of group N and HF while the serum levels of total protein and albumin in the ADR and ADR + HF groups decreased correspondingly. The serum levels of triglyceride, total cholesterol and low-density lipoprotein in the HF, ADR and ADR + HF groups increased. In the treatment groups, mesangial proliferation, matrix accumulation, tubular vacuolization, inflammatory cell infiltration and fat deposition were detected. These pathological changes were the most serious in the ADR + HF group. The expression of tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) were increased in each treatment group, especially in the ADR + HF group. Our results suggested that the inflammatory factors and abnormal lipid levels can activate the inflammatory response in kidney of the Wistar rats, and lead to a series of pathological changes in renal tissue, and inflammatory factors and lipid dysmetabolism can aggravate damage in the kidney.
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Affiliation(s)
| | - Wenhan Huang
- b Department of Rheumatology and Immunology , The Second Affiliated Hospital of Chongqing Medical University , Chongqing , China
| | - Hui Li
- c Yan'an Hospital Affiliated to Kunming Medical University , Yunnan , China
| | - Lin Tang
- b Department of Rheumatology and Immunology , The Second Affiliated Hospital of Chongqing Medical University , Chongqing , China
| | - Hang Sun
- d Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education , The Second Affiliated Hospital of Chongqing Medical University , Chongqing , China
| | - Qi Liu
- d Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education , The Second Affiliated Hospital of Chongqing Medical University , Chongqing , China
| | - Ling Zhang
- e Department of Nephrology , The Second Affiliated Hospital and Center of Lipid Research of Chongqing Medical University , Chongqing , China
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Sun SF, Tang PMK, Feng M, Xiao J, Huang XR, Li P, Ma RCW, Lan HY. Novel lncRNA Erbb4-IR Promotes Diabetic Kidney Injury in db/db Mice by Targeting miR-29b. Diabetes 2018; 67:731-744. [PMID: 29222368 DOI: 10.2337/db17-0816] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 11/30/2017] [Indexed: 11/13/2022]
Abstract
Transforming growth factor-β/Smad signaling plays an important role in diabetic nephropathy. The current study identified a novel Smad3-dependent long noncoding RNA (lncRNA) Erbb4-IR in the development of type 2 diabetic nephropathy (T2DN) in db/db mice. We found that Erbb4-IR was highly expressed in T2DN of db/db mice and specifically induced by advanced glycosylation end products (AGEs) via a Smad3-dependent mechanism. The functional role of Erbb4-IR in T2DN was revealed by kidney-specific silencing of Erbb4-IR to protect against the development of T2DN, such as elevated microalbuminuria, serum creatinine, and progressive renal fibrosis in db/db mice, and to block AGE-induced collagen I and IV expression in mouse mesangial cells (mMCs) and mouse tubular epithelial cells (mTECs). Mechanistically, we identified that the Erbb4-IR-microRNA (miR)-29b axis was a key mechanism of T2DN because Erbb4-IR was able to bind the 3' untranslated region of miR-29b genomic sequence to suppress miR-29b expression at transcriptional level. In contrast, silencing of renal Erbb4-IR increased miR-29b and therefore protected the kidney from progressive renal injury in db/db mice and prevented mTECs and mMCs from AGE-induced loss of miR-29b and fibrotic response in vitro. Collectively, we identify that Erbb4-IR is a Smad3-dependent lncRNA that promotes renal fibrosis in T2DN by suppressing miR-29b. Targeting Erbb4-IR may represent a novel therapy for T2DN.
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Affiliation(s)
- Si F Sun
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Patrick M K Tang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Min Feng
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jun Xiao
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiao R Huang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ping Li
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Ronald C W Ma
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hui Y Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
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Zhang H, Yang Y, Wang Y, Wang B, Li R. Renal-protective effect of thalidomide in streptozotocin-induced diabetic rats through anti-inflammatory pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:89-98. [PMID: 29386886 PMCID: PMC5765978 DOI: 10.2147/dddt.s149298] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Background Diabetic nephropathy (DN) is a major microvascular complication in diabetes. An increasing body of evidence has shown that DN is related to chronic inflammation, kidney hypertrophy, and fibrosis. While thalidomide has been shown to have anti-inflammatory and antifibrotic effects, the effects of thalidomide on the pathogenesis of DN are unclear. This study was undertaken to explore whether thalidomide has renal-protective effects in diabetic rats. Methods Male Sprague Dawley rats were injected intraperitoneally with 50 mg/kg streptozotocin to induce diabetes. Diabetic rats were treated with thalidomide (200 mg/kg/d) for 8 weeks, and then blood and urine were collected for measurement of renal function-related parameters. Histopathology, immunohistochemistry, enzyme-linked immunosorbent assay, and Western blot analyses were performed to assess renal proinflammatory cytokines, fibrotic protein, and related signaling pathways. Results Diabetic rats exhibited obvious renal structural and functional abnormalities, as well as renal inflammation and fibrosis. Compared with diabetic control rats, those treated with thalidomide showed significantly improved histological alterations and biomarkers of renal function, as well as reduced expression of renal inflammatory cytokines, including NF-κB and MCP-1. Furthermore, renal fibrotic proteins, such as TGF-β1, TβRII, TβRI, smad3, collagen IV, and fibronectin were also remarkably suppressed. Treatment with thalidomide markedly stimulated the phosphorylation of AMPKα. Conclusion In this study, thalidomide suppressed the inflammatory and fibrotic processes in DN. These effects were partly mediated by the activation of AMPKα, and inhibition of the NF-κB/MCP-1 and TGF-β1/Smad signaling pathways. These results suggest that thalidomide may have therapeutic potential in diabetic renal injury through the anti-inflammatory pathway.
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Affiliation(s)
| | - Yanlan Yang
- Department of Endocrinology, Affiliated People's Hospital of Shanxi Medical University, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, People's Republic of China
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Du YG, Zhang KN, Gao ZL, Dai F, Wu XX, Chai KF. Tangshen formula improves inflammation in renal tissue of diabetic nephropathy through SIRT1/NF-κB pathway. Exp Ther Med 2017; 15:2156-2164. [PMID: 29434819 DOI: 10.3892/etm.2017.5621] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 02/24/2017] [Indexed: 12/28/2022] Open
Abstract
The present study investigated the mechanism underlying the anti-inflammatory effects of Tangshen formula (TS) in Sprague Dawley (SD) rats with diabetic nephropathy (DN). A rat model of DN was established by intraperitoneal injection of 1% (40 mg/kg) streptozotocin and administration of a high fat and glucose diet. Subsequently, SD rats were randomly divided into six groups (n=8): A DN group, a valsartan group, a high-dose TS group, a middle-dose TS group, a low-dose TS group and a control group with normal SD rats. Once rats received their allocated treatment for 12 weeks, body weight and kidney weight were recorded, and fasting blood glucose, ratio of urinary protein, β2-MG and creatinine clearance rate were determined. Furthermore, hemodynamic indices, including plasma viscosity and whole blood reduction viscosity were detected. Immunohistochemistry was used to detect the infiltration of macrophages in the kidneys of rats. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to investigate the activation; mRNA and protein expression levels of monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibitory factor (MIF), nuclear factor-κB (NF-κB) and sirtuin-1 (SIRT1) in each group. In comparison with the DN group, each biochemical indicator of rats in the high-dose TS group was significantly decreased (P<0.05). Blood viscosity in each treatment group was significantly decreased when compared with the DN group (P<0.01). Hematoxylin and eosin staining indicated that the infiltration of macrophages was significantly decreased in the high-dose TS group when compared with the DN group (P<0.01). mRNA and protein expression levels of MCP-1 and MIF in the high-dose TS group were significantly decreased when compared with the DN group (P<0.05). In the treatment groups, SITR1 mRNA expression levels were significantly increased, whereas the mRNA expression levels of NF-κB were significantly decreased (P<0.01). Western blotting results indicated a significant decrease in the protein expression levels of acetylated NF-κB in the treatment groups when compared with the DN group (P<0.01) and the propensity of protein expression of the other inflammatory factors were consistent with the mRNA findings. The results of the high-dose TS group were similar to those of the valsartan group. The present study indicates that TS was able to activate SITR1, which lead to NF-κB deacetylation, thus reducing the release of inflammatory factors and decreasing the severity of diabetic nephropathy.
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Affiliation(s)
- Yue-Guang Du
- Department of Pathology, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Ke-Na Zhang
- Department of Pathology, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Zong-Lei Gao
- National Traditional Chinese Medicine Clinical Research Center, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Fengjiao Dai
- National Traditional Chinese Medicine Clinical Research Center, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Xi-Xi Wu
- National Traditional Chinese Medicine Clinical Research Center, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Ke-Fu Chai
- National Traditional Chinese Medicine Clinical Research Center, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
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Ikewuchi CC, Ikewuchi JC, Ifeanacho MO. Restoration of plasma markers of liver and kidney functions/integrity in alloxan-induced diabetic rabbits by aqueous extract of Pleurotus tuberregium sclerotia. Biomed Pharmacother 2017; 95:1809-1814. [PMID: 28968925 DOI: 10.1016/j.biopha.2017.09.075] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 09/13/2017] [Accepted: 09/18/2017] [Indexed: 02/09/2023] Open
Abstract
The effect of aqueous extract of the sclerotia of Pleurotus tuberregium on the plasma electrolytes, and markers of liver and kidney functions/integrity of normal and alloxan-induced rabbits was investigated. Diabetes mellitus was induced by injection of alloxan (120mg/kg body weight), via the marginal ear vein. The extract was administered orally at 100, 200 and 300mg/kg (both to normal and diabetic rabbits), and metformin at 50mg/kg. Gas chromatographic-flame ionization detector analysis of the extract revealed the presence of twelve known phenolic acids, consisting mainly of caffeic acid (80.24%), chlorogenic acid (11.08%), piperic acid (6.11%), sinapinic acid (2.14%) and ferulic acid (0.34%). Compared to test control, the treatment significantly (p<0.05) lowered plasma activities of alkaline phosphatase, gamma glutamyltransferase, and alanine and aspartate transaminases. Also lowered were plasma unconjugated/conjugated bilirubin ratio and concentrations of urea, blood urea nitrogen, creatinine, sodium, and total and unconjugated bilirubin. It however, significantly (p<0.05) raised plasma potassium and calcium levels. Therefore, the modulation of plasma sodium and potassium is an indication of the diuretic potential of the extract. In addition, the extract had no deleterious effect on the liver and kidney of the treated animals, at least at the doses administered in this study.
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Affiliation(s)
- Catherine Chidinma Ikewuchi
- Department of Biochemistry, Faculty of Science, University of Port Harcourt, P.M.B. 5323, Port Harcourt, Nigeria.
| | - Jude Chigozie Ikewuchi
- Department of Biochemistry, Faculty of Science, University of Port Harcourt, P.M.B. 5323, Port Harcourt, Nigeria.
| | - Mercy Onuekwuzu Ifeanacho
- Department of Biochemistry, Faculty of Science, University of Port Harcourt, P.M.B. 5323, Port Harcourt, Nigeria.
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Tangshen Formula Attenuates Colonic Structure Remodeling in Type 2 Diabetic Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:4064156. [PMID: 28303157 PMCID: PMC5338308 DOI: 10.1155/2017/4064156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 12/26/2016] [Indexed: 12/20/2022]
Abstract
Aim. This study investigated the effect and mechanism of the Chinese herbal medicine Tangshen Formula (TSF) on GI structure remodeling in the rat model of diabetes. Methods. Type 2 diabetic rats were used. Wet weight per unit length, layer thicknesses, levels of collagens I and III, nuclear factor kappa B (NF-κB), interferon-γ (IFN-γ), interleukin-6 (IL-6), transforming growth factor-β1 (TGF-β1), and Smad2/3 expression in the rat colon were measured. Results. Compared with the control group animals, wet weight and layer thicknesses of the colon increased, and expressions of collagens I and III, NF-κB, IFN-γ, IL-6, TGF-β1, and Smad2/3 increased significantly in the diabetic animals. TSF inhibited increase in colonic wet weight and layer thicknesses, downregulated expressions of collagens I and III in the mucosal layer, and downregulated expressions of NF-κB, IFN-γ, IL-6, TGF-β1, and Smad2/3 in the colon wall. Furthermore, level of expression of NF-κB was associated with those of TGF-β1 and Smad2/3. Expression of TGF-β1 was associated with the most histomorphometric parameters including colonic weight, mucosal and muscle thicknesses, and levels of collagens I and III in mucosal layer. Conclusion. TSF appears to attenuate colonic structure remodeling in type 2 diabetic rats through inhibiting the overactivated pathway of NF-κB, thus reducing expressions of TGF-β1.
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Sutariya B, Saraf M. Betanin, isolated from fruits of Opuntia elatior Mill attenuates renal fibrosis in diabetic rats through regulating oxidative stress and TGF-β pathway. JOURNAL OF ETHNOPHARMACOLOGY 2017; 198:432-443. [PMID: 28111218 DOI: 10.1016/j.jep.2016.12.048] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 12/05/2016] [Accepted: 12/31/2016] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The fruits of Opuntia elatior Mill are being used traditionally in different disease condition like diabetes, obesity, asthma, inflammatory disorders, and anemia. Betanin, a compound isolated from fruits of Opuntia elatior Mill has potent anti-oxidative and anti-inflammatory activity. Recent study from our lab indicated the protective effect of betanin against high glucose induced rat renal epithelial cell fibrosis and matrix accumulation, major features of diabetic nephropathy (DN). However the molecular mechanism of betanin in DN has not yet been fully elucidated. AIM OF THE STUDY The aim of the present study was to further investigate the anti-fibrotic mechanisms of betanin against streptozotocin (STZ) induced DN. MATERIALS AND METHODS Betanin was isolated from fruits of Opuntia elatior Mill (Cactaceae) and structure was elucidated using spectroscopy (UV, IR, 1H-NMR and mass). STZ was injected intraperitoneally with single dose of 50mg/kg for diabetes induction. In order to develop DN the animals were left in diabetes condition without any treatment during the following 4 weeks. Betanin (25, 50 and 100mg/kg/day) and lisinopril (5mg/kg/day, reference compound) were orally administered for 8 weeks after the induction of DN. Renal function, blood glucose, serum creatinine, blood urea nitrogen (BUN) and antioxidant enzyme activities in the kidney tissue were measured. Kidney tissue samples were used for glomerulosclerosis, tubulointerstitial fibrosis and morphometric studies. The expression of transforming growth factor-beta (TGF-β), type IV collagen, alpha-smooth muscle actin (α-SMA) and E-cadherin in kidney tissue were evaluated using reverse transcription-polymerase chain reaction, and immunohistochemistry. RESULTS Betanin was successfully isolated from fruits of Opuntia elatior Mill (Cactaceae) and purified by column chromatography. The results showed that betanin attenuated diabetic kidney injury by significantly inhibiting proteinuria, blood glucose, serum creatinine and BUN levels and restored antioxidant enzyme activities in kidney tissue. Histological studies exhibited that betanin treatment reduced the glomerular surface area, glomerulosclerosis and tubulointerstitial fibrosis. Furthermore, betanin modulated mRNA and protein expression of TGF-β, type IV collagen, α-SMA and E-cadherin in kidney. CONCLUSIONS The results conclude that betanin can effectively suppress renal fibrosis in DN, and may slow down the progression to end-stage renal disease by regulating TGF-β signal pathway.
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Affiliation(s)
- Brijesh Sutariya
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Santacruz (East), Mumbai 400068, Maharashtra, India
| | - Madhusudan Saraf
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Santacruz (East), Mumbai 400068, Maharashtra, India.
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Zhao H, Li X, Zhao T, Zhang H, Yan M, Dong X, Chen P, Ma L, Li P. Tangshen formula attenuates diabetic renal injuries by upregulating autophagy via inhibition of PLZF expression. PLoS One 2017; 12:e0171475. [PMID: 28182710 PMCID: PMC5300159 DOI: 10.1371/journal.pone.0171475] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/20/2017] [Indexed: 12/14/2022] Open
Abstract
The Chinese herbal granule Tangshen Formula (TSF) has been proven to decrease proteinuria and improve estimated glomerular filtration rate (eGFR) in diabetic kidney disease (DKD) patients. However, the underlying mechanism of TSF on treatment of diabetic nephropathy (DN) remains unclear. The present study aimed to identify the therapeutic target of TSF in diabetic renal injuries through microarray-based gene expression profiling and establish its underlying mechanism. TSF treatment significantly attenuated diabetic renal injuries by inhibiting urinary excretion of albumin and renal histological injuries in diabetic (db/db) mice. We found that PLZF might be the molecular target of TSF in DN. In vivo, the db/db mice showed a significant increase in renal protein expression of PLZF and collagen III, and decrease in renal autophagy levels (downregulated LC3 II and upregulated p62/SQSTM1) compared to db/m mice. The application of TSF resulted in the downregulation of PLZF and collagen III and upregulation of autophagy level in the kidneys of db/db mice. In vitro, TSF reduced high glucose (HG)-induced cell proliferation for NRK52E cells. Further studies indicated that the exposure of NRK52E cells to high levels of glucose resulted in the downregulation of cellular autophagy and upregulation of collagen III protein, which was reversed by TSF treatment by decreasing PLZF expression. In conclusion, TSF might have induced cellular autophagy by inhibiting PLZF expression, which in turn resulted in an increase in autophagic degradation of collagen III that attenuated diabetic renal injuries.
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Affiliation(s)
- Hailing Zhao
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing, China
| | - Xin Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing, China
| | - Tingting Zhao
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing, China
| | - Haojun Zhang
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing, China
| | - Meihua Yan
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing, China
| | - Xi Dong
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing, China
| | - Pengmin Chen
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing, China
| | - Liang Ma
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing, China
- Clinical laboratory, China–Japan Friendship Hospital, Beijing, China
| | - Ping Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing, China
- * E-mail:
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Chen GT, Yang M, Chen BB, Song Y, Zhang W, Zhang Y. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-d-glucoside exerted protective effects on diabetic nephropathy in mice with hyperglycemia induced by streptozotocin. Food Funct 2016; 7:4628-4636. [DOI: 10.1039/c6fo01319h] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
This study demonstrated that the inhibition of the RAS with TSG effectively prevented renal injury in diabetic nephropathy.
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Affiliation(s)
- Guang-Tong Chen
- School of Pharmacy
- Nantong University
- Nantong 226001
- P.R. China
| | - Min Yang
- School of Pharmacy
- Nantong University
- Nantong 226001
- P.R. China
| | - Bing-Bing Chen
- School of Medical Instrument and Food Engineering
- University of Shanghai for Science and Technology
- Shanghai 200093
- P.R. China
| | - Yan Song
- School of Pharmacy
- Nantong University
- Nantong 226001
- P.R. China
| | - Wei Zhang
- School of Pharmacy
- Nantong University
- Nantong 226001
- P.R. China
| | - Yan Zhang
- School of Pharmacy
- Nantong University
- Nantong 226001
- P.R. China
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