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Zhao Y, Ding Q, He Q, Zu T, Rong Z, Wu Y, Shmanai VV, Jiao J, Zheng R. Reno protective potential of taxifolin liposomes modified by chitosan in diabetic mice. Int J Biol Macromol 2025; 306:141464. [PMID: 40015419 DOI: 10.1016/j.ijbiomac.2025.141464] [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: 06/23/2024] [Revised: 02/13/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
The objective of this study was to develop chitosan-modified taxifolin liposomes (CTL) to enhance the treatment of diabetic kidney injury in mice and to address the limitations of taxifolin (TAX) solubility and bioavailability. Taxifolin liposomes (TL) were fabricated via film dispersion and subsequently modified with chitosan to obtain CTL. Characterisation analyses confirmed the successful construction of the liposomes. In vivo pharmacokinetic studies compared the bioavailability of CTL with those of free TAX and unmodified TL. A streptozotocin-induced diabetic nephropathy mouse model was used to investigate the reno protective effects of CTL. TL had an encapsulation efficiency (EE) of 89.61 % ± 2.51 % and drug-loading capacity (DL) of 16.07 % ± 0.70 %, while CTL had an EE of 84.57 % ± 2.95 % and DL of 14.48 % ± 0.41 %. The zeta potential of TL was -33.16 ± 5.22 mV, whereas that of CTL was +31.41 ± 3.05 mV. The particle size of TL and CTL was 136.69 ± 0.37 nm and 286.68 ± 4.99 nm, respectively. CTL showed superior bioavailability; reduced serum urea nitrogen, creatinine, total cholesterol, and triglyceride levels in diabetic mice; and improved kidney tissue damage. Importantly, CTL inhibited the activation of the NF-κB/NLRP3/caspase-1/IL-1β signalling pathway and ameliorated kidney injury. In conclusion, CTL enhanced the sustained release of TAX from simulated gastrointestinal fluids, improved pharmacokinetics, reduced pathological markers, and protected the kidneys at the molecular level.
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Affiliation(s)
- Yingchun Zhao
- The Second Affiliated Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Qiteng Ding
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Qingbin He
- The Second Affiliated Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Tingjian Zu
- The Second Affiliated Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Zhonghou Rong
- The Second Affiliated Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Yaguang Wu
- The Second Affiliated Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Vadim V Shmanai
- The Institute of Physical Organic Chemistry of the National Academy of Sciences of Belarus, Minsk 220072, Belarus
| | - Jianwei Jiao
- The Second Affiliated Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
| | - Runxiao Zheng
- The Second Affiliated Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
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Xia C, Wang X, Qi Z, Liu F, Li D, Zhang X, Zhang L, Wang D, Chen Z. Inhibitory and Curative Effects and Mode of Action of Hydroxychloroquine on Botrytis cinerea of Tomato. PHYTOPATHOLOGY 2025; 115:469-484. [PMID: 39813015 DOI: 10.1094/phyto-12-24-0397-r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Gray mold is an important disease of crops and is widespread, harmful, difficult to control, and prone to developing fungicide resistance. Screening new fungicides is an important step in controlling this disease. Hydroxychloroquine is an anti-inflammatory and antimalarial agent that has shown marked inhibitory activity against many fungi in medicine. This study evaluated the inhibitory activity of hydroxychloroquine against several phytopathogenic fungi, finding a half-maximal effective concentration of 113.82 μg/ml against the hyphal growth of Botrytis cinerea, with significant in vivo curative effects of 92.37 or 78.37% for gray mold on detached tomato leaves or fruits at 10.0 or 200.0 mg/ml, respectively. Ultrastructural studies indicated that hydroxychloroquine induced collapse of hyphae, with a wrinkled surface, unclear organelle boundaries, and organelle disintegration. Transcriptomic assays revealed that hydroxychloroquine could affect the expression of metabolism-related genes. Molecular docking and molecular dynamics analyses indicated that hydroxychloroquine bound to glucose-methanol-choline oxidoreductase, with a low free energy value of -11.4 kcal/mol. Cell membrane permeability assays and hyphal staining confirmed that hydroxychloroquine damaged the cell membrane, causing leakage of hyphal contents and disturbing cell function. Biochemical assays indicated that hydroxychloroquine reduced the concentration of soluble proteins and reducing sugars in the hyphae. Overall, hydroxychloroquine disturbed amino acid metabolism, therefore inhibiting the production of biomacromolecules, damaging the cell membrane, and restraining the growth of hyphae, hence inhibiting gray mold on tomato. This study explored the use of medicine in the development of agricultural fungicides and their application in managing crop diseases, providing valuable background information.
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Affiliation(s)
- Chengyan Xia
- State Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, China
| | - Xiansu Wang
- State Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, China
| | - Zeqi Qi
- State Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, China
| | - Fenghua Liu
- State Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, China
| | - Dongxue Li
- State Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, China
| | - Xiaolin Zhang
- State Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, China
| | - Libo Zhang
- State Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, China
| | - Delu Wang
- College of Forestry, Guizhou University, Guiyang, Guizhou 550025, China
| | - Zhuo Chen
- State Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, China
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Cao H, Li Z, Ye J, Lv Y, Zhang C, Liang T, Wang Y. Emerging roles of exosomes in the diagnosis and treatment of kidney diseases. Front Pharmacol 2025; 16:1525314. [PMID: 40308771 PMCID: PMC12041035 DOI: 10.3389/fphar.2025.1525314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 03/20/2025] [Indexed: 05/02/2025] Open
Abstract
The complex etiology and spectrum of kidney diseases necessitate vigilant attention; the focus on early diagnosis and intervention in kidney diseases remains a critical issue in medical research. Recently, with the expanding studies on extracellular vesicles, exosomes have garnered increasing interest as a promising tool for the diagnosis and treatment of kidney diseases. Exosomes are nano-sized extracellular vesicles that transport a diverse array of bioactive substances, which can influence various pathological processes associated with kidney diseases and exhibit detrimental or beneficial effects. Within the kidney, exosomes derived from the glomeruli and renal tubules possess the ability to enter systemic circulation or urine. The biomarkers they carry can reflect alterations in the pathological state of the kidneys, thereby offering novel avenues for early diagnosis. Furthermore, research studies have confirmed that exosomes originating from multiple cell types exhibit therapeutic potential in treating kidney disease; notably, those derived from mesenchymal stem cells (MSCs) have shown significant treatment efficacy. This comprehensive review summarizes the contributions of exosomes from different cell types within the kidneys while exploring their physiological and pathological roles therein. Additionally, we emphasize recent advancements in exosome applications for the diagnosis and treatment of various forms of kidney diseases over the past decades. We not only introduce the urinary and blood biomarkers linked to kidney diseases found within exosomes but also explore their therapeutic effects. Finally, we discuss existing challenges and future directions concerning the clinical applications of exosomes for diagnostic and therapeutic purposes.
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Affiliation(s)
- Huanhuan Cao
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zixi Li
- Department of Clinical Laboratory, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiajia Ye
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Lv
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Liang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yumei Wang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Bao L, Bian X, Ren L, Bao S, Zhang A. Different doses of hydroxychloroquine regulate the structure of intestinal flora and glycosyltransferase activity in rats with IgA nephropathy. Immunobiology 2025; 230:152891. [PMID: 40112730 DOI: 10.1016/j.imbio.2025.152891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/20/2025] [Accepted: 03/10/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Hydroxychloroquine (HCQ), by virtue of its ability to reduce proteinuria, is an alternative therapy for Immunoglobulin A nephropathy (IgAN). This study investigated the effects of different doses of HCQ on the structure of intestinal flora and glycosyltransferase activity in IgAN rats. METHODS IgAN model rats constructed by treatment of bovine serum albumin, castor oil and lipopolysaccharide were administered with HCQ (18 or 36 mg/kg) by gavage. Then the number of urine erythrocyte and the renal function of rats were evaluated. The levels of galactose-deficient IgA1 (Gd-IgA1), B cell activation factor (BAFF) and C-reactive protein (CRP) in serum and those of inflammatory factors in renal tissue were detected by ELISA. Renal tissue injury and IgA deposition were assessed by histological analysis. The expressions of Core 1 beta1,3-galactosyltransferase (C1GALT1), Core 1 synthase specific molecular chaperone (COSMC) and ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 2 (ST6GALNAC2) were quantified by qRT-PCR, Western blot or in vitro enzyme assays. 16 s rDNA sequencing was used to analyze the structure of intestinal flora in rats. RESULTS HCQ dose-dependently decreased the levels of serum creatinine, UREA, Gd-IgA1, BAFF, CRP and urine protein, waned the number of urine erythrocyte, inhibited the expressions of inflammatory factors and IgA deposition in renal tissue, and up-regulated the expressions of C1GALT1, COSMC and down-regulated ST6GALNAC2 expression in peripheral blood mononuclear cells (PBMCs). CONCLUSION HCQ could reduce glomerular swelling in mesangial area and improve the imbalance of intestinal flora in IgAN rats.
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Affiliation(s)
- Lingling Bao
- Department of Nephrology, The First Affiliated Hospital of Ningbo University, China
| | - Xueyan Bian
- Department of Nephrology, The First Affiliated Hospital of Ningbo University, China.
| | - Liling Ren
- Department of Nephrology, The First Affiliated Hospital of Ningbo University, China
| | - Sizeng Bao
- Department of Nephrology, The First Affiliated Hospital of Ningbo University, China
| | - Aiwei Zhang
- Department of Nephrology, The First Affiliated Hospital of Ningbo University, China
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Ou H, Qiu S, Ye X, Wang X. Screening of Herbs with Potential Modulation of NLRP3 Inflammasomes for Acute Liver Failure: A Study Based on the Herb-Compound-Target Network and the ssGSEA Algorithm. Curr Top Med Chem 2025; 25:318-334. [PMID: 39528455 DOI: 10.2174/0115680266331775241024064136] [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: 05/19/2024] [Revised: 09/25/2024] [Accepted: 10/04/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVE NLRP3 inflammasomes are considered to be key factors in the pathogenesis of Acute Liver Failure (ALF). Some Traditional Chinese Medicines (TCMs) have shown protective and therapeutic effects against ALF by inhibiting NLRP3 inflammasomes. However, the inhibitory effects of most TCMs on ALF remain to be further elucidated. This study aimed to screen potential herbs that can treat ALF based on the inhibition of NLRP3 inflammasomes. METHODS Initially, we constructed the target set for 502 herbs. Subsequently, based on the target set and the gene set related to the NLRP3 inflammasome, using the ssGSEA algorithm, we evaluated herb scores and NLRP3 scores in the ALF expression matrix and performed a preliminary herb screening based on score correlations. Through bioinformatics approaches, we identified the key targets for candidate herbs and determined core herbs based on the herb-compound-target network. Furthermore, molecular docking and molecular biology methods validated the screening results of the herbs. RESULTS A total of 18 crucial targets associated with the inhibition of the NLRP3 inflammasome were identified, which included ALDH2, HMOX1, and VEGFA. Subsequently, based on these key targets, a set of 10 primary herbs was chosen, notably Qinghao, Duzhong, and Gouteng. Moreover, the results were verified through molecular docking and molecular dynamic simulation. CONCLUSION Ten key herbs have been identified as potential inhibitors of the NLRP3 inflammasome, offering insights into ALF therapy for drug development.
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Affiliation(s)
- Haiya Ou
- Shenzhen Bao'an Chinese Medicine Hospital, The Seventh Clinical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Susu Qiu
- Shenzhen Bao'an Chinese Medicine Hospital, The Seventh Clinical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Xiaopeng Ye
- Shenzhen Bao'an Chinese Medicine Hospital, The Seventh Clinical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Xiaotong Wang
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
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Liu Y, Wu Q, Huang Z, Zhou D, Cai C, Luo W, Feng P. TLR4 Inhibitor TAK-242 Protected Henoch-Schonlein Purpura Nephritis in Rats by Regulating Inflammatory Response and Immune Competence via NF- κB/NLRP3 Signalling. Clin Exp Pharmacol Physiol 2025; 52:e70008. [PMID: 39564921 DOI: 10.1111/1440-1681.70008] [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: 01/30/2024] [Revised: 10/10/2024] [Accepted: 10/20/2024] [Indexed: 11/21/2024]
Abstract
This study aimed to explore the effect of toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) signalling on Henoch-Schonlein purpura nephritis (HSPN). We established a HSPN rat model in a high-altitude hypoxic (HH) environment. Renal tissue lesions were observed by haematoxylin and Eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL), CD20-postive B cells and CD68-postive macrophage cells were detected by immunohistochemistry, T-cell activation was detected by flow cytometry and toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) signalling was detected by western blot. TAK-242 inhibited the expression of TLR4/NF-κB/NLRP3 signalling related-proteins, decreased the levels of 24 h urinary protein, serum creatinine, circular immune complex (CIC) and kidney immunoglobulin A (IgA), and improved renal histopathological damage in HH-HSPN rats. Furthermore, TAK-242 attenuated the infiltration of CD20 and CD68 into the kidney and increased the percentage of CD3+, CD4+ and CD4+/CD8+ cells in the blood of HH-HSPN rats. The study revealed that suppressing TLR4/NF-κB/NLRP3 signalling improved renal function and histopathological damage, and this improvement was related to inhibiting the inflammatory response and enhancing immune competence.
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Affiliation(s)
- Yirong Liu
- Department of Nephrology, First People's Hospital of Xining City, Xining, China
| | - Qiong Wu
- Department of Pathophysiology, Qinghai University Medical College, Xining, China
| | - Zhenxing Huang
- Department of Nephrology, First People's Hospital of Xining City, Xining, China
| | - Dongmei Zhou
- Department of Endocrinology, First People's Hospital of Xining City, Xining, China
| | - Chao Cai
- Department of Pathophysiology, Qinghai University Medical College, Xining, China
| | - Wenliang Luo
- Department of Pathophysiology, Qinghai University Medical College, Xining, China
| | - Ping Feng
- Department of Endocrinology, First People's Hospital of Xining City, Xining, China
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Yan Q, Zhao Z, Liu D, Li J, Pan S, Duan J, Liu Z. Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy. Ren Fail 2024; 46:2337288. [PMID: 38628140 PMCID: PMC11025414 DOI: 10.1080/0886022x.2024.2337288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 03/27/2024] [Indexed: 04/19/2024] Open
Abstract
The mechanisms underlying the complex correlation between immunoglobulin A nephropathy (IgAN) and inflammatory bowel disease (IBD) remain unclear. This study aimed to identify the optimal cross-talk genes, potential pathways, and mutual immune-infiltrating microenvironments between IBD and IgAN to elucidate the linkage between patients with IBD and IgAN. The IgAN and IBD datasets were obtained from the Gene Expression Omnibus (GEO). Three algorithms, CIBERSORTx, ssGSEA, and xCell, were used to evaluate the similarities in the infiltrating microenvironment between the two diseases. Weighted gene co-expression network analysis (WGCNA) was implemented in the IBD dataset to identify the major immune infiltration modules, and the Boruta algorithm, RFE algorithm, and LASSO regression were applied to filter the cross-talk genes. Next, multiple machine learning models were applied to confirm the optimal cross-talk genes. Finally, the relevant findings were validated using histology and immunohistochemistry analysis of IBD mice. Immune infiltration analysis showed no significant differences between IBD and IgAN samples in most immune cells. The three algorithms identified 10 diagnostic genes, MAPK3, NFKB1, FDX1, EPHX2, SYNPO, KDF1, METTL7A, RIDA, HSDL2, and RIPK2; FDX1 and NFKB1 were enhanced in the kidney of IBD mice. Kyoto Encyclopedia of Genes and Genomes analysis showed 15 mutual pathways between the two diseases, with lipid metabolism playing a vital role in the cross-talk. Our findings offer insights into the shared immune mechanisms of IgAN and IBD. These common pathways, diagnostic cross-talk genes, and cell-mediated abnormal immunity may inform further experimental studies.
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Affiliation(s)
- Qianqian Yan
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P. R. China
| | - Zihao Zhao
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P. R. China
| | - Dongwei Liu
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P. R. China
| | - Jia Li
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P. R. China
| | - Shaokang Pan
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P. R. China
| | - Jiayu Duan
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P. R. China
| | - Zhangsuo Liu
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P. R. China
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Xu Y, Han S, Guo T, Li Y, Li D, Ding Y. Qingre huazhuo tang regulates IgA nephropathy through immune checkpoints and ferroptosis. J Tradit Complement Med 2024. [DOI: 10.1016/j.jtcme.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
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Long Z, Xiang W, Xiao W, Min Y, Qu F, Zhang B, Zeng L. Advances in the study of artemisinin and its derivatives for the treatment of rheumatic skeletal disorders, autoimmune inflammatory diseases, and autoimmune disorders: a comprehensive review. Front Immunol 2024; 15:1432625. [PMID: 39524446 PMCID: PMC11543433 DOI: 10.3389/fimmu.2024.1432625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 09/16/2024] [Indexed: 11/16/2024] Open
Abstract
Artemisinin and its derivatives are widely recognized as first-line treatments for malaria worldwide. Recent studies have demonstrated that artemisinin-based antimalarial drugs, such as artesunate, dihydroartemisinin, and artemether, not only possess excellent antimalarial properties but also exhibit antitumor, antifungal, and immunomodulatory effects. Researchers globally have synthesized artemisinin derivatives like SM735, SM905, and SM934, which offer advantages such as low toxicity, high bioavailability, and potential immunosuppressive properties. These compounds induce immunosuppression by inhibiting the activation of pathogenic T cells, suppressing B cell activation and antibody production, and enhancing the differentiation of regulatory T cells. This review summarized the mechanisms by which artemisinin and its analogs modulate excessive inflammation and immune responses in rheumatic and skeletal diseases, autoimmune inflammatory diseases, and autoimmune disorders, through pathways including TNF, Toll-like receptors, IL-6, RANKL, MAPK, PI3K/AKT/mTOR, JAK/STAT, and NRF2/GPX4. Notably, in the context of the NF-κB pathway, artemisinin not only inhibits NF-κB expression by disrupting upstream cascades and/or directly binding to NF-κB but also downregulates multiple downstream genes controlled by NF-κB, including inflammatory chemokines and their receptors. These downstream targets regulate various immune cell functions, apoptosis, proliferation, signal transduction, and antioxidant responses, ultimately intervening in systemic autoimmune diseases and autoimmune responses in organs such as the kidneys, nervous system, skin, liver, and biliary system by modulating immune dysregulation and inflammatory responses. Ongoing multicenter randomized clinical trials are investigating the effects of these compounds on rheumatic, inflammatory, and autoimmune diseases, with the aim of translating promising preclinical data into clinical applications.
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Affiliation(s)
- Zhiyong Long
- Department of Physical Medicine and Rehabilitation, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
| | - Wang Xiang
- Department of Rheumatology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
| | - Wei Xiao
- Department of Rheumatology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
| | - Yu Min
- Department of Physical Medicine and Rehabilitation, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
| | - Fei Qu
- Department of Acupuncture and Massage, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
| | | | - Liuting Zeng
- Department of Physical Medicine and Rehabilitation, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
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Ji Y, Hua H, Jia Z, Zhang A, Ding G. Therapy Targeted to the NLRP3 Inflammasome in Chronic Kidney Disease. KIDNEY DISEASES (BASEL, SWITZERLAND) 2024; 10:369-383. [PMID: 39430292 PMCID: PMC11488838 DOI: 10.1159/000539496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 05/07/2024] [Indexed: 10/22/2024]
Abstract
Background The NLRP3 inflammasome is a cytoplasmic polymeric protein complex composed of the cytoplasmic sensor NLRP3, the apoptosis-related spot-like protein ASC, and the inflammatory protease caspase-1. NLRP3 activates and releases IL-1β through classical pathways, and IL-18 mediates inflammation and activates gasdermin-D protein to induce cellular pyroptosis. Numerous studies have also emphasized the non-classical pathway activated by the NLRP3 inflammasome in chronic kidney disease (CKD) and the inflammasome-independent function of NLRP3. Summary The NLRP3-targeting inflammasome and its associated pathways have thus been widely studied in models of CKD treatment, but no drug that targets NLRP3 has thus far been approved for the treatment of CKD. Key Messages We herein reviewed the current interventional methods for targeting the NLRP3 inflammasome in various CKD models, analyzed their underlying mechanisms of action, classified and compared them, and discussed the advantages and follow-up directions of various interventional methods. This review therefore provides novel ideas and a reference for the development of targeted NLRP3-inflammasome therapy in CKD.
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Affiliation(s)
- Yong Ji
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Hu Hua
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Zhanjun Jia
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Aihua Zhang
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Guixia Ding
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
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Xia L, Qiu Y, Li J, Xu M, Dong Z. The Potential Role of Artemisinins Against Neurodegenerative Diseases. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:1641-1660. [PMID: 39343990 DOI: 10.1142/s0192415x24500642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Artemisinin (ART) and its derivatives, collectively referred to as artemisinins (ARTs), have been approved for the treatment of malaria for decades. ARTs are converted into dihydroartemisinin (DHA), the only active form, which is reductive in vivo. In this review, we provide a brief overview of the neuroprotective potential of ARTs and the underlying mechanisms on several of the most common neurodegenerative diseases, particularly considering their potential application in those associated with cognitive and motor impairments including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). ARTs act as autophagy balancers to alleviate AD and PD. They inhibit neuroinflammatory responses by regulating phosphorylation of signal transduction proteins, such as AKT, PI3K, ERK, NF-κB, p38 MAPK, IκBα. In addition, ARTs regulate GABAergic signaling in a dose-dependent manner. Although they competitively inhibit the binding of gephyrin to GABAergic receptors, low doses of ARTs enhance GABAergic signaling. ARTs can also inhibit ferroptosis, activate the Akt/Bcl-2, AMPK, or ERK/CREB pathways to reduce oxidative stress, and maintain mitochondrial homeostasis, protecting neurons from oxidative stress injury. More importantly, ARTs structurally combine with and suppress β-Amyloid (A[Formula: see text]-induced neurotoxicity, reduce P-tau, and maintain O-GlcNAcylation/Phosphorylation balance, leading to relieved pathological changes in neurodegenerative diseases. Collectively, these natural properties endow ARTs with unique potential for application in neurodegenerative diseases.
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Affiliation(s)
- Lei Xia
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education, Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, P. R. China
| | - Yiqiong Qiu
- Medical Laboratory of Changshou District Hospital of Traditional Chinese Medicine, Chongqing 401220, P. R. China
| | - Junjie Li
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education, Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, P. R. China
| | - Mingliang Xu
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education, Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, P. R. China
| | - Zhifang Dong
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education, Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, P. R. China
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Li B, Qi C, Zhang Y, Shi L, Zhang J, Qian H, Ji C. Frontier role of extracellular vesicles in kidney disease. J Nanobiotechnology 2024; 22:583. [PMID: 39304945 DOI: 10.1186/s12951-024-02852-3] [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: 07/16/2024] [Accepted: 09/11/2024] [Indexed: 09/22/2024] Open
Abstract
Kidney diseases represent a diverse range of conditions that compromise renal function and structure which characterized by a progressive deterioration of kidney function, may ultimately necessitate dialysis or kidney transplantation as end-stage treatment options. This review explores the complex landscape of kidney diseases, highlighting the limitations of existing treatments and the pressing need for innovative strategies. The paper delves into the role of extracellular vesicles (EVs) as emerging biomarkers and therapeutic agents in the context of kidney pathophysiology. Urinary extracellular vesicles (uEVs), in particular, offer a non-invasive means of assessing renal injury and monitoring disease progression. Additionally, mesenchymal stem cell-derived EVs (MSC-EVs) are examined for their immunomodulatory and tissue repair capabilities, presenting a promising avenue for novel therapeutic interventions. And discusses the potential of engineering EVs to enhance their targeting and therapeutic efficacy. This paper systematically integrates the latest research findings and aims to provide a comprehensive overview of the role of EVs in kidney disease, providing cutting-edge insights into their potential as a diagnostic and therapeutic tool.
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Affiliation(s)
- Bei Li
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Chen Qi
- Department of Clinical Laboratory, Suzhou Municipal Hospital of Anhui Province, Anhui, 234000, China
| | - Yifan Zhang
- College of Medical Imaging, Dalian Medical University, Dalian, Liaoning, 116000, China
| | - Linru Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Jiahui Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
| | - Cheng Ji
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
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Câmara JS, Perestrelo R, Ferreira R, Berenguer CV, Pereira JAM, Castilho PC. Plant-Derived Terpenoids: A Plethora of Bioactive Compounds with Several Health Functions and Industrial Applications-A Comprehensive Overview. Molecules 2024; 29:3861. [PMID: 39202940 PMCID: PMC11357518 DOI: 10.3390/molecules29163861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/06/2024] [Accepted: 08/08/2024] [Indexed: 09/03/2024] Open
Abstract
Terpenoids are a large class of natural secondary plant metabolites which are highly diverse in structure, formed from isoprene units (C-5), associated with a wide range of biological properties, including antioxidant, antimicrobial, anti-inflammatory, antiallergic, anticancer, antimetastatic, antiangiogenesis, and apoptosis induction, and are considered for potential application in the food, cosmetics, pharmaceutical, and medical industries. In plants, terpenoids exert a variety of basic functions in growth and development. This review gives an overview, highlighting the current knowledge of terpenoids and recent advances in our understanding of the organization, regulation, and diversification of core and specialized terpenoid metabolic pathways and addressing the most important functions of volatile and non-volatile specialized terpenoid metabolites in plants. A comprehensive description of different aspects of plant-derived terpenoids as a sustainable source of bioactive compounds, their biosynthetic pathway, the several biological properties attributed to these secondary metabolites associated with health-promoting effects, and their potential industrial applications in several fields will be provided, and emerging and green extraction methods will also be discussed. In addition, future research perspectives within this framework will be highlighted. Literature selection was carried out using the National Library of Medicine, PubMed, and international reference data for the period from 2010 to 2024 using the keyword "terpenoids". A total of 177,633 published papers were found, of which 196 original and review papers were included in this review according to the criteria of their scientific reliability, their completeness, and their relevance to the theme considered.
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Affiliation(s)
- José S. Câmara
- CQM—Centro de Química da Madeira, NPRG, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal; (R.P.); (R.F.); (C.V.B.); (J.A.M.P.); (P.C.C.)
- Departamento de Química, Faculdade de Ciências Exatas e da Engenharia da Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal
| | - Rosa Perestrelo
- CQM—Centro de Química da Madeira, NPRG, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal; (R.P.); (R.F.); (C.V.B.); (J.A.M.P.); (P.C.C.)
| | - Rui Ferreira
- CQM—Centro de Química da Madeira, NPRG, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal; (R.P.); (R.F.); (C.V.B.); (J.A.M.P.); (P.C.C.)
| | - Cristina V. Berenguer
- CQM—Centro de Química da Madeira, NPRG, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal; (R.P.); (R.F.); (C.V.B.); (J.A.M.P.); (P.C.C.)
| | - Jorge A. M. Pereira
- CQM—Centro de Química da Madeira, NPRG, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal; (R.P.); (R.F.); (C.V.B.); (J.A.M.P.); (P.C.C.)
| | - Paula C. Castilho
- CQM—Centro de Química da Madeira, NPRG, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal; (R.P.); (R.F.); (C.V.B.); (J.A.M.P.); (P.C.C.)
- Departamento de Química, Faculdade de Ciências Exatas e da Engenharia da Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal
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Zhu W, Chen Y, Xiao J, Cheng C, Ma G, Wang Y, Zhang Y, Chen M. Ferroptosis-Related Genes in IgA Nephropathy: Screening for Potential Targets of the Mechanism. Int J Genomics 2024; 2024:8851124. [PMID: 39171207 PMCID: PMC11338665 DOI: 10.1155/2024/8851124] [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: 05/16/2023] [Revised: 06/04/2024] [Accepted: 07/20/2024] [Indexed: 08/23/2024] Open
Abstract
Aims: Exploring key genes and potential molecular pathways of ferroptosis in immunoglobulin A nephropathy (IgAN). Methods: The IgAN datasets and ferroptosis-related genes (FRGs) were obtained in the Gene Expression Omnibus (GEO) and FerrDb database. Differentially expressed genes (DEGs) were identified using R software and intersected with FRGs to obtain differentially expressed FRGs (DE-FRGs). After that, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis (PEA) and Gene Ontology (GO) functional annotation were performed on DE-FRGs. In the Search Tool for the Retrieval of Interacting Genes (STRING) website, we construct a protein-protein interaction (PPI) network. The PPI network was further investigated with screening hub genes with Cytoscape software. The core genes were then subjected to gene set enrichment analysis (GSEA). Finally, the samples were analyzed for immune infiltration in R, and the correlation between hub genes and immune cells was analyzed. Results: A total of 347 DEGs were identified. CD44, CDO1, CYBB, IL1B, RRM2, AKR1C1, activated transcription factor-3 (ATF3), CDKN1A, GDF15, JUN, MGST1, MIOX, MT1G, NR4A1, PDK4, TNFAIP3, and ZFP36 were determined as DE-FRGs. JUN, IL1B, and ATF3 were then screened as hub genes. GSEA and immune infiltration analysis revealed that the hub genes were closely associated with immune inflammatory responses such as NOD-like receptor signaling, IL-17 signaling, and TNF signaling. Conclusions: Our results show that JUN and ATF3 are possibly critical genes in the process of IgAN ferroptosis and may be related with immune cell infiltration.
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Affiliation(s)
- Wenhui Zhu
- Department of Renal DivisionHeilongjiang Academy of Chinese Medicine Sciences, Harbin, China
- College of Traditional Chinese MedicineChangchun University of Chinese Medicine, Changchun, China
| | - Yao Chen
- Department of Renal DivisionHeilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Jing Xiao
- Department of Renal DivisionHeilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Chuchu Cheng
- Department of Renal DivisionHeilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Guijie Ma
- Department of Renal DivisionHeilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yang Wang
- Department of Renal DivisionHeilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yonggang Zhang
- Department of Renal DivisionFirst People's Hospital of Qiqihar City, Qiqihar, China
| | - Ming Chen
- Department of Renal DivisionHeilongjiang Academy of Chinese Medicine Sciences, Harbin, China
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Wang L, Wang J, Xu A, Wei L, Pei M, Shen T, Xian X, Yang K, Fei L, Pan Y, Yang H, Wang X. Future embracing: exosomes driving a revolutionary approach to the diagnosis and treatment of idiopathic membranous nephropathy. J Nanobiotechnology 2024; 22:472. [PMID: 39118155 PMCID: PMC11312222 DOI: 10.1186/s12951-024-02633-y] [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: 03/09/2024] [Accepted: 06/13/2024] [Indexed: 08/10/2024] Open
Abstract
Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and is associated with high rates of end-stage renal disease. Early detection and precise interventions are crucial for improving patient prognosis and quality of life. However, the current diagnosis primarily relies on renal biopsies and traditional biomarkers, which have limitations. Additionally, targeted therapeutic strategies are lacking. Exosomes, small vesicles that facilitate intercellular communication, have emerged as potential noninvasive diagnostic markers due to their stability, diverse cargo, and rapid detectability. They also hold promise as carriers for gene and drug delivery, presenting innovative opportunities in renal disease prognosis and treatment. However, research on exosomes in the context of idiopathic membranous nephropathy (IMN) remains limited, with a focus on exploring urinary exosomes as IMN markers. In this review, we summarize the current status of MN diagnosis and treatment, highlight the fundamental characteristics of exosomes, and discuss recent advancements in their application to IMN diagnosis and therapy. We provide insights into the clinical prospects of exosomes in IMN and acknowledge potential challenges. This article aims to offer forward-looking insights into the future of exosome-mediated IMN diagnosis and treatment, indicating a revolutionary transformation in this field.
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Affiliation(s)
- Lin Wang
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Jinxiang Wang
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Guangdong, 518107, China
| | - Ao Xu
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Lijuan Wei
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
| | - Ming Pei
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
| | - Tuwei Shen
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xian Xian
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Kang Yang
- Nephrology Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, 450099, China
| | - Lingyan Fei
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Guangdong, 518107, China.
| | - Hongtao Yang
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, China.
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Xianwen Wang
- School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials, Anhui Medical University, Hefei, 230032, People's Republic of China.
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Tang C, Chen P, Xu LL, Lv JC, Shi SF, Zhou XJ, Liu LJ, Zhang H. Circulating Proteins and IgA Nephropathy: A Multiancestry Proteome-Wide Mendelian Randomization Study. J Am Soc Nephrol 2024; 35:1045-1057. [PMID: 38687828 PMCID: PMC11377805 DOI: 10.1681/asn.0000000000000379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/23/2024] [Indexed: 05/02/2024] Open
Abstract
Key Points
A multiancestry proteome-wide Mendelian randomization analysis was conducted for IgA nephropathy.The findings from the study would help prioritize new drug targets and drug-repurposing opportunities.
Background
The therapeutic options for IgA nephropathy are rapidly evolving, but early diagnosis and targeted treatment remain challenging. We aimed to identify circulating plasma proteins associated with IgA nephropathy by proteome-wide Mendelian randomization studies across multiple ancestry populations.
Methods
In this study, we applied Mendelian randomization and colocalization analyses to estimate the putative causal effects of 2615 proteins on IgA nephropathy in Europeans and 235 proteins in East Asians. Following two-stage network Mendelian randomization, multitrait colocalization analysis and protein-altering variant annotation were performed to strengthen the reliability of the results. A protein–protein interaction network was constructed to investigate the interactions between the identified proteins and the targets of existing medications.
Results
Putative causal effects of 184 and 13 protein–disease pairs in European and East Asian ancestries were identified, respectively. Two protein–disease pairs showed shared causal effects across them (CFHR1 and FCRL2). Supported by the evidence from colocalization analysis, potential therapeutic targets were prioritized and four drug-repurposing opportunities were suggested. The protein–protein interaction network further provided strong evidence for existing medications and pathways that are known to be therapeutically important.
Conclusions
Our study identified a number of circulating proteins associated with IgA nephropathy and prioritized several potential drug targets that require further investigation.
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Affiliation(s)
- Chen Tang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China; and Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
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He WJ, Wang J, Liu N, Li GY, Zhu XW, Yao L, Liu LL. The efficacy and safety of hydroxychloroquine versus leflunomide in patients with IgA nephropathy: a single-center experience. J Nephrol 2024; 37:933-940. [PMID: 38225440 PMCID: PMC11239748 DOI: 10.1007/s40620-023-01839-x] [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: 07/18/2023] [Accepted: 11/18/2023] [Indexed: 01/17/2024]
Abstract
PURPOSE To date, our understanding of IgA nephropathy (IgAN) pathophysiology has remained incomplete; therefore, treatment remains largely empiric, and the efficacy and safety of immunosuppressants remain controversial. We aimed to assess the efficacy and safety of hydroxychloroquine and leflunomide therapy in a retrospective cohort of patients with IgAN. METHODS We screened the IgAN registration database in our department, and a total of 159 kidney patients with biopsy-confirmed IgAN were enrolled, with 57 patients receiving hydroxychloroquine plus a renin-angiotensin system inhibitor (hydroxychloroquine group), 52 patients receiving leflunomide plus a renin-angiotensin system inhibitor (leflunomide group), and 50 patients receiving only a renin-angiotensin system inhibitor (renin-angiotensin system inhibitor-only group). Changes in proteinuria, hematuria, and the estimated glomerular filtration rate (eGFR), as well as adverse events, were analyzed during the follow-up period. RESULTS At the end of 6-month follow-up, proteinuria significantly decreased by 70.36 (57.54, 79.33)%, 57.29 (46.79, 67.29)% and 41.20 (25.76, 48.94)% in the hydroxychloroquine, leflunomide and renin-angiotensin system inhibitor-only groups, respectively, compared to baseline (all P values < 0.001). Hematuria significantly decreased by 71.07 (56.48, 82.47)% in the leflunomide group (P < 0.001). The eGFR improved by 3.72 ± 2.97%, 3.16 ± 2.00% and 1.91 ± 2.41%, respectively, in the hydroxychloroquine, leflunomide and renin-angiotensin system inhibitor-only groups, but without statistical significance. No serious adverse events occurred during the follow-up period. CONCLUSION Both hydroxychloroquine combined with a renin-angiotensin system inhibitor and leflunomide combined with a renin-angiotensin system inhibitor were more effective than a renin-angiotensin system inhibitor alone in improving proteinuria in IgAN patients. Hydroxychloroquine was more effective in reducing proteinuria, and leflunomide showed superiority in reducing hematuria. Our results need to be verified in large-scale randomized controlled trials.
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Affiliation(s)
- Wei-Jie He
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 Nan Jing North Street, He Ping District, Shenyang, 110001, Liaoning, China
| | - Juan Wang
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 Nan Jing North Street, He Ping District, Shenyang, 110001, Liaoning, China
| | - Nan Liu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 Nan Jing North Street, He Ping District, Shenyang, 110001, Liaoning, China
| | - Gu-Yue Li
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Xin-Wang Zhu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 Nan Jing North Street, He Ping District, Shenyang, 110001, Liaoning, China
| | - Li Yao
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 Nan Jing North Street, He Ping District, Shenyang, 110001, Liaoning, China
| | - Lin-Lin Liu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 Nan Jing North Street, He Ping District, Shenyang, 110001, Liaoning, China.
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Chen Y, Lu M, Lin M, Gao Q. Network pharmacology and molecular docking to elucidate the common mechanism of hydroxychloroquine treatment in lupus nephritis and IgA nephropathy. Lupus 2024; 33:347-356. [PMID: 38285068 DOI: 10.1177/09612033241230377] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2024]
Abstract
OBJECTIVE Hydroxychloroquine (HCQ), characterized by a broad effect on immune regulation, has been widely used in the treatment of autoimmune glomerulonephritis such as lupus nephritis (LN) and immunoglobulin A nephropathy (IgAN). The current research investigates whether HCQ plays a role in the treatment of LN and IgAN through common mechanisms since the pathogenesis of both LN and IgAN is closely related to immune complex deposition, complement activation, and ultimately inflammation. METHODS Seventy-two common targets were obtained related to the common mechanism of HCQ treatment of LN and IgAN. Targets associated with LN and IgAN were collected based on DisGeNET, GeneCards, and OMIM databases. Possible HCQ targets were obtained from the PubChem database and PharmMapper databases. The overlapping targets of HCQ ingredients, IgAN, and LN were discovered via the Venn 2.1.0 online platform. Through the DAVID database, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted. Cytoscape (v3.9.1) was used to build a protein-protein interaction (PPI) network. Molecular docking was performed by using AutoDockTools 1.5.6 software and PyMol software to match the binding activity between HCQ and the 10 core targets. RESULTS The results showed that core targets (including MMP 2, PPARG, IL-2, MAPK14, MMP 9, and SRC), three signaling pathways (including the PI3K-Akt, AGE-RAGE, and MAPK), and cell differentiation (including Th1, Th2, and Th17) might be related to the body's immunity and inflammation. These results suggested that HCQ might act on targets and pathways involved in inflammation and immune regulation to exert a common effect on the treatment of LN and IgAN. CONCLUSIONS The current study provided new evidence for the protective mechanism and clinical utility of HCQ against LN and IgAN.
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Affiliation(s)
- Yixuan Chen
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Meiqi Lu
- Department of Nephrology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Mengshu Lin
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Qing Gao
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
- Department of Nephrology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
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Gao X, Lin X, Wang Q, Chen J. Artemisinins: Promising drug candidates for the treatment of autoimmune diseases. Med Res Rev 2024; 44:867-891. [PMID: 38054758 DOI: 10.1002/med.22001] [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: 09/21/2023] [Revised: 11/02/2023] [Accepted: 11/22/2023] [Indexed: 12/07/2023]
Abstract
Autoimmune diseases are characterized by the immune system's attack on one's own tissues which are highly diverse and diseases differ in severity, causing damage in virtually all human systems including connective tissue (e.g., rheumatoid arthritis), neurological system (e.g., multiple sclerosis) and digestive system (e.g., inflammatory bowel disease). Historically, treatments normally include pain-killing medication, anti-inflammatory drugs, corticosteroids, and immunosuppressant drugs. However, given the above characteristics, treatment of autoimmune diseases has always been a challenge. Artemisinin is a natural sesquiterpene lactone initially extracted and separated from Chinese medicine Artemisia annua L., which has a long history of curing malaria. Artemisinin's derivatives such as artesunate, dihydroartemisinin, artemether, artemisitene, and so forth, are a family of artemisinins with antimalarial activity. Over the past decades, accumulating evidence have indicated the promising therapeutic potential of artemisinins in autoimmune diseases. Herein, we systematically summarized the research regarding the immunoregulatory properties of artemisinins including artemisinin and its derivatives, discussing their potential therapeutic viability toward major autoimmune diseases and the underlying mechanisms. This review will provide new directions for basic research and clinical translational medicine of artemisinins.
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Affiliation(s)
- Xu Gao
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China
- Institute of Immunology and Inflammatory Diseases, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
- Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen, China
| | - Xian Lin
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China
- Institute of Immunology and Inflammatory Diseases, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
- Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen, China
| | - Qingwen Wang
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China
- Institute of Immunology and Inflammatory Diseases, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
- Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen, China
| | - Jian Chen
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China
- Institute of Immunology and Inflammatory Diseases, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
- Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen, China
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Liu P, Wang Y, Tian K, Bai X, Wang Y, Wang Y. Artesunate inhibits macrophage-like phenotype switching of vascular smooth muscle cells and attenuates vascular inflammatory injury in atherosclerosis via NLRP3. Biomed Pharmacother 2024; 172:116255. [PMID: 38325261 DOI: 10.1016/j.biopha.2024.116255] [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: 11/12/2023] [Revised: 01/23/2024] [Accepted: 02/02/2024] [Indexed: 02/09/2024] Open
Abstract
Inflammation is one of the main pathogenic factors of atherosclerosis (AS), and the phenotypic transformation of macrophages in human vascular smooth muscle cells (HVSMCs) contributes to the inflammatory injury of blood vessels and the formation of atherosclerotic plaques. Artesunate reportedly exerts anti-inflammatory activity against AS. Herein, we aimed to explore the artesunate-mediated anti-inflammatory and HVSMC phenotypic switch effects against AS and elucidate potential underlying mechanisms. In vitro, artesunate decreased expression of NLRP3, caspase-1, and interleukin (IL)- 1β. Artesunate significantly inhibited low-density lipoprotein (LDL) expression in HVSMCs and macrophages. In vivo, artesunate reduced atherosclerotic plaque formation in high-fat diet (HFD)-fed ApoE-/- mice, as well as decreased NLRP3 and CD68 expression in atherosclerotic plaques. Artesunate decreased serum levels of triglycerides and increased high-density lipoprotein levels in HFD-med mice; however, serum levels of total cholesterol and LDL were unaltered. Treatment with artesunate substantially increased α-smooth muscle actin expression in aortic tissues while inhibiting expression levels of NLRP3, IL-1β, heparinase, matrix metalloproteinase 9, and Krüppel-like factor 4 (KLF4). Collectively, our findings suggest that artesunate-mediated effects may involve inhibition of the ERK1/2/NF-κB/IL-1β pathway in HVSMCs via the downregulation of NLRP3 expression. Thus, artesunate could serve as a novel strategy to treat AS by inhibiting AS plaque formation and suppressing macrophage-like phenotype switching of HVSMCs.
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Affiliation(s)
- Ping Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Yuqi Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Keke Tian
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Xinyu Bai
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Yaowen Wang
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmias Therapeutic Service Center, Chongqing 400010, China.
| | - Yan Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China.
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21
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Li X, Ji LJ, Feng KD, Huang H, Liang MR, Cheng SJ, Meng XD. Emerging role of exosomes in ulcerative colitis: Targeting NOD-like receptor family pyrin domain containing 3 inflammasome. World J Gastroenterol 2024; 30:527-541. [PMID: 38463022 PMCID: PMC10921143 DOI: 10.3748/wjg.v30.i6.527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/21/2023] [Accepted: 01/09/2024] [Indexed: 02/05/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease. Despite ongoing advances in our understanding of UC, its pathogenesis is yet unelucidated, underscoring the urgent need for novel treatment strategies for patients with UC. Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules, such as proteins, RNAs, DNA, and metabolites. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β (IL-1β) and IL-18, triggering the inflammatory response to a pathogenic agent or injury. Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome, with vital roles in the pathological process of UC. Here, recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC. First, the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized. Finally, an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are highlighted.
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Affiliation(s)
- Xin Li
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| | - Li-Jiang Ji
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Kai-Di Feng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hua Huang
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Mei-Rou Liang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shi-Jin Cheng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiu-Dong Meng
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
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22
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Ren N, Wang WF, Zou L, Zhao YL, Miao H, Zhao YY. The nuclear factor kappa B signaling pathway is a master regulator of renal fibrosis. Front Pharmacol 2024; 14:1335094. [PMID: 38293668 PMCID: PMC10824958 DOI: 10.3389/fphar.2023.1335094] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/28/2023] [Indexed: 02/01/2024] Open
Abstract
Renal fibrosis is increasingly recognized as a global public health problem. Acute kidney injury (AKI) and chronic kidney disease (CKD) both result in renal fibrosis. Oxidative stress and inflammation play central roles in progressive renal fibrosis. Oxidative stress and inflammation are closely linked and form a vicious cycle in which oxidative stress induces inflammation through various molecular mechanisms. Ample evidence has indicated that a hyperactive nuclear factor kappa B (NF-ƙB) signaling pathway plays a pivotal role in renal fibrosis. Hyperactive NF-ƙB causes the activation and recruitment of immune cells. Inflammation, in turn, triggers oxidative stress through the production of reactive oxygen species and nitrogen species by activating leukocytes and resident cells. These events mediate organ injury through apoptosis, necrosis, and fibrosis. Therefore, developing a strategy to target the NF-ƙB signaling pathway is important for the effective treatment of renal fibrosis. This Review summarizes the effect of the NF-ƙB signaling pathway on renal fibrosis in the context of AKI and CKD (immunoglobulin A nephropathy, membranous nephropathy, diabetic nephropathy, hypertensive nephropathy, and kidney transplantation). Therapies targeting the NF-ƙB signaling pathway, including natural products, are also discussed. In addition, NF-ƙB-dependent non-coding RNAs are involved in renal inflammation and fibrosis and are crucial targets in the development of effective treatments for kidney disease. This Review provides a clear pathophysiological rationale and specific concept-driven therapeutic strategy for the treatment of renal fibrosis by targeting the NF-ƙB signaling pathway.
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Affiliation(s)
- Na Ren
- The First School of Clinical Medicine, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Wen-Feng Wang
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Liang Zou
- School of Food and Bioengineering, Chengdu University, Chengdu, Sichuan, China
| | - Yan-Long Zhao
- Dialysis Department of Nephrology Hospital, Shaanxi Traditional Chinese Medicine Hospital, Xi’an, Shaanxi, China
| | - Hua Miao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Ying-Yong Zhao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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23
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Jin C, Cao Y, Li Y. Bone Mesenchymal Stem Cells Origin Exosomes are Effective Against Sepsis-Induced Acute Kidney Injury in Rat Model. Int J Nanomedicine 2023; 18:7745-7758. [PMID: 38144514 PMCID: PMC10743757 DOI: 10.2147/ijn.s417627] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 12/13/2023] [Indexed: 12/26/2023] Open
Abstract
Introduction The incidence and mortality rates of sepsis-induced acute kidney injury (SAKI) remain high, posing a substantial healthcare burden. Studies have implicated a connection between the development of SAKI and inflammation response, apoptosis, and autophagy. Moreover, evidence suggests that manipulating autophagy could potentially influence the prognosis of this condition. Notably, exosomes derived from bone mesenchymal stem cells (BMSCs-Exo) have exhibited promise in mitigating cellular damage by modulating pathways associated with inflammation, apoptosis, and autophagy. Thus, this study aims to investigate the influence of BMSCs-Exo on SAKI and the potential mechanisms that drive this impact. Methods The SAKI model was induced in HK-2 cells using lipopolysaccharide (LPS), while rats underwent cecal ligation and puncture (CLP) to simulate the condition. Cell viability was assessed using the CCK-8 kit, and kidney damage was evaluated through HE staining, blood urea nitrogen (BUN), and serum creatinine (SCr) measurements. Inflammatory-related RNAs and proteins were quantified via qPCR and ELISA, respectively. Apoptosis was determined through apoptosis-related protein levels, flow cytometry, and TUNEL staining. Western blot analysis was utilized to measure associated protein expressions. Results In vivo, BMSCs-Exo ameliorated kidney injury in CLP-induced SAKI rats, reducing inflammatory cytokine production and apoptosis levels. Fluorescence microscope observed the absorption of BMSCs-Exo by renal cells following injection via tail vein. In the SAKI rat kidney tissue, there was an upregulation of LC3-II/LC3-I, p62, and phosphorylated AMP-activated protein kinase (p-AMPK) expressions, indicating blocked autophagic flux, while phosphorylated mammalian target of rapamycin (p-mTOR) expression was downregulated. However, BMSCs-Exo enhanced LC3-II/LC3-I and p-AMPK expression, concurrently reducing p62 and p-mTOR levels. In vitro, BMSCs-Exo enhanced cell viability in LPS-treated HK-2 cells, and exerted anti-inflammation and anti-apoptosis effects which were consistent with the results in vivo. Similarly, rapamycin (Rapa) exhibited a protective effect comparable to BMSCs-Exo, albeit partially abrogated by 3-methyladenine (3-MA). Conclusion BMSCs-Exo mitigate inflammation and apoptosis through autophagy in SAKI, offering a promising avenue for SAKI treatment.
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Affiliation(s)
- Cui Jin
- Department of Critical Care Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China
| | - Yongmei Cao
- Department of Critical Care Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China
| | - Yingchuan Li
- Department of Critical Care Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China
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24
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Wang Z, Liu M, Ai Y, Zheng S, Chen Y, Du H, Yuan S, Guo X, Yuan Y, Li G, Song J, Deng C. The compound artemisinin-hydroxychloroquine ameliorates bleomycin-induced pulmonary fibrosis in rats by inhibiting TGF-β1/Smad2/3 signaling pathway. Pulm Pharmacol Ther 2023; 83:102268. [PMID: 37967761 DOI: 10.1016/j.pupt.2023.102268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/27/2023] [Accepted: 11/09/2023] [Indexed: 11/17/2023]
Abstract
Pulmonary fibrosis (PF) is a lethal disease characterized by a progressive decline in lung function. Currently, lung transplantation remains the only available treatment for PF. However, both artemisinin (ART) and hydroxychloroquine (HCQ) possess potential antifibrotic properties. This study aimed to investigate the effects and mechanisms of a compound known as Artemisinin-Hydroxychloroquine (AH) in treating PF, specifically by targeting the TGF-β1/Smad2/3 pathway. To do this, we utilized an animal model of PF induced by a single tracheal drip of bleomycin (BLM) in Sprague-Dawley (SD) rats. The PF animal models were administered various doses of AH, and the efficacy and safety of AH were evaluated through pulmonary function testing, blood routine tests, serum biochemistry tests, organ index measurements, and pathological examinations. Additionally, Elisa, western blotting, and qPCR techniques were employed to explore the potential molecular mechanisms of AH in treating PF. Our findings reveal that AH effectively and safely alleviate PF by inhibiting BLM-induced specific inflammation, reducing extracellular matrix (ECM) deposition, and interfering with the TGF-β1/Smad2/3 signaling pathway. Notably, the windfall for this study is that the inhibition of ECM may initiate self-healing in the BLM-induced PF animal model. In conclusion, AH shows promise as a potential therapeutic drug for PF, as it inhibits disease progression through the TGF-β1/Smad2/3 signaling pathway.
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Affiliation(s)
- Zhaojia Wang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Min Liu
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Ying Ai
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Shaoqin Zheng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China; Institute of Science and Technology, Guangzhou University of Chinese Medicine, 26 Chentai Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Yingyi Chen
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Hujun Du
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Shijia Yuan
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Xueying Guo
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Yueming Yuan
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China; Institute of Science and Technology, Guangzhou University of Chinese Medicine, 26 Chentai Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Guoming Li
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Jianping Song
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China
| | - Changsheng Deng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Airport Road, Baiyun District, Guangzhou, 510080, People's Republic of China.
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25
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Zhang Z, Shi C, Wang Z. The physiological functions and therapeutic potential of exosomes during the development and treatment of polycystic ovary syndrome. Front Physiol 2023; 14:1279469. [PMID: 38028777 PMCID: PMC10657906 DOI: 10.3389/fphys.2023.1279469] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
Polycystic ovary syndrome is a very common disease of gynecological endocrine, accompanied by irregular menstruation, hyperandrogenism, metabolic abnormalities, reproductive disorders and other clinical symptoms, which seriously endangers women's physical and mental health, but its etiology and pathogenesis are not completely clear. Recently, the contribution of exosomes to the diagnosis and treatment of various diseases in the biomedical field has attracted much attention, including PCOS. Exosomes are extracellular vesicles secreted by cells, containing various biologically active molecules such as cell-specific proteins, lipids, and nucleic acids. They are important signaling regulators in vivo and widely participate in various physiopathological processes. They are new targets for disease diagnosis and treatment. Considering the important role of non-coding RNAs during the development and treatment of PCOS, this article takes exosomal miRNAs as the breakthrough point for elucidating the physiological functions and therapeutic potential of exosomes during the development and treatment of PCOS through analyzing the effects of exosomal miRNAs on ovarian follicle development, hormone secretion, oxidative stress, inflammatory response and insulin resistance, thus providing new research directions and theoretical basis for PCOS pathogenesis, clinical diagnosis and prognosis improvement.
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Affiliation(s)
| | | | - Zhengchao Wang
- Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, China
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26
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Lee M, Suzuki H, Ogiwara K, Aoki R, Kato R, Nakayama M, Fukao Y, Nihei Y, Kano T, Makita Y, Muto M, Yamada K, Suzuki Y. The nucleotide-sensing Toll-Like Receptor 9/Toll-Like Receptor 7 system is a potential therapeutic target for IgA nephropathy. Kidney Int 2023; 104:943-955. [PMID: 37648155 DOI: 10.1016/j.kint.2023.08.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 07/26/2023] [Accepted: 08/07/2023] [Indexed: 09/01/2023]
Abstract
The progression determinants of IgA nephropathy (IgAN) are still not fully elucidated. We have previously demonstrated that the mucosal activation of toll-like receptor (TLR) 9, which senses microbial unmethylated CpG DNA, influences progression by producing aberrantly glycosylated IgA. However, numerous recent reports of patients with IgAN presenting with gross hematuria after the mRNA vaccination for coronavirus disease 2019 suggest that the RNA-sensing system also exacerbates IgAN. Here, we investigated whether TLR7, which recognizes microbial RNA, is also involved in IgAN progression using a murine model and tonsil tissue from 53 patients with IgAN compared to samples from 40 patients with chronic tonsillitis and 12 patients with sleep apnea syndrome as controls. We nasally administered imiquimod, the ligand of TLR7, to IgAN-prone ddY mice and found that TLR7 stimulation elevated the serum levels of aberrantly glycosylated IgA and induced glomerular IgA depositions and proteinuria. Co-administered hydroxychloroquine, which inhibits TLRs, canceled the kidney injuries. In vitro, stimulating splenocytes from ddY mice with imiquimod increased interleukin-6 and aberrantly glycosylated IgA levels. The expression of TLR7 in the tonsils was elevated in patients with IgAN and positively correlated with that of a proliferation-inducing ligand (APRIL) involved in the production of aberrantly glycosylated IgA. Mechanistically, TLR7 stimulation enhanced the synthesis of aberrantly glycosylated IgA through the modulation of enzymes involved in the glycosylation of IgA. Thus, our findings suggest that nucleotide-sensing TLR9 and TLR7 play a crucial role in the pathogenesis of IgAN. Hence, nucleotide-sensing TLRs could be reasonably strong candidates for disease-specific therapeutic targets in IgAN.
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Affiliation(s)
- Mingfeng Lee
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Hitoshi Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan; Department of Nephrology, Juntendo University Urayasu Hospital, Chiba, Japan.
| | - Kei Ogiwara
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Ryosuke Aoki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Rina Kato
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Maiko Nakayama
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Fukao
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yoshihito Nihei
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Toshiki Kano
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yuko Makita
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Masahiro Muto
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Koshi Yamada
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
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Tang L, Xu Y, Wang L, Pan J. Adipose-derived stem cell exosomes ameliorate traumatic brain injury through the NLRP3 signaling pathway. Neuroreport 2023; 34:677-684. [PMID: 37506308 PMCID: PMC10399942 DOI: 10.1097/wnr.0000000000001941] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023]
Abstract
The exosomes of mesenchymal stem cells have immunoregulatory properties and can effectively mitigate secondary neuroinflammation due to traumatic brain injury (TBI). In this study, we found that adipose-derived stem cell exosomes (ADSCs-Exo) could reduce the inflammatory response after traumatic brain injury by reducing NLRP3 inflammasome secretion by microglial. ADSCs-Exo were monitored by Western blot and electron microscopy. An in-vitro lipopolysaccharide (LPS)-caused primary microglia model and a TBI rat model were constructed. Functional recovery was examined using the modified neurological severity score and foot fault tests. Inflammasome inactivation in LPS-stimulated microglial, ADSCs-Exo can reduce the secretion of interleukin (IL)-1β, IL-6 and tumor necrosis factor α. Compared with PBS-processed controls, the sensorimotor functional recovery was significantly improved by exosome treatment after injury at 14-35 days. Additionally, NLRP3 inflammasome was stimulated within 24 h after TBI. ADSCs-Exo application led to remarkable down-expression of NLRP3 and caspase-1. ADSCs-Exo can ameliorate LPS-induced inflammatory activation by reducing microglial pro-inflammatory cytokines. Moreover, the neuroprotective effect of ADSCs-Exo may be partially attributed to the inhibition thereof on the formation of NLRP3-mediated inflammasome. Such findings imply a potential function of ADSCs-Exo in treating TBI.
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Affiliation(s)
- Linjun Tang
- Department of Neurosurgery, The Second People’s Hospital of Wuhu, Wuhu, Anhui, China
| | - Yong Xu
- Department of Neurosurgery, The Second People’s Hospital of Wuhu, Wuhu, Anhui, China
| | - Liangwei Wang
- Department of Neurosurgery, The Second People’s Hospital of Wuhu, Wuhu, Anhui, China
| | - Jingjing Pan
- Department of Neurosurgery, The Second People’s Hospital of Wuhu, Wuhu, Anhui, China
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28
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Zhu XY, Li J. Potential targets of natural medicines: preventing lung cancer pre-metastatic niche formation by regulating exosomes. Front Oncol 2023; 13:1137007. [PMID: 37700835 PMCID: PMC10493872 DOI: 10.3389/fonc.2023.1137007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 08/11/2023] [Indexed: 09/14/2023] Open
Abstract
Lung cancer is one of the most devastating diseases worldwide with high incidence and mortality, and the incidence continues to rise. Metastasis is the leading cause of death in lung cancer patients, yet the molecular effectors underlying tumor dissemination remain poorly defined. Research findings in recent years confirmed primed microenvironment of future metastatic sites, called the pre-metastatic niche, is a prerequisite for overt metastasis. Exosomes have recently emerged as important players in pre-metastatic niche formation. Natural medicines have traditionally been rich sources of drug discovery. Some of them exhibit favorable anti-lung cancer activity. The review focused on the latest advances in the regulation of the pre-metastatic niche formation in lung cancer by the contents of exosomes of representative natural medicines. Additionally, the mechanism of natural medicines was summarized in detail, which would provide new insights for anti-cancer new drug development.
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Affiliation(s)
| | - Jie Li
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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29
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Posadino AM, Giordo R, Pintus G, Mohammed SA, Orhan IE, Fokou PVT, Sharopov F, Adetunji CO, Gulsunoglu-Konuskan Z, Ydyrys A, Armstrong L, Sytar O, Martorell M, Razis AFA, Modu B, Calina D, Habtemariam S, Sharifi-Rad J, Cho WC. Medicinal and mechanistic overview of artemisinin in the treatment of human diseases. Biomed Pharmacother 2023; 163:114866. [PMID: 37182516 DOI: 10.1016/j.biopha.2023.114866] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/28/2023] [Accepted: 05/08/2023] [Indexed: 05/16/2023] Open
Abstract
Artemisinin (ART) is a bioactive compound isolated from the plant Artemisia annua and has been traditionally used to treat conditions such as malaria, cancer, viral infections, bacterial infections, and some cardiovascular diseases, especially in Asia, North America, Europe and other parts of the world. This comprehensive review aims to update the biomedical potential of ART and its derivatives for treating human diseases highlighting its pharmacokinetic and pharmacological properties based on the results of experimental pharmacological studies in vitro and in vivo. Cellular and molecular mechanisms of action, tested doses and toxic effects of artemisinin were also described. The analysis of data based on an up-to-date literature search showed that ART and its derivatives display anticancer effects along with a wide range of pharmacological activities such as antibacterial, antiviral, antimalarial, antioxidant and cardioprotective effects. These compounds have great potential for discovering new drugs used as adjunctive therapies in cancer and various other diseases. Detailed translational and experimental studies are however needed to fully understand the pharmacological effects of these compounds.
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Affiliation(s)
- Anna Maria Posadino
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro, 07100 Sassari, Italy
| | - Roberta Giordo
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro, 07100 Sassari, Italy
| | - Gianfranco Pintus
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro, 07100 Sassari, Italy; Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, University City Rd, Sharjah 27272, United Arab Emirates
| | - Soheb Anwar Mohammed
- Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine, University of Pittsburgh, PA 15213, USA
| | - Ilkay Erdogan Orhan
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey; Turkish Academy of Sciences (TÜBA), Vedat Dalokay Cad., No. 112, 06670 Ankara, Turkey
| | | | - Farukh Sharopov
- V.I. Nikitin Chemistry Institute of the National Academy of Sciences of Tajikistan, Ayni 299/2, 734063 Dushanbe, Tajikistan
| | - Charles Oluwaseun Adetunji
- Applied Microbiology, Biotechnology and Nanotechnology Laboratory, Department of Microbiology, Edo State University Uzairue, Iyamho, PMB 04 Auchi, Edo State, Nigeria
| | - Zehra Gulsunoglu-Konuskan
- Faculty of Health Science, Nutrition and Dietetics Department, Istanbul Aydin University, Istanbul 34295, Turkey
| | - Alibek Ydyrys
- Biomedical Research Centre, Al-Farabi Kazakh National University, Al-Farabi ave. 71, 050040 Almaty, Kazakhstan
| | - Lorene Armstrong
- State University of Ponta Grossa, Departament of Pharmaceutical Sciences, 84030900 Ponta Grossa, Paraná, Brazil; Federal University of Paraná, Department of Pharmacy, 80210170 Curitiba, Paraná, Brazil
| | - Oksana Sytar
- Institute of Plant and Environmental Sciences, Slovak Agricultural University in Nitra, 94976 Nitra, Slovakia
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, 4070386 Concepción, Chile; Universidad de Concepción, Unidad de Desarrollo Tecnológico, UDT, 4070386 Concepción, Chile.
| | - Ahmad Faizal Abdull Razis
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
| | - Babagana Modu
- Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Department of Biochemistry, Faculty of Science, University of Maiduguri, 1069 Maiduguri, Borno State, Nigeria
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania.
| | - Solomon Habtemariam
- Pharmacognosy Research & Herbal Analysis Services UK, University of Greenwich, Central Avenue, Chatham-Maritime, Kent ME4 4TB, UK
| | | | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong Special Administrative Region.
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Yang WG, Sun A, Zhu R, Liu N, He WJ, Liu LL. Exploration of Artemisinin Against IgA Nephropathy via AKT/Nrf2 Pathway by Bioinformatics and Experimental Validation. Drug Des Devel Ther 2023; 17:1679-1697. [PMID: 37309415 PMCID: PMC10257916 DOI: 10.2147/dddt.s403422] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/27/2023] [Indexed: 06/14/2023] Open
Abstract
Background Artemisinin (ART) is a safe and effective antimalarial drug. In recent years, antimalarial drugs have demonstrated a good therapeutic efficacy in IgA nephropathy, suggesting that this may become a new treatment option. Purpose We aimed to evaluate the effect and mechanism of artemisinin in IgA nephropathy. Methods In this study, CMap database was used to predict the artemisinin therapeutic effect for IgA nephropathy. A network pharmacology approach was applied to explore the unknown mechanism of artemisinin in IgA nephropathy. We used molecular docking to predict the binding affinity of artemisinin with the targets. A mouse model of IgA nephropathy was established to investigate the therapeutic effect of artemisinin on IgA nephropathy. In vitro, the cell counting Kit-8 assay was used to evaluate the cytotoxicity of artemisinin. Flow cytometry and PCR assays were used to detect the effects of artemisinin on oxidative stress and fibrosis in lipopolysaccharide (LPS)-stimulated mesangial cells. Western blot and immunofluorescence were used to detect the expression of pathway proteins. Results CMap analysis showed artemisinin may reverse the expression levels of differentially expressed genes in IgA nephropathy. Eighty-seven potential targets of artemisinin in the treatment of IgA nephropathy were screened. Among them, 15 hub targets were identified. Enrichment analysis and GSEA analysis indicated that response to reactive oxygen species is the core biological process. AKT1 and EGFR had the highest docking affinity with artemisinin. In vivo, artemisinin could improve renal injury and fibrosis in mice. In vitro, artemisinin attenuated LPS-induced oxidative stress and fibrosis promoted AKT phosphorylation and Nrf2 nuclear translocation. Conclusion Artemisinin reduced the level of fibrosis and oxidative stress with IgA nephropathy through the AKT/Nrf2 pathway, which provided an alternative treatment for IgAN.
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Affiliation(s)
- Wei-guang Yang
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shen Yang, Liao Ning, People’s Republic of China
| | - Ao Sun
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shen Yang, Liao Ning, People’s Republic of China
| | - Rong Zhu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shen Yang, Liao Ning, People’s Republic of China
| | - Nan Liu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shen Yang, Liao Ning, People’s Republic of China
| | - Wei-jie He
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shen Yang, Liao Ning, People’s Republic of China
| | - Lin-lin Liu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shen Yang, Liao Ning, People’s Republic of China
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Cui J, Hong P, Li Z, Lin J, Wu X, Nie K, Zhang X, Wan J. Chloroquine inhibits NLRP3 inflammasomes activation and alleviates renal fibrosis in mouse model of hyperuricemic nephropathy with aggravation by a high-fat-diet. Int Immunopharmacol 2023; 120:110353. [PMID: 37276828 DOI: 10.1016/j.intimp.2023.110353] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/03/2023] [Accepted: 05/13/2023] [Indexed: 06/07/2023]
Abstract
Numerous epidemiological studies have demonstrated that hyperuricemia (HUA) is a risk factor for renal diseases and renal fibrosis. Dietary patterns can influence serum urate levels and hyperuricemic nephropathy (HN). NLRP3 inflammasomes play a crucial role in various inflammatory responses and contribute to HN progression. Chloroquine (CQ) is an anti-inflammatory and disease-modifying anti-rheumatic drug (DMARD) utilized in treating autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. In this study, we examined the effects and underlying mechanisms of CQ in a high-fat-diet (HFD) exacerbated mouse model of HN. C57BL/6 mice were randomized into either a control group or an HN group (induced by adenine/potassium oxonate treatment), followed by a normal diet or HFD, with or without CQ treatment. Our findings revealed that the HN group exhibited elevated serum levels of blood urea nitrogen (BUN) and creatinine compared to the control group. Additionally, the HN + HFD group displayed increased serum levels of uric acid, BUN, and creatinine relative to the control + HFD group. Moreover, the HFD exacerbated renal uric acid crystal deposition and fibrosis in HN mice compared to a normal diet. CQ ameliorated renal dysfunction, as evidenced by reduced serum creatinine levels, renal fibrosis, and renal tubular injury scores, and significantly decreased NLRP3, ASC, caspase-1, and IL-1β levels in HN mice. These findings suggest that CQ inhibits the activation of NLRP3 inflammasomes and may serve as a potential therapeutic strategy for HN treatment.
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Affiliation(s)
- Jiong Cui
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Pianpian Hong
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Zhenzhou Li
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Jiaqun Lin
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Xiaoting Wu
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Kun Nie
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Xiaohong Zhang
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Jianxin Wan
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
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Jin Q, Liu T, Chen D, Yang L, Mao H, Ma F, Wang Y, Li P, Zhan Y. Therapeutic potential of artemisinin and its derivatives in managing kidney diseases. Front Pharmacol 2023; 14:1097206. [PMID: 36874000 PMCID: PMC9974673 DOI: 10.3389/fphar.2023.1097206] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 02/06/2023] [Indexed: 02/17/2023] Open
Abstract
Artemisinin, an antimalarial traditional Chinese herb, is isolated from Artemisia annua. L, and has shown fewer side effects. Several pieces of evidence have demonstrated that artemisinin and its derivatives exhibited therapeutic effects on diseases like malaria, cancer, immune disorders, and inflammatory diseases. Additionally, the antimalarial drugs demonstrated antioxidant and anti-inflammatory activities, regulating the immune system and autophagy and modulating glycolipid metabolism properties, suggesting an alternative for managing kidney disease. This review assessed the pharmacological activities of artemisinin. It summarized the critical outcomes and probable mechanism of artemisinins in treating kidney diseases, including inflammatory, oxidative stress, autophagy, mitochondrial homeostasis, endoplasmic reticulum stress, glycolipid metabolism, insulin resistance, diabetic nephropathy, lupus nephritis, membranous nephropathy, IgA nephropathy, and acute kidney injury, suggesting the therapeutic potential of artemisinin and its derivatives in managing kidney diseases, especially the podocyte-associated kidney diseases.
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Affiliation(s)
- Qi Jin
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Tongtong Liu
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Danqian Chen
- China-Japan Friendship Hospital, Institute of Clinical Medical Sciences, Beijing, China
| | - Liping Yang
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Huimin Mao
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Fang Ma
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Yuyang Wang
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Ping Li
- China-Japan Friendship Hospital, Institute of Clinical Medical Sciences, Beijing, China
| | - Yongli Zhan
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
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The Role of NLRP3 Inflammasome in IgA Nephropathy. MEDICINA (KAUNAS, LITHUANIA) 2022; 59:medicina59010082. [PMID: 36676706 PMCID: PMC9866943 DOI: 10.3390/medicina59010082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/22/2022] [Accepted: 12/29/2022] [Indexed: 12/31/2022]
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide today. The NLRP3 inflammasome is a polyprotein complex and an important participant in inflammation. Accumulating studies have shown that the NLRP3 inflammasome participates in a variety of kidney diseases, including IgAN. This review focuses on the role of the NLRP3 inflammasome in IgAN and summarizes multiple involved pathways, which may provide novel treatments for IgAN treatment.
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Hua L, Liang S, Zhou Y, Wu X, Cai H, Liu Z, Ou Y, Chen Y, Chen X, Yan Y, Wu D, Sun P, Hu W, Yang Z. Artemisinin-derived artemisitene blocks ROS-mediated NLRP3 inflammasome and alleviates ulcerative colitis. Int Immunopharmacol 2022; 113:109431. [PMID: 36384076 DOI: 10.1016/j.intimp.2022.109431] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/23/2022] [Accepted: 11/03/2022] [Indexed: 11/15/2022]
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Guan H, Lin H, Wang X, Xu Y, Zheng Y, Zhou X, Diao X, Ye Z, Xiao J. Autophagy-dependent Na +-K +-ATPase signalling and abnormal urate reabsorption in hyperuricaemia-induced renal tubular injury. Eur J Pharmacol 2022; 932:175237. [PMID: 36063871 DOI: 10.1016/j.ejphar.2022.175237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/03/2022]
Abstract
Increasing evidence indicates that hyperuricaemia (HUA) is not only a result of decreased renal urate excretion but also a contributor to kidney disease. Na+-K+-ATPase (NKA), which establishes the sodium gradient for urate transport in proximal tubular epithelial cells (PTECs), its impairment leads to HUA-induced nephropathy. However, the specific mechanism underlying NKA impairment-mediated renal tubular injury and increased urate reabsorption in HUA is not well understood. In this study, we investigated whether autophagy plays a key role in the NKA impairment signalling and increased urate reabsorption in HUA-induced renal tubular injury. Protein spectrum analysis of exosomes from the urine of HUA patients revealed the activation of lysosomal processes, and exosomal expression of lysosome membrane protein 2 was associated with increased serum levels and decreased renal urate excretion in patients. We demonstrated that high uric acid (UA) induced lysosome dysfunction, autophagy and inflammation in a time- and dose-dependent manner and that high UA and/or NKA α1 siRNA significantly increased mitochondrial abnormalities, such as reductions in mitochondrial respiratory complexes and cellular ATP levels, accompanied by increased apoptosis in cultured PTECs. The autophagy inhibitor hydroxychloroquine (HCQ) ameliorated NKA impairment-mediated mitochondrial dysfunction, Nod-like receptor pyrin domain-containing protein 3 (NLRP3)-interleukin-1β (IL-1β) production, and abnormal urate reabsorption in PTECs stimulated with high UA and in rats with oxonic acid (OA)-induced HUA. Our findings suggest that autophagy plays a pivotal role in NKA impairment-mediated signalling and abnormal urate reabsorption in HUA-induced renal tubular injury and that inhibition of autophagy by HCQ could be a promising treatment for HUA.
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Affiliation(s)
- Haochen Guan
- Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China
| | - Huagang Lin
- Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China
| | - Xiaojun Wang
- Department of Traditional Chinese Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China
| | - Ying Xu
- Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China
| | - Yuqi Zheng
- Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China
| | - Xun Zhou
- Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China
| | - Xuehong Diao
- Department of Ultrasound, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China
| | - Zhibin Ye
- Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China.
| | - Jing Xiao
- Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China.
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Mo C, Zhao J, Liang J, Wang H, Chen Y, Huang G. Exosomes: A novel insight into traditional Chinese medicine. Front Pharmacol 2022; 13:844782. [PMID: 36105201 PMCID: PMC9465299 DOI: 10.3389/fphar.2022.844782] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 07/22/2022] [Indexed: 11/13/2022] Open
Abstract
Exosomes are small extracellular vesicles and play an essential role in the mediation of intercellular communication both in health and disease. Traditional Chinese medicine (TCM) has historically been used to maintain human health and treat various diseases up till today. The interplay between exosomes and TCM has attracted researchers’ growing attention. By integrating the available evidence, TCM formulas and compounds isolated from TCM as exosome modulators have beneficial effects on multiple disorders, such as tumors, kidney diseases, and hepatic disease, which may associate with inhibiting cells proliferation, anti-inflammation, anti-oxidation, and attenuating fibrosis. Exosomes, a natural delivery system, are essential in delivering compounds isolated from TCM to target cells or tissues. Moreover, exosomes may be the potential biomarkers for TCM syndromes, providing strategies for TCM treatment. These findings may provide a novel insight into TCM from exosomes and serve as evidence for better understanding and development of TCM.
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Affiliation(s)
- Chao Mo
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
- Department of Nephrology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Jie Zhao
- Graduate School, Hunan University of Chinese Medicine, Changsha, China
| | - Jingyan Liang
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Huiling Wang
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Yu Chen
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Guodong Huang
- Department of Nephrology, Guangxi International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
- *Correspondence: Guodong Huang,
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Jianping W, Wei X, Li J, Zhang R, Han Q, Yang Q. Identifying DUSP-1 and FOSB as hub genes in immunoglobulin A nephropathy by WGCNA and DEG screening and validation. PeerJ 2022; 10:e13725. [PMID: 35910761 PMCID: PMC9332322 DOI: 10.7717/peerj.13725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 06/22/2022] [Indexed: 01/17/2023] Open
Abstract
Background The mechanism of immunoglobulin A nephropathy (IgAN) is still unknown. A bioinformatics analysis is a powerful method to identify the biomarkers and possible therapeutic targets of a certain disease from related datasets. Methods The GSE93973 dataset, obtained from the Gene Expression Omnibus (GEO) database, was used to construct a weighted gene co-expression network (WGCNA) and filter differentially expressed genes (DEGs). The biological process (BP) enrichment among all the genes in the key modules was analyzed through a Gene Ontology (GO) enrichment analysis. We selected the overlap of hub genes in the WGCNA and Protein-Protein Interaction (PPI) network as the final hub genes in IgAN. We verified the final hub genes in two other datasets and in clinical kidney tissue specimens. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of hub genes for IgAN. Results The turquoise module, which contained 1,806 genes, was the module with the highest correlation coefficient with IgAN in the GSE93973 dataset. The GO enrichment analysis showed that these 1,806 genes were mainly enriched in inflammation and immune responses. There were five hub genes identified by WGCNA and 34 hub genes identified in a DEG analysis in the GSE93973 dataset. DUSP1 and FOSB were identified as the final hub genes in IgAN. The validation results of the final hub genes in two other databases and clinical kidney tissue specimens validated the result that, compared to the control group, FOSB and DUSP1 were expressed at lower levels in the glomerulus of IgAN patients. The ROC curve indicated that DUSP1 and FOSB were good diagnostic indicators for IgAN. Conclusions Our analysis identified two hub genes that might be potential targets for the intervention and treatment of IgAN.
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Thongboonkerd V, Kanlaya R. The divergent roles of exosomes in kidney diseases: Pathogenesis, diagnostics, prognostics and therapeutics. Int J Biochem Cell Biol 2022; 149:106262. [PMID: 35787447 DOI: 10.1016/j.biocel.2022.106262] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 06/30/2022] [Indexed: 11/16/2022]
Abstract
Exosomes are the self-packed nanoscale vesicles (nanovesicles) derived from late endosomes and released from the cells to the extracellular milieu. Exosomal biogenesis is based on endosomal pathway to form the nanovesicles surrounded by membrane originated from plasma membranes of the parental cells. During biogenesis, exosomes selectively encapsulate an array of biomolecules (proteins, nucleic acids, lipids, metabolites, etc.), thereby conveying diverse messages for cell-cell communications. Once released, these exosomal contents trigger signaling and trafficking that play roles in cell growth, development, immune responses, homeostasis, remodeling, etc. Recent advances in exosomal research have provided a wealth of useful information that enhances our knowledge on the roles for exosomes in pathogenic mechanisms of human diseases involving a wide variety of organ systems. In the kidney, exosomes play divergent roles, ranging from pathogenesis to therapeutics, based on their original sources and type of interventions. Herein, we summarize and update the current knowledge on the divergent roles of exosomes involving the pathogenesis, diagnostics, prognostics, and therapeutics in various groups of kidney diseases, including acute kidney injury, immune-mediated kidney diseases (e.g., IgA nephropathy, lupus nephritis, membranous nephropathy, focal segmental glomerulosclerosis), chronic kidney disease (caused by diabetic nephropathy and others), renal cell carcinoma, nephrolithiasis, kidney transplantation and related complications, and polycystic kidney disease. Finally, the future perspectives on research in this area are discussed.
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Affiliation(s)
- Visith Thongboonkerd
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
| | - Rattiyaporn Kanlaya
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Wang Y, Tian L, Sun L, Zhou W, Zhi W, Qing J, Abdi Saed Y, Dong L, Zhang X, Li Y. Gut Microbes in Immunoglobulin A Nephropathy and Their Potential Therapeutic Applications. Front Med (Lausanne) 2022; 9:823267. [PMID: 35655857 PMCID: PMC9152025 DOI: 10.3389/fmed.2022.823267] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 04/15/2022] [Indexed: 11/13/2022] Open
Abstract
Microbial ecosystem consists of a complex community of bacterial interactions and its host microenvironment (tissue, cell, metabolite). Because the interaction between gut microbiota and host involves many diseases and seriously affects human health, the study of the interaction mechanism between gut microbiota and host has attracted great attention. The gut microbiome is made up of 100 trillion bacteria that have both beneficial and adverse effects on human health. The development of IgA Nephropathy results in changes in the intestinal microbial ecosystem that affect host physiology and health. Similarly, changes in intestinal microbiota also affect the development of IgA Nephropathy. Thus, the gut microbiome represents a novel therapeutic target for improving the outcome of IgA Nephropathy, including hematuria symptoms and disease progression. In this review, we summarize the effect of intestinal microbiota on IgA Nephropathy in recent years and it has been clarified that the intestinal microbiota has a great influence on the pathogenesis and treatment of IgA Nephropathy.
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Affiliation(s)
- Yi Wang
- The Third Clinical College, Shanxi University of Chinese Medicine, Taiyuan, China
| | - Lingling Tian
- The Third Clinical College, Shanxi University of Chinese Medicine, Taiyuan, China
| | - Lin Sun
- College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, China
| | - Wenjing Zhou
- School of Medical Sciences, Shanxi University of Chinese Medicine, Jinzhong, China
| | - Wenqiang Zhi
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China
| | - Jianbo Qing
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China
| | - Yasin Abdi Saed
- Department of Nephrology, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
| | - Lina Dong
- Core Laboratory, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
| | - Xiadong Zhang
- Core Laboratory, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
| | - Yafeng Li
- Department of Nephrology, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China.,Core Laboratory, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China.,Shanxi Provincial Key Laboratory of Kidney Disease, Taiyuan, China.,Academy of Microbial Ecology, Shanxi Medical University, Taiyuan, China
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Efficacy and safety of artesunate for patients with IgA nephropathy: a study protocol for a multicenter, double-blind, randomized, placebo-controlled trial. Trials 2022; 23:444. [PMID: 35614482 PMCID: PMC9134594 DOI: 10.1186/s13063-022-06336-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 02/15/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND IgA nephropathy is the most common glomerular disease and is a common cause of progression to end-stage renal disease in patients with kidney diseases. Proteinuria levels are critical for the prognosis of patients with IgA nephropathy, but many patients are still unable to effectively control their proteinuria levels after receiving RAAS blockers. Antimalarial drugs have shown good efficacy in the treatment of kidney disease in previous studies; however, there have been no strictly designed randomized controlled trials to confirm the clinical efficacy of artesunate for treating IgA nephropathy patients. Therefore, we designed this clinical trial to compare the effect of artesunate versus placebo in patients with IgA nephropathy. METHODS This study is a randomized, double-blind, three-group-parallel, placebo-controlled clinical trial. One hundred and twenty eligible IgA nephropathy patients at risk of progression will be randomly divided into the artesunate 100-mg group, artesunate 50-mg group, and placebo group. Changes in proteinuria and renal function will be measured 6 months after the intervention. The levels of Gd-IgA1 and anti-Gd-IgA1 in the patient's blood will also be tested to explore the possible immune mechanisms. DISCUSSION Clinical evidence supporting artesunate treatment of IgA nephropathy is currently lacking, and we expect that the results of this trial will provide high-quality clinical evidence for artesunate as a treatment option for IgA nephropathy in the future. TRIAL REGISTRATION Chinese Clinical Trial Registry ChiCTR2000038104 . Registered on 10 September 2020.
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Roberti A, Chaffey LE, Greaves DR. NF-κB Signaling and Inflammation-Drug Repurposing to Treat Inflammatory Disorders? BIOLOGY 2022; 11:372. [PMID: 35336746 PMCID: PMC8945680 DOI: 10.3390/biology11030372] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/12/2022] [Accepted: 02/15/2022] [Indexed: 12/15/2022]
Abstract
NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Thus, modulation of NF-κB signaling is being widely investigated as an approach to treat chronic inflammatory diseases, autoimmunity and cancer. The emergence of COVID-19 in late 2019, the subsequent pandemic and the huge clinical burden of patients with life-threatening SARS-CoV-2 pneumonia led to a massive scramble to repurpose existing medicines to treat lung inflammation in a wide range of healthcare systems. These efforts continue and have proven to be controversial. Drug repurposing strategies are a promising alternative to de novo drug development, as they minimize drug development timelines and reduce the risk of failure due to unexpected side effects. Different experimental approaches have been applied to identify existing medicines which inhibit NF-κB that could be repurposed as anti-inflammatory drugs.
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Affiliation(s)
| | | | - David R. Greaves
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; (A.R.); (L.E.C.)
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42
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Amin S, Aktar S, Rahman MM, Chowdhury MMH. NLRP3 inflammasome activation in COVID-19: an interlink between risk factors and disease severity. Microbes Infect 2022; 24:104913. [PMID: 34838941 PMCID: PMC8613976 DOI: 10.1016/j.micinf.2021.104913] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 02/08/2023]
Abstract
NLRP3 inflammasome is a critical immune component that plays a crucial role in mounting innate immune responses. The deleterious effects of inflammasome activation have been correlated with the COVID-19 disease severity. In the presence of several underlying disorders, the immune components of our bodies are dysregulated, creating conditions that could adversely affect us other than providing a required level of protection. In this review, we focused on the occurrence of NLRP3 inflammasome activation in response to SARS-COV-2 infection, dysregulation of NLRP3 activation events in the presence of several comorbidities, the contribution of activated NLRP3 inflammasome to the severity of COVID-19, and available therapeutics for the treatment of such NLRP3 inflammasome related diseases based on current knowledge. The primed state of immunity in individuals with comorbidities (risk factors) could accelerate many deaths and severe COVID-19 cases via activation of NLRP3 inflammasome and the release of downstream inflammatory molecules. Therefore, a detailed understanding of the host-pathogen interaction is needed to clarify the pathophysiology and select a potential therapeutic approach.
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Affiliation(s)
- Saiful Amin
- Chittagong Medical University, Chattogram, Bangladesh
| | - Salma Aktar
- Department of Microbiology, Noakhali Science and Technology University, Sonapur, Noakhali 3814, Bangladesh.
| | - Md Mijanur Rahman
- Department of Microbiology, Noakhali Science and Technology University, Sonapur, Noakhali 3814, Bangladesh
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43
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Li Z, Chen X, Tao J, Shi A, Zhang J, Yu P. Exosomes Regulate NLRP3 Inflammasome in Diseases. Front Cell Dev Biol 2022; 9:802509. [PMID: 35047512 PMCID: PMC8762245 DOI: 10.3389/fcell.2021.802509] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/03/2021] [Indexed: 12/11/2022] Open
Abstract
Emerging evidence has suggested the unique and critical role of exosomes as signal molecules vector in various diseases. Numerous researchers have been trying to identify how these exosomes function in immune progression, as this could promote their use as biomarkers for the disease process and potential promising diagnostic tools. NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3), a tripartite protein, contains three functional domains a central nucleotide-binding and oligomerization domain (NACHT), an N-terminal pyrin domain (PYD), and a leucine-rich repeat domain (LRR). Of note, existing studies have identified exosome as a novel mediator of the NLRP3 inflammasome, which is critical in diseases progression. However, the actual mechanisms and clinical treatment related to exosomes and NLRP3 are still not fully understood. Herein, we presented an up-to-date review of exosomes and NLRP3 in diseases, outlining what is known about the role of exosomes in the activation of NLRP3 inflammasome and also highlighting areas of this topic that warrant further study.
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Affiliation(s)
- Zhangwang Li
- The Second Affiliated Hospital of Nanchang University, The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Xinyue Chen
- The Second Affiliated Hospital of Nanchang University, The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Junjie Tao
- The Second Affiliated Hospital of Nanchang University, The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Ao Shi
- School of Medicine, University of Nicosia, Nicosia, Cyprus.,School of Medicine, St. George University of London, London, United Kingdom
| | - Jing Zhang
- The Second Affiliated Hospital of Nanchang University, The Second Clinical Medical College of Nanchang University, Nanchang, China.,Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Peng Yu
- The Second Affiliated Hospital of Nanchang University, The Second Clinical Medical College of Nanchang University, Nanchang, China.,Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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44
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Hua F, Shi L, Zhou P. Phenols and terpenoids: natural products as inhibitors of NLRP3 inflammasome in cardiovascular diseases. Inflammopharmacology 2022; 30:137-147. [PMID: 35039992 DOI: 10.1007/s10787-021-00918-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 12/27/2021] [Indexed: 12/27/2022]
Abstract
Inflammatory infiltration has been implicated in the pathogenesis of cardiovascular diseases (CVDs). The NLRP3 inflammasome is involved in the development of several types of CVDs, including myocardial infarction, myocardial ischemia-reperfusion damage, heart failure, atrial fibrillation, and hypertension. Inhibiting the activity of NLRP3 inflammasome can inhibit the progress of CVDs. However, there is no NLRP3 inflammasome inhibitor in clinic, and it is very important to find a safe and effective NLRP3 inhibitor. Phenols and terpenoids are naturally natural products that have many anti-inflammatory effects in CVDs by modulating the NLRP3 inflammatory pathway. Thus, 20 natural products from phenols and terpenoids for the treatment of cardiovascular disease based on the inhibition of NLRP3 inflammasome were summarized and screened. Docking results showed salvianolic acid B and ellagic acid in phenols, and oridonin and triptolide in terpenoids had a better binding activity with NLRP3, which can provide theoretical support for finding novel NLRP3 inflammasome inhibitors or lead compounds in the future.
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Affiliation(s)
- Fang Hua
- Pharmacy School, Anhui Xinhua University, Hefei, 230088, People's Republic of China
| | - Lingli Shi
- Pharmacy School, Anhui Xinhua University, Hefei, 230088, People's Republic of China
| | - Peng Zhou
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, People's Republic of China. .,Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, 230012, People's Republic of China.
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45
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Tang C, Si FL, Yao YX, Lv JC, Shi SF, Chen YQ, Liu LJ, Zhang H. The efficacy and safety of hydroxychloroquine in pregnant patients with IgA nephropathy: A retrospective cohort study. Nephrology (Carlton) 2021; 27:155-161. [PMID: 34713949 DOI: 10.1111/nep.13991] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/21/2021] [Accepted: 10/21/2021] [Indexed: 11/29/2022]
Abstract
AIM Hydroxychloroquine (HCQ) is used to control proteinuria in IgA Nephropathy (IgAN) However, its efficacy and safety in pregnant IgAN patients remains unknown. This study aimed to verify the safety of HCQ in pregnant IgAN patients and compare renal function and pregnancy outcomes with those of patients not treated with HCQ. METHODS We retrospectively reviewed medical records of all pregnant IgAN patients and singleton gestations at Peking University First Hospital from 2003-2021. Patients who did and did not receive HCQ treatment during pregnancy were compared. RESULTS We found no significant pre- or post-pregnancy differences in proteinuria or renal function between the two groups. However, the HCQ (+) group had higher proteinuria at the time of kidney biopsy (2.04 [1.26, 2.56] g/d vs. 0.80 [0.44, 1.11] g/d, P < .001); the proteinuria level at HCQ therapy initiation was also higher than that at the beginning of pregnancy (1.87 [1.30, 2.59] g/d vs. 1.08 [0.75, 1.50] g/d, P = .001). Despite no difference in preterm birth, birth weight, preeclampsia or postpartum haemorrhage, the proportion of patients with a previous history of spontaneous abortion was higher in the HCQ (+) group than in the HCQ (-) group (48.0% vs. 20.6%, P = .010). The eGFR (regression coefficient, 0.981; 95%CI 0.964-0.998) was a predictive factor for obstetrical complications. CONCLUSION HCQ is safe for IgAN treatment during pregnancy with effective reduction of proteinuria. HCQ might also be helpful in patients with a history of spontaneous abortion.
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Affiliation(s)
- Chen Tang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Feng-Lei Si
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Yu-Xuan Yao
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Ji-Cheng Lv
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Su-Fang Shi
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Yu-Qing Chen
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Li-Jun Liu
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
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46
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Huang X, Xu G. An Update on Targeted Treatment of IgA Nephropathy: An Autoimmune Perspective. Front Pharmacol 2021; 12:715253. [PMID: 34497518 PMCID: PMC8419281 DOI: 10.3389/fphar.2021.715253] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Immunoglobulin (Ig) A nephropathy (IgAN) is the commonest form of primary glomerulonephritis worldwide and is, considered a significant cause of end-stage renal disease in young adults. The precise pathogenesis of IgAN is unclear. The clinical and pathological features vary significantly between individuals and races, which makes treating IgAN difficult. Currently, the therapeutic strategies in IgAN are still optimal blood pressure control and proteinuria remission to improve the renal function in most cases. Immunosuppressive drugs such as corticosteroids can be considered in patients with persistent proteinuria and a high risk of renal function decline; however, they include a high toxicity profile. Therefore, the safety and selectivity of medications are critical concerns in the treatment of IgAN. Various pharmacological therapeutic targets have emerged based on the evolving understanding of the autoimmune pathogenesis of IgAN, which involves the immune response, mucosal immunity, renal inflammation, complement activation, and autophagy; treatments based on these mechanisms have been explored in preclinical and clinical studies. This review summarizes the progress concerning targeted therapeutic strategies and the relevant autoimmune pathogenesis in IgAN.
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Affiliation(s)
- Xin Huang
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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47
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Qiu F, Liu J, Mo X, Liu H, Chen Y, Dai Z. Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs. Front Immunol 2021; 12:751772. [PMID: 34567013 PMCID: PMC8458561 DOI: 10.3389/fimmu.2021.751772] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 08/25/2021] [Indexed: 01/11/2023] Open
Abstract
Artemisinin and its derivatives (ARTs) are known as conventional antimalarial drugs with clinical safety and efficacy. Youyou Tu was awarded a Nobel Prize in Physiology and Medicine due to her discovery of artemisinin and its therapeutic effects on malaria. Apart from antimalarial effects, mounting evidence has demonstrated that ARTs exert therapeutic effects on inflammation and autoimmune disorders because of their anti-inflammatory and immunoregulatory properties. In this aspect, tremendous progress has been made during the past five to seven years. Therefore, the present review summarizes recent studies that have explored the anti-inflammatory and immunomodulatory effects of ARTs on autoimmune diseases and transplant rejection. In this review, we also discuss the cellular and molecular mechanisms underlying the immunomodulatory effects of ARTs. Recent preclinical studies will help lay the groundwork for clinical trials using ARTs to treat various immune-based disorders, especially autoimmune diseases.
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Affiliation(s)
- Feifei Qiu
- Section of Immunology & Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences & Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Junfeng Liu
- Section of Immunology & Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences & Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiumei Mo
- Section of Immunology & Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences & Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huazhen Liu
- Section of Immunology & Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences & Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuchao Chen
- Section of Immunology & Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences & Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhenhua Dai
- Section of Immunology & Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences & Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Diseases, Guangzhou University of Chinese Medicine, Guangzhou, China
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48
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IgA Vasculitis: a Review and Update on the Management of Renal and Extrarenal Disease, Highlighting What’s New for Biomarkers and Treatment. CURRENT PEDIATRICS REPORTS 2021. [DOI: 10.1007/s40124-021-00247-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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49
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Jianping W, Xuelian Z, Anjiang W, Haiying X. Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Metabolic Associated Fatty Liver Disease: A Systematic Review and Meta-analysis. J Clin Gastroenterol 2021; 55:586-593. [PMID: 34039937 DOI: 10.1097/mcg.0000000000001556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Clinical trials examining the therapeutic benefits of glucagon-like peptide-1 receptor agonists (GLP-1RA) on patients with metabolic associated fatty liver disease (MAFLD) have reported inconsistent results. The aim of this meta-analysis was to verify the role of GLP-1RA in the treatment of MAFLD patients. MATERIALS AND METHODS We searched PubMed, Embase, Medline, and the Cochrane Library for randomized controlled trials published that compared GLP-1RA with the control treatment in patients with MAFLD till to July 30, 2020. The effects of GLP-1RA on liver histology, body mass index, waist circumference (WC), aspartate aminotransferase, total cholesterol, triglycerides (TG), low-density lipoprotein and high-density lipoprotein were evaluated. RESULTS Thirteen trials involving 704 patients were included in the meta-analysis. Compared with the control treatment, GLP-1RA treatment induced a greater resolution of steatohepatitis [RR=2.87; 95% confidence interval (CI): 0.89 to 9.23], delayed the progression of liver fibrosis (RR=3.83, 95% CI: 0.91 to 16.07) and reduced liver fat deposition (MD: -1.40; 95% CI: -2.75 to -0.05). In addition, it reduced the body mass index (MD: -1.15; 95% CI: -2.26 to -0.04), WC (MD: -3.33; 95% CI: -6.31 to -0.35) and improved serum aspartate aminotransferase (MD: -3.04; 95% CI: -5.93 to -0.16) and total cholesterol (MD: -0.20; 95% CI: -0.28 to -0.13). CONCLUSION GLP-1RA improves liver steatosis and fibrosis. It is also beneficial to metabolic syndrome as it reduces BMI, WC, and hyperlipidemia.
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Affiliation(s)
- Wu Jianping
- Departments of Gastroenterology
- Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zheng Xuelian
- Pharmacy, The First Affiliated Hospital of Nanchang University
| | | | - Xiao Haiying
- Department of Gastroenterology, Nanchang Third Hospital, Nanchang, Jiangxi
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Li Y, Xia M, Peng L, Liu H, Chen G, Wang C, Yuan D, Liu Y, Liu H. Downregulation of miR‑214-3p attenuates mesangial hypercellularity by targeting PTEN‑mediated JNK/c-Jun signaling in IgA nephropathy. Int J Biol Sci 2021; 17:3343-3355. [PMID: 34512151 PMCID: PMC8416718 DOI: 10.7150/ijbs.61274] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/21/2021] [Indexed: 01/05/2023] Open
Abstract
Mesangial cell (MC) proliferation and matrix expansion are basic pathological characteristics of IgA nephropathy (IgAN). However, the stepwise mechanism of MC proliferation and the exact set of related signaling molecules remain largely unclear. In this study, we found a significant upregulation of miR-214-3p in the renal cortex of IgAN mice by miRNA sequencing. In situ hybridization analysis showed that miR-214-3p expression was obviously elevated in MCs in the renal cortex in IgAN. Functionally, knockdown of miR-214-3p alleviated mesangial hypercellularity and renal lesions in IgAN mice. In vitro, the inhibition of miR-214-3p suppressed MC proliferation and arrested G1-S cell cycle pSrogression in IgAN. Mechanistically, a luciferase reporter assay verified PTEN as a direct target of miR-214-3p. Downregulation of miR-214-3p increased PTEN expression and reduced p-JNK and p-c-Jun levels, thereby inhibiting MC proliferation and ameliorating renal lesions in IgAN. Moreover, these changes could be attenuated by co-transfection with PTEN siRNA. Collectively, these results illustrated that miR-214-3p accelerated MC proliferation in IgAN by directly targeting PTEN to modulate JNK/c-Jun signaling. Therefore, miR-214-3p may represent a novel therapeutic target for IgAN.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Hong Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
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