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Zhao Q, Dong J, Liu H, Chen H, Yu H, Ye S, Yu S, Li Y, Qiu L, Song N, Xu H, Liu Q, Luo Z, Li Y, Wang R, Chen G, Jiang X. Design and discovery of a highly potent ultralong-acting GLP-1 and glucagon co-agonist for attenuating renal fibrosis. Acta Pharm Sin B 2024; 14:1283-1301. [PMID: 38486997 PMCID: PMC10935026 DOI: 10.1016/j.apsb.2023.11.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/09/2023] [Accepted: 11/09/2023] [Indexed: 03/17/2024] Open
Abstract
The role of co-agonists of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) in chronic kidney disease (CKD) remains unclear. Herein we found that GLP-1R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease severity. Interestingly, GLP-1R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruction (UUO). Based on the importance of GLP-1R and GCGR in CKD, we reported a novel monomeric peptide, 1907-B, with dual-agonism on both GLP-1R and GCGR. The data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys (∼2-3 fold) and exhibited better therapeutic contribution to CKD than best-in-class monoagonists, semaglutide, or glucagon, in db/db mice and UUO mice. Various lock-of-function models, including selective pharmacological activation and genetic knockdown, confirmed that 1907-B's effects on ameliorating diabetic nephropathy in db/db mice, as well as inhibiting kidney fibrosis in UUO mice, were mediated through GLP-1 and glucagon signaling. These findings highlight that 1907-B, a novel GLP-1R and GCGR co-agonist, exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.
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Affiliation(s)
- Qian Zhao
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Jiale Dong
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Han Liu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Hui Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Huan Yu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Shuyin Ye
- Shenzhen Turier Biotech. Co., Ltd., Shenzhen 518118, China
| | - Shuangjin Yu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, China
| | - Yu Li
- Shenzhen Turier Biotech. Co., Ltd., Shenzhen 518118, China
| | - Longhui Qiu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, China
| | - Nazi Song
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Hongjiao Xu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Qi Liu
- Shenzhen Turier Biotech. Co., Ltd., Shenzhen 518118, China
| | - Zhiteng Luo
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Yuyi Li
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510006, China
| | - Rui Wang
- School of Life Sciences, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Lanzhou University, Lanzhou 730000, China
| | - Guodong Chen
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, China
| | - Xianxing Jiang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
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Melica ME, Angelotti ML, Antonelli G, Peired AJ, Conte C, De Chiara L, Mazzinghi B, Lazzeri E, Lasagni L, Romagnani P. Preparation of Human Kidney Progenitor Cultures and Their Differentiation into Podocytes. Bio Protoc 2023; 13:e4757. [PMID: 37638296 PMCID: PMC10450739 DOI: 10.21769/bioprotoc.4757] [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: 01/03/2023] [Revised: 03/27/2023] [Accepted: 05/24/2023] [Indexed: 08/29/2023] Open
Abstract
Kidney diseases are a global health concern. Modeling of kidney disease for translational research is often challenging because of species specificities or the postmitotic status of kidney epithelial cells that make primary cultures, for example podocytes. Here, we report a protocol for preparing primary cultures of podocytes based on the isolation and in vitro propagation of immature kidney progenitor cells subsequently differentiated into mature podocytes. This protocol can be useful for studying physiology and pathophysiology of human kidney progenitors and to obtain differentiated podocytes for modeling podocytopathies and other kidney disorders involving podocytes.
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Affiliation(s)
- Maria Elena Melica
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Maria Lucia Angelotti
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Giulia Antonelli
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Nephrology and Dialysis Unit, Meyer Children’s Hospital IRCCS, Florence, Italy
| | - Anna J. Peired
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Carolina Conte
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Nephrology and Dialysis Unit, Meyer Children’s Hospital IRCCS, Florence, Italy
| | - Letizia De Chiara
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Benedetta Mazzinghi
- Nephrology and Dialysis Unit, Meyer Children’s Hospital IRCCS, Florence, Italy
| | - Elena Lazzeri
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Laura Lasagni
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Paola Romagnani
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Nephrology and Dialysis Unit, Meyer Children’s Hospital IRCCS, Florence, Italy
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Xie X, Lou H, Shi Y, Gan G, Deng H, Ma X, Meng M, Gao X. A network pharmacological-based study of the mechanism of Liuwei Dihuang pill in the treatment of chronic kidney disease. Medicine (Baltimore) 2023; 102:e33727. [PMID: 37171332 PMCID: PMC10174353 DOI: 10.1097/md.0000000000033727] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 03/17/2023] [Accepted: 04/19/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a progressive disease that poses a huge economic burden to society. Liuwei Dihuanng pill is an effective treatment for chronic kidney disease, but its treatment mechanism is unclear. The rapid development of network pharmacology has provided new strategies for studying Chinese medicine. METHOD The traditional Chinese medicine systems pharmacology database and analysis platform was used to obtain the bioactive components and targets of Liuwei Dihuanng pill. The sources for the CKD-related targets were then obtained from the Genecards, OMIM, TTD, and DisGeNET databases. R was used to identify the intersecting genes for Liuwei Dihuang pill and CKD-related targets. Analysis of protein-protein interactions (PPI) was performed using STRING, and PPI networks and drug-component-target networks were constructed using Cytoscape software. Kyoto encyclopedia of genes and genomes pathway and gene ontology enrichment analyses were performed using R. Finally, molecular docking was performed to determine the binding activity between bioactive components and the targets. RESULT After screening and data de-duplication of 74 active components, 209 drug targets, and 14,794 disease targets, a total of 204 drug-disease targets were acquired. Subsequently, a drug-component-target network and PPI network were established. The primary components of Liuwei Dihuang pill included quercetin, stigmasterol, kaempferol, beta-sitosterol, tetrahydroalstonine, kadsurenone, hederagenin, hancinone C, diosgenin, and sitosterol. In addition, JUN, AKT1, TP53, RELA, MAPK1, FOS, TNF, IL6, ESR1, and RXRA were identified as the main targets. Gene ontology function enrichment analysis revealed that these targets were involved in reactive oxygen species metabolic processes, responses to metal ions and to chemical stimuli, G protein-coupled amine receptor activity, and nuclear factor receptor activity. Kyoto encyclopedia of genes and genomes enrichment analysis showed that these targets were involved in the AGE-RAGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, and so on. Molecular docking results indicated good binding activity between the core targets and core components. CONCLUSION The potential mechanism of Liuwei Dihuanng pill in the treatment of CKD was preliminarily discussed in this study, providing a theoretical basis and evidence for further experimental research.
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Affiliation(s)
- Xi Xie
- The First Clinical Medical College of Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Hongjun Lou
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Ye Shi
- College of Integrated Chinese and Western Medicine, Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Guang Gan
- College of Integrated Chinese and Western Medicine, Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Hanqing Deng
- The First Clinical Medical College of Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Xinwei Ma
- The First Clinical Medical College of Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Mingfang Meng
- The First Clinical Medical College of Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Xi Gao
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, China
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Ruby M, Gifford CC, Pandey R, Raj VS, Sabbisetti VS, Ajay AK. Autophagy as a Therapeutic Target for Chronic Kidney Disease and the Roles of TGF-β1 in Autophagy and Kidney Fibrosis. Cells 2023; 12:412. [PMID: 36766754 PMCID: PMC9913737 DOI: 10.3390/cells12030412] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/27/2023] Open
Abstract
Autophagy is a lysosomal protein degradation system that eliminates cytoplasmic components such as protein aggregates, damaged organelles, and even invading pathogens. Autophagy is an evolutionarily conserved homoeostatic strategy for cell survival in stressful conditions and has been linked to a variety of biological processes and disorders. It is vital for the homeostasis and survival of renal cells such as podocytes and tubular epithelial cells, as well as immune cells in the healthy kidney. Autophagy activation protects renal cells under stressed conditions, whereas autophagy deficiency increases the vulnerability of the kidney to injury, resulting in several aberrant processes that ultimately lead to renal failure. Renal fibrosis is a condition that, if chronic, will progress to end-stage kidney disease, which at this point is incurable. Chronic Kidney Disease (CKD) is linked to significant alterations in cell signaling such as the activation of the pleiotropic cytokine transforming growth factor-β1 (TGF-β1). While the expression of TGF-β1 can promote fibrogenesis, it can also activate autophagy, which suppresses renal tubulointerstitial fibrosis. Autophagy has a complex variety of impacts depending on the context, cell types, and pathological circumstances, and can be profibrotic or antifibrotic. Induction of autophagy in tubular cells, particularly in the proximal tubular epithelial cells (PTECs) protects cells against stresses such as proteinuria-induced apoptosis and ischemia-induced acute kidney injury (AKI), whereas the loss of autophagy in renal cells scores a significant increase in sensitivity to several renal diseases. In this review, we discuss new findings that emphasize the various functions of TGF-β1 in producing not just renal fibrosis but also the beneficial TGF-β1 signaling mechanisms in autophagy.
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Affiliation(s)
- Miss Ruby
- Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, Haryana, India
| | - Cody C. Gifford
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - RamendraPati Pandey
- Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, Haryana, India
| | - V. Samuel Raj
- Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, Haryana, India
| | - Venkata S. Sabbisetti
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Amrendra K. Ajay
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
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5
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Sholokh A, Klussmann E. Local cyclic adenosine monophosphate signalling cascades-Roles and targets in chronic kidney disease. Acta Physiol (Oxf) 2021; 232:e13641. [PMID: 33660401 DOI: 10.1111/apha.13641] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 12/20/2022]
Abstract
The molecular mechanisms underlying chronic kidney disease (CKD) are poorly understood and treatment options are limited, a situation underpinning the need for elucidating the causative molecular mechanisms and for identifying innovative treatment options. It is emerging that cyclic 3',5'-adenosine monophosphate (cAMP) signalling occurs in defined cellular compartments within nanometre dimensions in processes whose dysregulation is associated with CKD. cAMP compartmentalization is tightly controlled by a specific set of proteins, including A-kinase anchoring proteins (AKAPs) and phosphodiesterases (PDEs). AKAPs such as AKAP18, AKAP220, AKAP-Lbc and STUB1, and PDE4 coordinate arginine-vasopressin (AVP)-induced water reabsorption by collecting duct principal cells. However, hyperactivation of the AVP system is associated with kidney damage and CKD. Podocyte injury involves aberrant AKAP signalling. cAMP signalling in immune cells can be local and slow the progression of inflammatory processes typical for CKD. A major risk factor of CKD is hypertension. cAMP directs the release of the blood pressure regulator, renin, from juxtaglomerular cells, and plays a role in Na+ reabsorption through ENaC, NKCC2 and NCC in the kidney. Mutations in the cAMP hydrolysing PDE3A that cause lowering of cAMP lead to hypertension. Another major risk factor of CKD is diabetes mellitus. AKAP18 and AKAP150 and several PDEs are involved in insulin release. Despite the increasing amount of data, an understanding of functions of compartmentalized cAMP signalling with relevance for CKD is fragmentary. Uncovering functions will improve the understanding of physiological processes and identification of disease-relevant aberrations may guide towards new therapeutic concepts for the treatment of CKD.
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Affiliation(s)
- Anastasiia Sholokh
- Max‐Delbrück‐Center for Molecular Medicine (MDC) Helmholtz Association Berlin Germany
| | - Enno Klussmann
- Max‐Delbrück‐Center for Molecular Medicine (MDC) Helmholtz Association Berlin Germany
- DZHK (German Centre for Cardiovascular Research) Berlin Germany
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Abstract
BACKGROUND Acute coronary syndrome (ACS) is prevalent in continuous ambulatory peritoneal dialysis (CAPD) patients. However, the association between the apoprotein profile and ACS is not well known. Therefore, we aimed to investigate the relationship between apoproteins and ACS in CAPD patients. METHODS Eighty-one CAPD patients were included in this retrospective study. The primary endpoint was ACS. Predictors were baseline apoprotein levels, particularly the ratio of apoprotein A1 (Apo A1)/apoprotein B (Apo B). Cox regression was used to determine the relationship between Apo A1/Apo B and ACS. RESULTS During follow-up, 34 (41.98%) CAPD patients experienced an ACS. ACS patients had higher levels of total cholesterol (p = 0.03), low-density lipoprotein cholesterol (LDL-C) (p = 0.04), C-reactive protein (p = 0.01), and Apo B (p < 0.01). However, hemoglobin (p = 0.01) and Apo A1/Apo B (p < 0.01) were lower in the ACS group than the non-ACS group. Patients with Apo A1/Apo B ≥ 1.105 experienced fewer ACS compared with those with Apo A1/Apo B < 1.105 (33.33% vs. 75.56%, p = 0.03). In Cox regression, Apo A1/Apo B (RR, 0.06; 95% CI, 0.00-0.77; p = 0.03) was independently associated with ACS. CONCLUSIONS Apo A1/Apo B was strongly associated with ACS and may be considered as a predictor of future ACS in CAPD patients.
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Affiliation(s)
- Tianlei Chen
- Department of Nephrology, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, PR China
| | - Min Yang
- Department of Nephrology, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, PR China
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Li Q, Zheng D, Lin H, Zhong F, Liu J, Wu Y, Wang Z, Guan Q, Zhao M, Gao L, Zhao J. High Circulating Follicle-Stimulating Hormone Level Is a Potential Risk Factor for Renal Dysfunction in Post-Menopausal Women. Front Endocrinol (Lausanne) 2021; 12:627903. [PMID: 33868168 PMCID: PMC8047631 DOI: 10.3389/fendo.2021.627903] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 03/18/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Menopause contributes to renal dysfunction in women, which is generally attributed to estrogen withdrawal. In addition to decreased estrogen level, serum follicle-stimulating hormone (FSH) level increases after menopause. This study investigated the association between high circulating FSH level and renal function in post-menopausal women. METHODS This observational cross-sectional study included 624 pre-menopausal, 121 peri-menopausal, and 2540 post-menopausal women. The levels of female sex hormones were examined by chemiluminescence and indices of renal function were measured using a clinical chemistry analyzer. The post-menopausal women were grouped into quartiles according to serum FSH levels. RESULTS Renal function progressively declined from pre-menopause to peri-menopause to post-menopause, which was accompanied by increasing serum FSH level. In post-menopausal women, serum creatinine level increased with increasing FSH quartile, which was accompanied by a decrease in estimated glomerular filtration rate (eGFR) (p for trend <0.001); moreover, the prevalence of declined eGFR (<90 ml/min/1.73 m2) and chronic kidney disease (CKD; eGFR <60 ml/min/1.73 m2) increased (p for trend <0.001). Even after adjusting for confounders, the odds ratios (ORs) of declined eGFR and CKD increased with increasing FSH quartiles in post-menopausal women. The ORs of declined eGFR (OR=2.19, 95% confidence interval [CI]: 1.63-2.92) and CKD (OR=10.09, 95% CI: 2.28-44.65) in the highest FSH quartile were approximately 2- and 10-fold higher, respectively, than in the lowest FSH quartile (p<0.05). After stratifying post-menopausal women by median age (61 years), the OR for declined eGFR for each FSH quartile in the older group was higher than that for the corresponding FSH quartile in the younger group. CONCLUSIONS A high circulating FSH level is an independent risk factor for renal dysfunction in women after menopause. Additionally, aging may aggravate the association of high FSH levels with reduced renal function in post-menopausal women.
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Affiliation(s)
- Qihang Li
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Dongmei Zheng
- Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Haiyan Lin
- Health Management Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Fang Zhong
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Jing Liu
- Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yafei Wu
- Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhixiang Wang
- Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qingbo Guan
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Meng Zhao
- Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ling Gao
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Department of Scientific Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- *Correspondence: Jiajun Zhao,
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Andrianova NV, Zorova LD, Pevzner IB, Popkov VA, Chernikov VP, Silachev DN, Plotnikov EY, Zorov DB. Resemblance and differences in dietary restriction nephroprotective mechanisms in young and old rats. Aging (Albany NY) 2020; 12:18693-18715. [PMID: 32970613 PMCID: PMC7585108 DOI: 10.18632/aging.103960] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/21/2020] [Indexed: 01/24/2023]
Abstract
Dietary restriction (DR) is the strategy ameliorating the morbidity of various pathologies, including age-associated diseases. Acute kidney injury (AKI) remains a problem for the elderly with DR being a promising approach for diminishing its consequences. We evaluated the possible nephroprotective potential of short-term DR in young and old rats. DR in young rats resulted in pronounced beneficial effects normalizing lipid metabolism (triglycerides concentration, adiponectin level) activating autophagic-lysosomal system evaluated by LC3II/LC3I ratio, LAMP1, p62/SQSTM1 levels, and LysoTracker Green staining. DR had a remarkable recovering effect on mitochondrial structure and functions including regaining of mitochondrial membrane potential, the elevation of SIRT-3, PGC-1α, Bcl-XL levels and partial restoration of ultrastructure. The beneficial effects of DR resulted in the mitigation of oxidative stress including a decrease in levels of protein carbonylation and lipid peroxidation. Aging led to decreased activity of autophagy, elevated oxidative stress and impaired kidney regenerative capacity. Eventually, in old rats, even 8-week DR was not able to ameliorate AKI, but it caused some rejuvenating effects including elevation of mitochondrial membrane potential and Bcl-XL levels, as well as lowered severity of the oxidative stress. Thus, the age-associated decline of protective signaling demands extended DR to achieve nephroprotective potential in old animals.
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Affiliation(s)
- Nadezda V. Andrianova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119992, Russia
| | - Ljubava D. Zorova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia
| | - Irina B. Pevzner
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia
| | - Vasily A. Popkov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia
| | | | - Denis N. Silachev
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia
| | - Egor Y. Plotnikov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia,Sechenov First Moscow State Medical University, Institute of Molecular Medicine, Moscow 119991, Russia
| | - Dmitry B. Zorov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia
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9
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Machluf Y, Chaiter Y, Tal O. Gender medicine: Lessons from COVID-19 and other medical conditions for designing health policy. World J Clin Cases 2020; 8:3645-3668. [PMID: 32953842 PMCID: PMC7479575 DOI: 10.12998/wjcc.v8.i17.3645] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/29/2020] [Accepted: 08/12/2020] [Indexed: 02/05/2023] Open
Abstract
Gender-specific differences in the prevalence, incidence, comorbidities, prognosis, severity, risk factors, drug-related aspects and outcomes of various medical conditions are well documented. We present a literature review on the extent to which research in this field has developed over the years, and reveal gaps in gender-sensitive awareness between the clinical portrayal and the translation into gender-specific treatment regimens, guidelines and into gender-oriented preventive strategies and health policies. Subsequently, through the lens of gender, we describe these domains in detail for four selected medical conditions: Asthma, obesity and overweight, chronic kidney disease and coronavirus disease 2019. As some of the key gender differences become more apparent during adolescence, we focus on this developmental stage. Finally, we propose a model which is based on three influential issues: (1) Investigating gender-specific medical profiles of related health conditions, rather than a single disease; (2) The dynamics of gender disparities across developmental stages; and (3) An integrative approach which takes into account additional risk factors (ethnicity, socio-demographic variables, minorities, lifestyle habits etc.). Increasing the awareness of gender-specific medicine in daily practice and in tailored guidelines, already among adolescents, may reduce inequities, facilitate the prediction of future trends and properly address the characteristics and needs of certain subpopulations within each gender.
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Affiliation(s)
- Yossy Machluf
- Shamir Research Institute, University of Haifa, Kazerin 1290000, Israel
| | - Yoram Chaiter
- The Israeli Center for Emerging Technologies in Hospitals and Hospital-based Health Technology Assessment, Shamir (Assaf Harofeh) Medical Center, Zerifin 7030100, Israel
| | - Orna Tal
- The Israeli Center for Emerging Technologies in Hospitals and Hospital-based Health Technology Assessment, Shamir (Assaf Harofeh) Medical Center, Zerifin 7030100, Israel
- Shamir (Assaf Harofeh) Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Zerifin 7030100, Israel
- Department of Management, Program of Public Health and Health System Administration, Bar Ilan University, Ramat Gan 5290002, Israel
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10
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Li J, Yang Y, Wei S, Chen L, Xue L, Tian H, Tao S. Bixin Confers Prevention against Ureteral Obstruction-Caused Renal Interstitial Fibrosis through Activation of the Nuclear Factor Erythroid-2-Related Factor2 Pathway in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:8321-8329. [PMID: 32706966 DOI: 10.1021/acs.jafc.0c03674] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Bixin is a natural carotenoid isolated from the seeds of Bixa orellana, with numerous important pharmacological activities, including antioxidant and antifibrotic effects. The nuclear factor erythroid-2-related factor2 (Nrf2) signaling pathway induced by bixin is involved in the process. Excessive reactive oxygen species generation in tubular cells contributes to kidney interstitial fibrosis. The potential therapeutic strategy for bixin in alleviating kidney fibrosis remains largely unclear. In this study, we used unilateral ureteral obstruction (UUO) to establish a renal fibrotic model. Dramatic oxidative DNA damage occurs in kidneys, especially in tubular cells after UUO. In cultured tubular cells, bixin could induce Nrf2 signaling activation by suppressing Nrf2 ubiquitination and increasing its protein stability. Transforming growth factor beta 1-induced epithelial-to-mesenchymal transition (EMT) and extracellular matrix production were suppressed by bixin, and blockade of Nrf2 activation by small interfering RNA could largely reverse the protective effect of bixin. In vivo studies showed that administration of bixin induces Nrf2 signaling activation in tubular cells and markedly attenuates partial EMT of tubular cells and kidney interstitial fibrosis after subjecting to UUO. Together, this study implies that bixin may protect against kidney interstitial fibrosis through stimulating Nrf2 activation in renal tubular cells.
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Affiliation(s)
- Jianzhong Li
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Youjing Yang
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Shuhui Wei
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Ling Chen
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Lian Xue
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Hailin Tian
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Shasha Tao
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
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11
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Guo S, Sun J, Zhuang Y. Quercetin alleviates lipopolysaccharide-induced inflammatory responses by up-regulation miR-124 in human renal tubular epithelial cell line HK-2. Biofactors 2020; 46:402-410. [PMID: 31804760 DOI: 10.1002/biof.1596] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 11/22/2019] [Indexed: 12/15/2022]
Abstract
Chronic kidney disease (CKD) is a persistent kidney structural and functional disorder. Quercetin is one of active extracted flavonoids and has protective effects. Therefore, we proposed to survey the effect of Quercetin on CKD. HK-2 cells were preprocessed by Quercetin and then irritated with lipopolysaccharide (LPS). CCK-8 assay and flow cytometry were utilized to test viability and apoptosis. ELISA assay was utilized to estimate the IL-6 and TNF-α secretion. Western blot was performed to examine the expression of apoptosis and inflammation-associated mediators. After that HK-2 cells were transfected by miR-124 inhibitor. And the above-mentioned parameters were reassessed. LPS stimulated apoptosis and declined viability in HK-2 cells. Additionally, LPS stimulated inflammatory responses. Meanwhile, Quercetin attenuated LPS-stimulated apoptosis, production of IL-6, and TNF-α in experimental cells. Subsequently, MyD88 and miR-124 expression was elevated by LPS and alleviated by Quercetin. Finally, Quercetin exerted its protective function through NF-κB pathway via up-regulating miR-124. Our data demonstrated that Quercetin reduced apoptosis and inflammation stimulated by LPS in HK-2 cells. Moreover, Quercetin alleviated LPS-stimulated injury by up-regulating miR-124.
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Affiliation(s)
- Shuxia Guo
- Department of Nephrology, Linyi Central Hospital, Linyi, Shandong, China
| | - Juanjuan Sun
- Department of Nephrology, Linyi Central Hospital, Linyi, Shandong, China
| | - Yan Zhuang
- Department of Nephrology, Linyi Central Hospital, Linyi, Shandong, China
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12
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Bao N, Chen F, Dai D. The Regulation of Host Intestinal Microbiota by Polyphenols in the Development and Prevention of Chronic Kidney Disease. Front Immunol 2020; 10:2981. [PMID: 31969882 PMCID: PMC6960133 DOI: 10.3389/fimmu.2019.02981] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 12/04/2019] [Indexed: 12/13/2022] Open
Abstract
Polyphenols are essential antioxidants in our regular diet, and have shown potential antibacterial effects. Other important biological effects, such as anticancer or antibacterial activities, have been demonstrated by some polyphenols. In recent years, the benefits of polyphenols to human health have attracted increasing attention from the scientific community. Recent studies have shown that polyphenols such as anthocyanin, catechin, chlorogenic acid, and resveratrol can inhibit pathogenic bacteria such as Escherichia coli and Salmonella to help regulate intestinal microflora. An imbalance of intestinal microflora and the destruction of intestinal barrier function have been found to have a potential relationship with the occurrence of chronic kidney disease (CKD). Specifically, they can aberrantly trigger the immune system to cause inflammation, increase the production of uremic toxins, and further worsen the condition of CKD. Therefore, the maintenance of intestinal microflora and the intestinal tract in a stable and healthy state may be able to "immunize" patients against CKD, and treat pre-existing disease. The use of common antibiotics may lead to drug resistance in pathogens, and thus beneficial polyphenols may be suitable natural substitutes for antibiotics. Herein we review the ability of different polyphenols, such as anthocyanin, catechin, chlorogenic acid, and resveratrol, to regulate intestinal microorganisms, inhibit pathogenic bacteria, and improve inflammation. In addition, we review the ability of different polyphenols to reduce kidney injury, as described in recent studies.
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Affiliation(s)
- Naren Bao
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| | - Fangjie Chen
- Department of Medical Genetics, School of Life Sciences, China Medical University, Shenyang, China
| | - Di Dai
- Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, China
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13
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Notoginsenoside R1 protects human renal proximal tubular epithelial cells from lipopolysaccharide-stimulated inflammatory damage by up-regulation of miR-26a. Chem Biol Interact 2019; 308:364-371. [PMID: 31158334 DOI: 10.1016/j.cbi.2019.05.053] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 05/28/2019] [Accepted: 05/29/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND Notoginsenoside R1 (NGR1) is the main saponin isolated from the roots of Panax notoginseng (Burk.) F.H. Chen (Araliaceae). This study explored the protective effects of NGR1 on human renal proximal tubular epithelial cell inflammatory damage caused by lipopolysaccharide (LPS), as well as possible internal molecular mechanisms. METHODS Cell viability and apoptosis were assessed using CCK-8 assay and Annexin V-FITC/PI Apoptosis Detection kit, respectively. Reactive oxygen species (ROS) level was tested using DCFH-DA staining. qRT-PCR was used to measure microRNA-26a (miR-26a), interleukin 1β (IL-1β), IL-6 and tumor necrosis factor α (TNF-α) expressions. miRNA transfection was conducted to knock down miR-26a. The protein expression levels of key molecules related to cell apoptosis, inflammatory response and nuclear factor kappa B (NF-κB) pathway were detected using western blotting. RESULTS LPS stimulation caused human renal proximal tubular epithelial cell viability reduction, apoptosis and inflammatory cytokines expression. NGR1 treatment protected human renal proximal tubular epithelial cells from LPS-caused viability reduction, ROS level elevation, apoptosis and inflammatory cytokines expression. Mechanistically, NGR1 enhanced miR-26a expression in LPS-treated human renal proximal tubular epithelial cells. Knockdown of miR-26a reversed the protective effect of NGR1 on LPS-treated cells. Besides, NGR1 inactivated NF-κB pathway in LPS-treated human renal proximal tubular epithelial cells via up-regulating miR-26a. CONCLUSION NGR1 protected human renal proximal tubular epithelial cells from LPS-caused inflammatory damage at least partially via up-regulating miR-26a and then inactivating NF-κB pathway.
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El-Ghany SMA, El-Salam MA, Farag MM, El-Ashwah OA. Ocular Changes in Egyptian Children on Regular Hemodialysis. INTERNATIONAL JOURNAL OF CLINICAL MEDICINE 2019; 10:353-362. [DOI: 10.4236/ijcm.2019.106028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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15
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Xu MX, Qin YT, Ge CX, Gu TT, Lou DS, Li Q, Hu LF, Li YY, Yang WW, Tan J. Activated iRhom2 drives prolonged PM2.5 exposure-triggered renal injury in Nrf2-defective mice. Nanotoxicology 2018; 12:1045-1067. [DOI: 10.1080/17435390.2018.1513093] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Min-Xuan Xu
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China
- Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, PR China
| | - Yu-Ting Qin
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, PR China
| | - Chen-Xu Ge
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China
- Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, PR China
| | - Ting-Ting Gu
- College of Engineering and Applied Sciences, Nanjing University, Nanjing, PR China
| | - De-Shuai Lou
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China
- Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, PR China
| | - Qiang Li
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China
- Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, PR China
| | - Lin-Feng Hu
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China
- Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, PR China
| | - Yuan-Yuan Li
- School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, PR China
| | - Wei-Wei Yang
- Department of Nephrology, Huai’an First People’s Hospital, Nanjing Medical University, Nanjing, China
| | - Jun Tan
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China
- Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, PR China
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16
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Chironda G, Bhengu BR. Motivators of adherence to integrated management among patients with chronic kidney disease: A qualitative study. Nurs Health Sci 2018; 21:63-70. [DOI: 10.1111/nhs.12556] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Revised: 05/31/2018] [Accepted: 06/17/2018] [Indexed: 12/22/2022]
Affiliation(s)
- Geldine Chironda
- School of Nursing and Public Health; University of KwaZulu-Natal; Durban South Africa
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