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      Myricetin induces M2 macrophage polarization to alleviate renal tubulointerstitial fibrosis in diabetic nephropathy via PI3K/Akt pathway

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          Abstract

          BACKGROUND

          Development of end-stage renal disease is predominantly attributed to diabetic nephropathy (DN). Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue. Nevertheless, the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.

          AIM

          To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.

          METHODS

          Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk. Subsequently, blood and urine indexes were assessed, along with examination of renal tissue pathology. Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin, periodic acid–Schiff, Masson’s trichrome, and Sirius-red. Additionally, high-glucose culturing was conducted on the RAW 264.7 cell line, treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h. In both in vivo and in vitro settings, quantification of inflammation factor levels was conducted using western blotting, real-time qPCR and ELISA.

          RESULTS

          In db/db mice, administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis. Notably, we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin, along with a decrease in expressions of inflammatory cytokine-related factors. Furthermore, myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha, interleukin-6, and interluekin-1β induced by high glucose in RAW 264.7 cells. Additionally, myricetin modulated the M1-type polarization of the RAW 264.7 cells. Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin. The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.

          CONCLUSION

          This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.

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          Most cited references60

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          Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association: national cross sectional study

          Abstract Objective To assess the prevalence of diabetes and its risk factors. Design Population based, cross sectional study. Setting 31 provinces in mainland China with nationally representative cross sectional data from 2015 to 2017. Participants 75 880 participants aged 18 and older—a nationally representative sample of the mainland Chinese population. Main outcome measures Prevalence of diabetes among adults living in China, and the prevalence by sex, regions, and ethnic groups, estimated by the 2018 American Diabetes Association (ADA) and the World Health Organization diagnostic criteria. Demographic characteristics, lifestyle, and history of disease were recorded by participants on a questionnaire. Anthropometric and clinical assessments were made of serum concentrations of fasting plasma glucose (one measurement), two hour plasma glucose, and glycated haemoglobin (HbA1c). Results The weighted prevalence of total diabetes (n=9772), self-reported diabetes (n=4464), newly diagnosed diabetes (n=5308), and prediabetes (n=27 230) diagnosed by the ADA criteria were 12.8% (95% confidence interval 12.0% to 13.6%), 6.0% (5.4% to 6.7%), 6.8% (6.1% to 7.4%), and 35.2% (33.5% to 37.0%), respectively, among adults living in China. The weighted prevalence of total diabetes was higher among adults aged 50 and older and among men. The prevalence of total diabetes in 31 provinces ranged from 6.2% in Guizhou to 19.9% in Inner Mongolia. Han ethnicity had the highest prevalence of diabetes (12.8%) and Hui ethnicity had the lowest (6.3%) among five investigated ethnicities. The weighted prevalence of total diabetes (n=8385) using the WHO criteria was 11.2% (95% confidence interval 10.5% to 11.9%). Conclusion The prevalence of diabetes has increased slightly from 2007 to 2017 among adults living in China. The findings indicate that diabetes is an important public health problem in China.
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            Global estimates of diabetes prevalence for 2013 and projections for 2035.

            Diabetes is a serious and increasing global health burden and estimates of prevalence are essential for appropriate allocation of resources and monitoring of trends. We conducted a literature search of studies reporting the age-specific prevalence for diabetes and used the Analytic Hierarchy Process to systematically select studies to generate estimates for 219 countries and territories. Estimates for countries without available source data were modelled from pooled estimates of countries that were similar in regard to geography, ethnicity, and economic development. Logistic regression was applied to generate smoothed age-specific prevalence estimates for adults 20-79 years which were then applied to population estimates for 2013 and 2035. A total of 744 data sources were considered and 174 included, representing 130 countries. In 2013, 382 million people had diabetes; this number is expected to rise to 592 million by 2035. Most people with diabetes live in low- and middle-income countries and these will experience the greatest increase in cases of diabetes over the next 22 years. The new estimates of diabetes in adults confirm the large burden of diabetes, especially in developing countries. Estimates will be updated annually including the most recent, high-quality data available. Copyright © 2013. Published by Elsevier Ireland Ltd.
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              Molecular Mechanisms That Influence the Macrophage M1–M2 Polarization Balance

              As an essential component of innate immunity, macrophages have multiple functions in both inhibiting or promoting cell proliferation and tissue repair. Diversity and plasticity are hallmarks of macrophages. Classical M1 and alternative M2 activation of macrophages, mirroring the Th1–Th2 polarization of T cells, represent two extremes of a dynamic changing state of macrophage activation. M1-type macrophages release cytokines that inhibit the proliferation of surrounding cells and damage contiguous tissue, and M2-type macrophages release cytokines that promote the proliferation of contiguous cells and tissue repair. M1–M2 polarization of macrophage is a tightly controlled process entailing a set of signaling pathways, transcriptional and posttranscriptional regulatory networks. An imbalance of macrophage M1–M2 polarization is often associated with various diseases or inflammatory conditions. Therefore, identification of the molecules associated with the dynamic changes of macrophage polarization and understanding their interactions is crucial for elucidating the molecular basis of disease progression and designing novel macrophage-mediated therapeutic strategies.
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                Author and article information

                Contributors
                Journal
                World J Diabetes
                WJD
                World Journal of Diabetes
                Baishideng Publishing Group Inc
                1948-9358
                15 January 2024
                15 January 2024
                : 15
                : 1
                : 105-125
                Affiliations
                Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
                Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
                Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
                Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
                Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
                Department of Pharmacy, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
                Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
                Department of Pneumology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
                Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China. yujiangyi2007@ 123456163.com
                Author notes

                Co-first authors: Wei-Long Xu and Pei-Pei Zhou.

                Co-corresponding authors: Xiao Wu and Jiang-Yi Yu.

                Author contributions: Xu WL and Yu JY designed the study; Xu WL and Zhou PP carried out the experiments; Tian T, Yu X, and Bao JJ contributed experiment assistance; Yu X, Bao JJ, and Zha M analyzed the data; Xu WL and Zhou PP generated the figures; Ni CR donated the myricetin natural product; Xu WL, Zhou PP, Yu JY, and Wu X drafted and revised the manuscript; Yu JY and Wu X conceived and supervised the study; All authors approved the final version of the article. Xu WL and Zhou PP contributed equally to this work as co-first authors. Xu WL and Zhou PP together completed the chief experiments, formation of figures, and writing of initial manuscript, which were the most important and indispensable part of this study. Especially, Xu WL designed the study. Yu JY and Wu X contributed equally to this work as co-corresponding authors. Yu JY and Wu X revised the manuscript, conceived and supervised the study to make the study better presented. Especially, Yu JY provided enough financial support in the progress of experiments and ensured all the journal’s administrative requirements.

                Supported by National Natural Science Foundation of China, No. 82205025, No. 82374355 and No. 82174293; Subject of Jiangsu Province Hospital of Chinese Medicine, No. Y21023; and Forth Batch of Construction Program for Inheritance Office of Jiangsu Province Famous TCM Experts , No. [2021]7.

                Corresponding author: Jiang-Yi Yu, MD, Chief Doctor, Chief Physician, Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Qinhuai District, Nanjing 210000, Jiangsu Province, China. yujiangyi2007@ 123456163.com

                Article
                jWJD.v15.i1.pg105 88708
                10.4239/wjd.v15.i1.105
                10835493
                38313853
                83386a88-5f3e-4c25-a1ae-95de1b8f3fec
                ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                : 6 October 2023
                : 28 November 2023
                : 15 December 2023
                Categories
                Basic Study

                myricetin,diabetic nephropathy,pi3k/akt pathway,renal tubulointerstitial fibrosis,macrophage,polarization

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