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      Puerarin alleviates apoptosis and inflammation in kidney stone cells via the PI3K/AKT pathway: Network pharmacology and experimental verification

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          Abstract

          Puerarin(PUE), an isoflavonoid extracted from Pueraria root, has anti‐apoptotic effects. The objective of this research is to examine the impact of PUE on renal apoptosis and inflammation resulting from renal calculi and to elucidate its mechanism. The approach of network pharmacology and molecular docking was employed to discover potential targets and pathways of PUE. An animal model of calcium oxalate crystal deposition by intraperitoneal injection of glyoxylate and a model of COM‐induced human renal tubular epithelial cells (HK2) were used to investigate the pharmacological mechanisms of PUE against apoptosis and inflammation. We used haematoxylin–eosin (H&E) and Periodic Acid‐Schiff staining (PAS) to assess the effect of PUE on crystal deposition and damage. The mechanism of PUE was elucidated and validated using Western blotting, histology and immunohistochemical staining. Network pharmacology findings indicated that the PI3K/AKT pathway plays a crucial role in PUE. We experimentally demonstrate that PUE alleviated COM‐induced changes in apoptotic proteins, increased inflammatory indicators and changes in oxidative stress‐related indicators in HK2 cells by activating the PI3K/AKT pathway, reduced serum creatinine and urea nitrogen levels in mice caused by CaOx, alleviated crystal deposition and damage, and alleviated apoptosis, oxidative stress and inflammation. Puerarin attenuates renal apoptosis and inflammation caused by kidney stones through the PI3K/AKT pathway.

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          Free radicals in the physiological control of cell function.

          At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, however, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and reestablish "redox homeostasis." Higher organisms, however, have evolved the use of NO and ROS also as signaling molecules for other physiological functions. These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. In a given signaling protein, oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. Excessive amounts of ROS may arise either from excessive stimulation of NAD(P)H oxidases or from less well-regulated sources such as the mitochondrial electron-transport chain. In mitochondria, ROS are generated as undesirable side products of the oxidative energy metabolism. An excessive and/or sustained increase in ROS production has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and other diseases. In addition, free radicals have been implicated in the mechanism of senescence. That the process of aging may result, at least in part, from radical-mediated oxidative damage was proposed more than 40 years ago by Harman (J Gerontol 11: 298-300, 1956). There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
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            Prevalence of kidney stones in the United States.

            The last nationally representative assessment of kidney stone prevalence in the United States occurred in 1994. After a 13-yr hiatus, the National Health and Nutrition Examination Survey (NHANES) reinitiated data collection regarding kidney stone history. Describe the current prevalence of stone disease in the United States, and identify factors associated with a history of kidney stones. A cross-sectional analysis of responses to the 2007-2010 NHANES (n=12 110). Self-reported history of kidney stones. Percent prevalence was calculated and multivariable models were used to identify factors associated with a history of kidney stones. The prevalence of kidney stones was 8.8% (95% confidence interval [CI], 8.1-9.5). Among men, the prevalence of stones was 10.6% (95% CI, 9.4-11.9), compared with 7.1% (95% CI, 6.4-7.8) among women. Kidney stones were more common among obese than normal-weight individuals (11.2% [95% CI, 10.0-12.3] compared with 6.1% [95% CI, 4.8-7.4], respectively; p<0.001). Black, non-Hispanic and Hispanic individuals were less likely to report a history of stone disease than were white, non-Hispanic individuals (black, non-Hispanic: odds ratio [OR]: 0.37 [95% CI, 0.28-0.49], p<0.001; Hispanic: OR: 0.60 [95% CI, 0.49-0.73], p<0.001). Obesity and diabetes were strongly associated with a history of kidney stones in multivariable models. The cross-sectional survey design limits causal inference regarding potential risk factors for kidney stones. Kidney stones affect approximately 1 in 11 people in the United States. These data represent a marked increase in stone disease compared with the NHANES III cohort, particularly in black, non-Hispanic and Hispanic individuals. Diet and lifestyle factors likely play an important role in the changing epidemiology of kidney stones. Published by Elsevier B.V.
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              Kidney stones.

              Kidney stones are mineral deposits in the renal calyces and pelvis that are found free or attached to the renal papillae. They contain crystalline and organic components and are formed when the urine becomes supersaturated with respect to a mineral. Calcium oxalate is the main constituent of most stones, many of which form on a foundation of calcium phosphate called Randall's plaques, which are present on the renal papillary surface. Stone formation is highly prevalent, with rates of up to 14.8% and increasing, and a recurrence rate of up to 50% within the first 5 years of the initial stone episode. Obesity, diabetes, hypertension and metabolic syndrome are considered risk factors for stone formation, which, in turn, can lead to hypertension, chronic kidney disease and end-stage renal disease. Management of symptomatic kidney stones has evolved from open surgical lithotomy to minimally invasive endourological treatments leading to a reduction in patient morbidity, improved stone-free rates and better quality of life. Prevention of recurrence requires behavioural and nutritional interventions, as well as pharmacological treatments that are specific for the type of stone. There is a great need for recurrence prevention that requires a better understanding of the mechanisms involved in stone formation to facilitate the development of more-effective drugs.
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                Author and article information

                Contributors
                526545298@qq.com
                binggoaza@163.com
                haozongyao@ahmu.edu.cn
                Journal
                J Cell Mol Med
                J Cell Mol Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                27 October 2024
                October 2024
                : 28
                : 20 ( doiID: 10.1111/jcmm.v28.20 )
                : e70180
                Affiliations
                [ 1 ] Department of Urology The First Affiliated Hospital of Anhui Medical University Hefei China
                [ 2 ] Institute of Urology Anhui Medical University Hefei China
                [ 3 ] Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation Anhui Medical University Hefei China
                Author notes
                [*] [* ] Correspondence

                Yang Chen, Bingbing Hou and Zongyao Hao, Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

                Email: binggoaza@ 123456163.com ; 526545298@ 123456qq.com and haozongyao@ 123456ahmu.edu.cn

                Author information
                https://orcid.org/0000-0003-0986-5505
                Article
                JCMM70180 JCMM-06-2024-150.R1
                10.1111/jcmm.70180
                11512754
                39462270
                4fe43339-166f-4a7e-a6c2-c2f6d85d7c3c
                © 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 17 September 2024
                : 05 July 2024
                : 17 October 2024
                Page count
                Figures: 8, Tables: 2, Pages: 15, Words: 6600
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 82070724
                Award ID: 82370768
                Categories
                Original Article
                Original Article
                Custom metadata
                2.0
                October 2024
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.4.9 mode:remove_FC converted:27.10.2024

                Molecular medicine
                apoptosis,kidney stone,network pharmacology,puerarin
                Molecular medicine
                apoptosis, kidney stone, network pharmacology, puerarin

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