Renal protective effect and action mechanism of Huangkui capsule and its main five flavonoids

Cai, Hong-Die; Su, Shulan; Qian, Dawei; Guo, Sheng; Tao, Weiwei; Cong, Xu Dong; Tang, Renmao; Duan, Jin‐Ao

doi:10.1016/j.jep.2017.02.046

Cited by 53 publications

(41 citation statements)

References 21 publications

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“…HKC and its bioactive component hyperoside (HYP) can ameliorate proteinuria and renal dysfunction for patients and animal models with the early chronic kidney disease (CKD) (Chen et al, 2015 ; Ge et al, 2016 ). Recently, the increasing clinical evidences in China have been suggested that HKC at the safe and effective dose of 7.5 g/kg/day can reduce micro-urinary albumin (micro-UAlb) in the early DN patients and the IgA nephropathy patients (Liu et al, 2010 ; Li et al, 2017 ), and that its therapeutic action may be concerned with regulating transforming growth factor-β1 (TGF-β1) signaling in vivo (Tu et al, 2013 ), and inhibiting high-glucose (HG)-induced renal tubular epithelial-mesenchymal transition in vitro (Cai et al, 2017 ). In addition, our previous animal experiment as the first step revealed that, after the drug-intervention for 8 weeks, 2 g/kg/day dose of HKC can significantly attenuate the advanced renal fibrosis in the DN model rats induced by the unilateral nephrectomy combined with the intraperitoneal injection of streptozotocin (STZ) through regulating oxidative stress and p38 mitogen-activated protein kinase/Akt pathways (Mao et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Akt/mTOR/p70S6K Signaling Activity With Huangkui Capsule Alleviates the Early Glomerular Pathological Changes in Diabetic Nephropathy

Han

et al. 2018

Front. Pharmacol.

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Huangkui capsule (HKC), a Chinese modern patent medicine extracted from Abelmoschus manihot (L.) medic, has been widely applied to clinical therapy in the early diabetic nephropathy (DN) patients. However, it remains elusive whether HKC can ameliorate the inchoate glomerular injuries in hyperglycemia. Recently the activation of phosphatidylinositol-3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of rapamycin (mTOR) signaling and its downstream regulator, 70-kDa ribosomal protein S6 kinase (p70S6K), play important roles in the early glomerular pathological changes of DN including glomerular hypertrophy, glomerular basement membrane (GBM) thickening and mild mesangial expansion. This study thereby aimed to clarify therapeutic effects of HKC during the initial phase of DN and its underlying mechanisms. Fifteen rats were randomly divided into 3 groups: the normal group, the model group and the HKC group. The early DN model rats were induced by unilateral nephrectomy combined with intraperitoneal injection of streptozotocin, and administered with either HKC suspension or vehicle after modeling and for a period of 4 weeks. Changes in the incipient glomerular lesions-related parameters in urine and blood were analyzed. Kidneys were isolated for histomorphometry, immunohistochemistry, immunofluorescence and Western blotting (WB) at sacrifice. In vitro, murine mesangial cells (MCs) were used to investigate inhibitory actions of hyperoside (HYP), a bioactive component of HKC, on cellular hypertrophy-associated signaling pathway by WB, compared with rapamycin (RAP). For the early DN model rats, HKC ameliorated micro-urinary albumin, body weight and serum albumin, but had no significant effects on renal function and liver enzymes; HKC improved renal shape, kidney weight and kidney hypertrophy index; HKC attenuated glomerular hypertrophy, GBM thickening and mild mesangial expansion; HKC inhibited the phosphorylation of Akt, mTOR and p70S6K, and the protein over-expression of transforming growth factor-β1 in kidneys. In vitro, the phosphorylation of PI3K, Akt, mTOR and p70S6K in MCs induced by high-glucose was abrogated by treatment of HYP or RAP. On the whole, this study further demonstrated HKC safely and efficiently alleviates the early glomerular pathological changes of DN, likely by inhibiting Akt/mTOR/p70S6K signaling activity in vivo and in vitro, and provided the first evidence that HKC directly contributes to the prevention of the early DN.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Akt/mTOR/p70S6K Signaling Activity With Huangkui Capsule Alleviates the Early Glomerular Pathological Changes in Diabetic Nephropathy

Han

et al. 2018

Front. Pharmacol.

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“…Phytochemical investigations showed the main bioactive components of HKC; namely, quercetin, quercetin-3′- O -glucoside, isoquercitrin, and hyperoside. In particular, gossypetin-8- O -β-D-glucuronide, at a concentration of 100 µM, significantly inhibited the protein expression of α-smooth muscle actin, p-ERK1/2, NOX-1, NOX-2, and NOX-4 in HK-2 cells induced by high glucose levels in the same way as the NOX inhibitor diphenyleneiodonium ( Cai et al., 2017a ). These in vivo and in vitro results suggest that HKC and its major flavonoid components protect against tubulointerstitial fibrosis in rats with chronic renal failure by suppressing the NOX/reactive oxygen species (ROS)/ERK signaling pathway.…”

Section: Pharmacological Activitiesmentioning

confidence: 85%

“…HKC (at a dose of 0.75 g/kg [i.g.] for 28 days) significantly decreased the levels of BUN, serum creatinine, and urine protein in plasma, and molecular mechanisms demonstrated that HKC notably downregulated the protein expression of NADPH oxidase (NOX)-1, NOX-2, NOX-4, α-smooth muscle actin (α-SMA), and p-extracellular signal-regulated kinase (ERK) 1/2 by inhibiting the NADPH oxidase/ROS/ERK signaling pathways in renal tissue in rats with chronic renal failure induced by adenine in vivo ( Cai et al., 2017a ). Phytochemical investigations showed the main bioactive components of HKC; namely, quercetin, quercetin-3′- O -glucoside, isoquercitrin, and hyperoside.…”

Section: Pharmacological Activitiesmentioning

confidence: 99%

“…For hundreds of years, A. manihot has been widely used as a folk medicine in clinical practice in China to cure forms of chronic kidney disease (CKD) and exerts significant effects by decreasing the protein content in urine and protecting kidney function ( Peng et al., 2010 ; Wang and Gao, 2010 ; Zhu and Bi, 2010 ; Tsumbu et al., 2012 ). According to the Compendium of Materia Medica , a famous classical book of Chinese materia medica compiled by Shizhen Li (1518–1593 CE), the flowers of A. manihot have been recorded as an effective herb to treat malignant sores, cellulitis, and burns ( Jiang et al., 2012 ; Cai et al., 2017a ; Hou et al., 2020 ). Importantly, A. manihot flowers are listed in the 2015 edition of the Pharmacopoeia of the People’s Republic of China (a.k.a.…”

Section: Introductionmentioning

confidence: 99%

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Traditional Uses, Chemical Constituents, Biological Properties, Clinical Settings, and Toxicities of Abelmoschus manihot L.: A Comprehensive Review

Luan

Wu²,

Yang

et al. 2020

Front. Pharmacol.

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Abelmoschus manihot , an annual herbal flowering plant, is widely distributed throughout eastern Europe and in temperate and subtropical regions of Asia. Its flowers have been traditionally used for the treatment of chronic kidney disease in China. Currently, more than 128 phytochemical ingredients have been obtained and identified from the flowers, seeds, stems, and leaves of A. manihot . The primary components are flavonoids, amino acids, nucleosides, polysaccharides, organic acids, steroids, and volatile oils. A. manihot and its bioactive constituents possess a plethora of biological properties, including antidiabetic nephropathy, antioxidant, antiadipogenic, anti-inflammatory, analgesic, anticonvulsant, antidepressant, antiviral, antitumor, cardioprotective, antiplatelet, neuroprotective, immunomodulatory, and hepatoprotective activities, and have effects on cerebral infarction, bone loss, etc. However, insufficient utilization and excessive waste have already led to a rapid reduction of resources, meaning that a study on the sustainable use of A. manihot is urgent and necessary. Moreover, the major biologically active constituents and the mechanisms of action of the flowers have yet to be elucidated. The present paper provides an early and comprehensive review of the traditional uses, chemical constituents, pharmacological activities, and pharmaceutical, quality control, toxicological, and clinical settings to emphasize the benefits of this plant and lays a solid foundation for further development of A. manihot .

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“…Activated ERK can promote nuclear transport of its downstream transcription factors such as c-Myc, c-Ets, and CREB, which in turn improves the transcription of the corresponding target genes [15,16]. A previous study demonstrated that hyperoside could prevent HG-induced epithelial-mesenchymal transition via the inhibition of ERK1/2 activation in human kidney proximal tubule epithelial cells [17].…”

Section: Introductionmentioning

confidence: 98%

Hyperoside Alleviates High Glucose-Induced Proliferation of Mesangial Cells through the Inhibition of the ERK/CREB/miRNA-34a Signaling Pathway

Zhang

Dai

et al. 2020

International Journal of Endocrinology

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Purpose. Hyperoside, a flavonoid isolated from conventional medicinal herbs, has been demonstrated to exert a significant protective effect in diabetic nephropathy. This study aimed to determine the underlying mechanisms, by which hyperoside inhibits high glucose-(HG-) induced proliferation in mouse renal mesangial cells. Methods. Mouse glomerular mesangial cells line (SV40-MES13) was used to study the inhibitory effect of hyperoside on cell proliferation induced by 30 mM glucose, which was used to simulate a diabetic condition. Viable cell count was assessed using the Cell Counting Kit-8 and by the 5-ethynyl-20-deoxyuridine incorporation assay. The underlying mechanism involving miRNA-34a was further investigated by quantitative RT-PCR and transfection with miRNA-34a agomir. The phosphorylation levels of extracellular signal-regulated kinases (ERKs) and cAMP-response element-binding protein (CREB) were measured by Western blotting. The binding region and the critical binding sites of CREB in the miRNA-34a promoter were investigated by the chromatin immunoprecipitation assay and luciferase reporter assay, respectively. Results. We found that hyperoside could significantly decrease HG-induced proliferation of SV40-MES13 cells in a dose-dependent manner, without causing obvious cell death. In addition, hyperoside inhibited the activation of ERK pathway and phosphorylation of its downstream transcriptional factor CREB, as well as the miRNA-34a expression. We further confirmed that CREB-mediated regulation of miRNA-34a is dependent on the direct binding to specific sites in the promoter region of miRNA-34a. Conclusion. Our cumulative results suggested that hyperoside inhibits the proliferation of SV40-MES13 cells through the suppression of the ERK/CREB/miRNA-34a signaling pathway, which provides new insight to the current investigation on therapeutic strategies for diabetic nephropathy.

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Renal protective effect and action mechanism of Huangkui capsule and its main five flavonoids

Cited by 53 publications

References 21 publications

Inhibition of Akt/mTOR/p70S6K Signaling Activity With Huangkui Capsule Alleviates the Early Glomerular Pathological Changes in Diabetic Nephropathy

Inhibition of Akt/mTOR/p70S6K Signaling Activity With Huangkui Capsule Alleviates the Early Glomerular Pathological Changes in Diabetic Nephropathy

Traditional Uses, Chemical Constituents, Biological Properties, Clinical Settings, and Toxicities of Abelmoschus manihot L.: A Comprehensive Review

Hyperoside Alleviates High Glucose-Induced Proliferation of Mesangial Cells through the Inhibition of the ERK/CREB/miRNA-34a Signaling Pathway

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