Huangkui capsule in combination with metformin ameliorates diabetic nephropathy via the Klotho/TGF-β1/p38MAPK signaling pathway

Gu, Li-yuan; Yun-Sun,; Tang, Haitao; Xu, Zhengxin

doi:10.1016/j.jep.2020.113548

Cited by 27 publications

(23 citation statements)

References 48 publications

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“… 55 , 56 In addition, TGF-β pathway has been proposed to induce renal fibrosis through the expression of α-SMA. 57 , 58 Consistent with DN, the results obtained from this study demonstrated that the expression of TGF-β1, α-SMA, collagen-1and and fibronectin proteins were significantly upregulated in DN rats in contrast to the normal control rats and the administration of PCR displayed significant regulatory effects on the expression of these fibrosis-related biomarkers ( Figure 7 ). These results strongly suggested that PCR could improve renal fibrosis in DN model rats.…”

Section: Discussionsupporting

confidence: 72%

Antidiabetic and Nephroprotective Effects of Polysaccharide Extract from the Seaweed Caulerpa racemosa in High Fructose-Streptozotocin Induced Diabetic Nephropathy

Cao¹,

Li²,

Famurewa³

et al. 2021

DMSO

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Background: Nephropathy is a frontline complication of diabetes mellitus (DM) associated with impaired redox-inflammatory networks. The study investigated the antidiabetic and nephroprotective potentials of PCR against diabetic nephropathy (DN) in rats. Methods: DN was induced in rats using a combination of a high fructose solution for 4 weeks and an intraperitoneal injection of streptozotocin (35 mg/kg). Diabetic rats were treated with PCR (100 and 400 mg/kg body weight) for 8 weeks. Serum biochemical parameters as well as renal oxidative stress parameters, proinflammatory cytokines, Western blot and histopathological analyses were evaluated. Results: There were significant increases in fasting blood glucose, urinary albumin, serum creatinine, blood urea nitrogen (BUN), total cholesterol (TC), triglycerides (TG), and lowdensity lipoproteins (LDL-C) levels in diabetic rats compared to the non-diabetic control rats. DM-induced DN prominently depressed renal superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities, whereas renal malondialdehyde (MDA) level was markedly increased. Furthermore, renal inflammatory cytokines, IL-1β, IL-6, TNF-α and TGF-β, were considerably elevated compared to non-diabetic control rats. Additionally, DN rats showed a significant increase in renal fibrosis, as evidenced by increased expression of TGF-β1, collagen-1, fibronectin and alpha-smooth muscle actin (α-SMA) in the kidneys. Histopathological lesions were consistent with tubule thickening and glomerular hypertrophy. Conversely, PCR treatment exerted significant attenuation of hyperglycemia, dyslipidemia and renal oxidative stress indicators. The increased renal levels of IL-1β, IL-6, TNF-α and TGF-β were also notably reversed dose-dependently with alleviation of nephropathic histology. Furthermore, PCR reduced the expression of α-SMA, fibronectin, collagen-1 and TGF-β1 in the renal tissues. Conclusion:Our results suggest that PCR displayed antidiabetic and nephroprotective effects against DN by impeding oxidative stress and inflammation. As such, PCR has potentials as a food supplement for alleviating renal dysfunction caused by diabetes.

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Section: Discussionsupporting

confidence: 72%

Antidiabetic and Nephroprotective Effects of Polysaccharide Extract from the Seaweed Caulerpa racemosa in High Fructose-Streptozotocin Induced Diabetic Nephropathy

Cao¹,

Li²,

Famurewa³

et al. 2021

DMSO

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“…Similarly, the lower expression of MCP-1 and ICAM-1, which are inhibited by Klotho, reduced the accumulation of macrophages in the kidneys in animals with diabetic nephropathy and decreased tubulointerstitial injury after PKC-β inhibition by ruboxistaurin [8]. Additionally, in a rat model of streptozotocininduced diabetes-associated renal fibrosis, a combination of metformin and a plant extract (from Abelmoschus manihot (L.) medic), traditionally used against CKD, was proved to act in part via the Klotho/TGF-β1/p38MAPK signaling pathway and to significantly lower the weight of the rats with DN, reduce their blood glucose and urine protein level, and the degrees of renal tubule damage, apoptosis, glomerulopathy, and renal fibrosis [57]. A preservation of the Klotho level with simultaneous decrease in proteinuria in DN was also observed after administration of pentoxifylline in a phase 2 of the clinical trial [58].…”

Section: Klotho May Serve As a Key Molecule In Immunotherapy Of Diabetes And Diabetic Nephropathymentioning

confidence: 99%

Antiinflammatory Actions of Klotho: Implications for Therapy of Diabetic Nephropathy

Typiak

Piwkowska

2021

IJMS

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Klotho was initially introduced as an antiaging molecule. Klotho deficiency significantly reduces lifespan, and its overexpression extends it and protects against various pathological phenotypes, especially renal disease. It was shown to regulate phosphate and calcium metabolism, protect against oxidative stress, downregulate apoptosis, and have antiinflammatory and antifibrotic properties. The course of diabetes mellitus and diabetic nephropathy resembles premature cellular senescence and causes the activation of various proinflammatory and profibrotic processes. Klotho was shown to exert many beneficial effects in these disorders. The expression of Klotho protein is downregulated in early stages of inflammation and diabetic nephropathy by proinflammatory factors. Therefore, its therapeutic effects are diminished in this disorder. Significantly lower urine levels of Klotho may serve as an early biomarker of renal involvement in diabetes mellitus. Recombinant Klotho administration and Klotho overexpression may have immunotherapeutic potential for the treatment of both diabetes and diabetic nephropathy. Therefore, the current manuscript aims to characterize immunopathologies occurring in diabetes and diabetic nephropathy, and tries to match them with antiinflammatory actions of Klotho. It also gives reasons for Klotho to be used in diagnostics and immunotherapy of these disorders.

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“…A multicenter, randomized, open label clinical trial has showed that metformin and CHFs changed the gut microbiota composition of T2DM patients. Experiments in vivo and in vitro have validated that Huangkui capsules combined with metformin treatment effectively improved the weight, reduced blood glucose and ameliorated renal fibrosis via the Klotho/TGF-β1/p38 MAPK signalling pathway ( 28 ). Shin NR ( 63 ) mentioned that the Flos Lonicera, a bioactive component in CHFs, could modulate the gut microbial composition by reverting LPS-related pathways when combined with metformin.…”

Section: Discussionmentioning

confidence: 99%

“…Encouragingly, recent studies introduced the concept that metformin combined with CHFs had synergistic effects to improve the clinical efficacy of antidiabetic treatment for improving glucose and lipid metabolism through multiple pathways in line with reducing the associated adverse reactions ( 26 , 27 ). Huangkui capsules combined with metformin effectively improved diabetic nephropathy via the Klotho/TGF-β1/p38 MAPK signalling pathway ( 28 ). The application of Shenqi Jiangtang granules with metformin effectively controlled blood glucose and lipid levels, enhanced antioxidant capacity, and reduced the levels of inflammatory cytokines in gestational diabetes mellitus.…”

Section: Introductionmentioning

confidence: 99%

The effect of Chinese herbal formulas combined with metformin on modulating the gut microbiota in the amelioration of type 2 diabetes mellitus: A systematic review and meta-analysis

et al. 2022

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Huangkui capsule in combination with metformin ameliorates diabetic nephropathy via the Klotho/TGF-β1/p38MAPK signaling pathway

Cited by 27 publications

References 48 publications

Antidiabetic and Nephroprotective Effects of Polysaccharide Extract from the Seaweed Caulerpa racemosa in High Fructose-Streptozotocin Induced Diabetic Nephropathy

Antidiabetic and Nephroprotective Effects of Polysaccharide Extract from the Seaweed Caulerpa racemosa in High Fructose-Streptozotocin Induced Diabetic Nephropathy

Antiinflammatory Actions of Klotho: Implications for Therapy of Diabetic Nephropathy

The effect of Chinese herbal formulas combined with metformin on modulating the gut microbiota in the amelioration of type 2 diabetes mellitus: A systematic review and meta-analysis

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