OBJECTIVE Diabetic nephropathy(DN)has been one of the most common complications of diabetes and the leading cause of end-stage renal disease.Glomerular hyperfiltrationis central in earlystage of DN and leads to the pr...OBJECTIVE Diabetic nephropathy(DN)has been one of the most common complications of diabetes and the leading cause of end-stage renal disease.Glomerular hyperfiltrationis central in earlystage of DN and leads to the progression of renal architectonic and functional abnormalities.Salvianolic acid A(SalA)has been proved to protect diabetic complications such as hepatic fibrosis and neuropathy.The present study was designed to investigate the effects of SalA on glomerular endothelial dysfunctionand diabetic nephropathy.METHODS Primary glomerular endothelial cells were subjected to assess permeability under injury of advanced glycation end-products(AGEs).AGEs-induced changes of Rho A/ROCK pathway and cytoskeleton rearrangement were assessed bywestern blotandimmunofluorescence.The beneficial effects of SalA on diabetic nephropathy were investigated in a rat model induced by high-fat and high-glucose diet combined with low dose of streptozocin(35 mg·kg^(-1),ip).Renal function and architectonic changes were evaluated by biochemical assay and PAS staining.RESULTS SalA 3μMameliorated AGEs-induced glomerular endothelial permeability(P<0.05)and suppressed rearrangement of cytoskeleton through inhibiting AGE-RAGE-Rho A/ROCK pathway.SalA1 mg·kg^(-1)markedly reduced endothelium loss(P<0.01)and glomerular hyperfiltration(P<0.05)in diabetic kidney.Subsequently,SalA 1 mg·kg^(-1) suppressed glomerular hypertrophy and mesangial matrix expansion,eventually reduced 24 h-urinary albumin and ameliorated renal function by decreasing blood urine nitrogen(BUN),serum creatinine(Scr)and serum n-acetyl-β-d-glucosaminidase(NAG).AGEs-RAGE-Nox4-induced oxidative stress was suppressed by the treatment of SalA 1 mg·kg^(-1).CONCLUSION SalA ameliorated AGEs-induced glomerular endothelial hyperpermeability,and effectively protected against early-stage diabetic nephropathy by reducing hyperfiltration and alleviating renal structural deterioration through inhibiting AGEs and its downstream pathway.Thus,SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.展开更多
Diabetic nephropathy(DN)is one of the most common complications of diabetes.It is an important cause of diabetes disability and death.DN is a systemic metabolic syndrome.In its pathogenesis,the interaction of various ...Diabetic nephropathy(DN)is one of the most common complications of diabetes.It is an important cause of diabetes disability and death.DN is a systemic metabolic syndrome.In its pathogenesis,the interaction of various cell activities and a large number of cytokine biological activities,the activation of signal pathways and so on are involved in the development of DN.At present,the clinical treatment of DN is mainly Western medicine,but it has limitations such as strong toxicity,high side effects and poor compliance.Therefore,the discovery of natural anti-DN substances has also become an important means to treat DN.Mulberry leaves are the dry leaves of Morus alba L.It is not only a traditional Chinese medicine,but also a dual-purpose medicinal material for medicine and food.It has the effects of dispelling wind and clearing heat,cooling blood and brightening eyes,tonifying and so on.Mulberry leaf polysaccharide(MLP)is a kind of high molecular compound in mulberry leaves.It has many pharmacological effects,such as hypoglycemic,antioxidant,anti-stress,anti-virus and so on.Therefore,the pharmacological effects of mulberry leaf polysaccharides on diabetic nephropathy are reviewed in this paper,so as to provide references for further research and application.The pathogenesis of DN is complex,and the mechanism of renal injury has not been completely clarified.The current studies believe that DN is closely related to heredity,abnormal glucose metabolism,abnormal lipid metabolism,microcirculation disorder,cytokine action,oxidative stress and so on.Relevant studies show that the pharmacological effects of mulberry leaf polysaccharide in the prevention and treatment of DN mainly include:①Effect on transforming factor-β1(TGF-β1):TGF-β1 has become an important cytokine involved in the formation of renal fibrosis by regulating cell proliferation and differentiation and the production of extracellular matrix(ECM).MLP can significantly inhibit TGF-β1 protein,and then inhibit the synthesis of extracellular matrix by renal interstitial fibroblasts and inhibit the realization of fibrosis.②Effect on insulin receptor substrate(IRS-1):IRS-1 is an important signal molecule at the beginning of IR signal transduction.The decrease of IRS-1 gene expression or the decrease of expression can affect the effective transmission of IR signal and lead to the development and deterioration of diabetes. MPL can significantly increase the expression of IRS-1 mRNA in liver tissue of DN rats, so as to prevent and treat DN. ③ Effect on the expression of resistin protein in adipose tis sue. Resistin is a secretory polypeptide derived from adipose tissue and is specifically expressed in white adipose tissue and is closely related to type 2 diabetes mellitus (T2DM). Experimental studies show that MLP can effectively reduce the expression of resistin protein in white adipose tissue of T2DM rats, indicating that MLP may reduce the level of IR by inhibiting the expression of resistin in adipose tissue, thereby reducing the insulin resistance state of T2DM rats, so as to achieve the goal of treating diabetes. ④ Effect on adiponectin receptor 1 (AdipoR1): adiponectin can improve insulin resistance, reduce blood glucose and lipid. AdipoR1 is mainly expressed in skeletal muscle and kidney. Studies have shown that AdipoR1 is closely related to the occurrence and development of DN. The results showed that MLP could reduce the blood glucose and blood lipid level and up regulate the expression of AdipoR1 mRNA in DN rats, suggesting that MLP may delay the occurrence and development of DN. This article reviewed the pharmacological effects of mulberry leaf polysaccharides on diabetic nephropathy, and provided a useful basis for further development and utilization of mul berry leaf polysaccharides in the treatment of DN.展开更多
OBJECTIVE To investigate possible protective effect of berberine,an isoquinoline alkaloid,is the major active constituent of Rhizoma coptidis and Cortex phellodendri,on high-fat diet/streptozotocin-induced early diabe...OBJECTIVE To investigate possible protective effect of berberine,an isoquinoline alkaloid,is the major active constituent of Rhizoma coptidis and Cortex phellodendri,on high-fat diet/streptozotocin-induced early diabetic nephropathy in rats and various mechanisms underlie this effect.METHODS The diabetic rat model was generated by a single intraperitoneal injection of streptozotocin(STZ,50 mg·kg-1).Diabetic rats were randomlyassigned into the following five groups:control,DN,losartan(30 mg·kg-1·d-1),berberine(100,200 mg·kg-1·d-1).Berberine and losartan were given intragastricly for nine weeks.At the end of the experiment,urine of each group was collected in a 24 h period.Rats were weighed and then sacrificed.Plasma and kidneys were collected.The levels of blood glucose,creatinine(Cr),triglycerides(TG),total cholesterol(TCH)and malondialdehyde(MDA)in serum were determined using commercial kits according to the manufacturer′s instructions.Transforming growth factor(TGF)-β1and intracellular adhesion molecule-1(IAM-1)mR NA levels were evaluated by RT-PCR.The renal histopathology was observed by light microscopy.Further biochemical analysis of IKKβ1 and p65(nucleus/cytoplasm)was provided using Western blotting techniques.RESULTS Our study has demonstrated that berberine has various pharmacological activities.The DN rats had significantly higher kidney/body weight ratio(17.4±1.4)mg·g-1,and berberine treatment could reduce this ratio change 13.6±0.6 and(11.6±0.8)mg·g-1,respectively;glucose control still remains the only disease-modifying therapy for diabetic complications,FBG was also recorded in the experiment.The findings reveal that the DN group showed a significantly higher glucose level(28.67±2.78)mmol·L-1.Treatment with8 weeks of berberine improved these parameters except blood glucose〔(18.67±2.59)mmol·L-1and 16.45±1.80 vs(28.67±2.78)mmol·L-1:plasma levels of urea nitrogen(15.67±2.48)mmol·L-1and 14.45±2.40 vs(12.26±2.40)mmol·L-1〕;plasma levels of 24 h urine albuminuria〔30.48±1.56 and 25.72±2.24 vs(15.26±0.12)μg·d-1〕;based on these results,berberine supposed to improve renal functions in diabetic rats.Berberine also ameliorated the inflammatory changes of DN in diabetic animals;levels of TG,TCH and MDA in berberine-treatment rats were significantly lower compared with those in the DN group:TG〔2.78±0.24 and 2.45±0.36 vs(5.20±0.60)mmol·L-1〕;TCH〔4.26±0.46 and 3.74±0.68 vs(6.26±0.50)mmol·L-1〕;MDA〔4.94±1.19 and 4.28±0.64 vs(4.28±0.64)nu·mL-1〕.Chronic inflammation,as is observed in diabetes,is associated with increased production of TGF-β1and IAM-1.Compared with the renal tissues of DN group,TGF-β1and IAM-1 gene expressions in berberine treated groups were reduced at the dose levels(100 and 200 mg·kg-1).And TGF-β1and IAM-1levels in berberine treated groups were reduced in a dosedependent manner:Relative expression of TGF-β1mR NA level(3.56±0.28 and 3.12±0.14 vs 5.12±0.44);Relative expression of IAM-1 mR NA leve(l1.78±0.56 and 1.42±0.24vs 4.36±0.35).Research finds that the NF-κB signaling pathway is activated in the renal tissue of diabetic mice and berberine inhibits activation of the NF-κB pathway:staining score for IKKβ1(4.34±0.26 and 3.82±0.24 vs 6.23±0.76),staining score for p65(2.34±0.26 and 1.74±0.78 vs 6.23±0.24)in nucleus and staining score for p65(7.21±0.13 and8.15±0.45 vs 4.23±0.54)in cytoplasm.CONCLUSION In this field,berberine suppresses the increased expression of p65 in the nucleus and decreases it in cytoplasm,which leads to the inhibition of the NF-κB pathway.These changes will result in decreasing the transcription and translation of many inflammatory mediators,such as TGF-β1and IAM-1.Additionally,these changes decrease the number of inflammatory cells and mononuclear macrophage infiltration into glomeruli and renal interstitium.These results indicated that berberine can protect the kidney of STZ-diabetic rats by reducing the expression of TGF-β1and IAM-1 in the renal tubulointerstitium.And we propose that berberinemayfunction as an effective therapeutic agent for diabetic nephropathy and attenuate the progression of renal injury.展开更多
OBJECTIVE To investigate the effect of Urena lobataleaves extract on the inhibition of nephropathy diabetic complication.METHODS This study uses control group post test only with male Sprague dawley rats.Diabetic rats...OBJECTIVE To investigate the effect of Urena lobataleaves extract on the inhibition of nephropathy diabetic complication.METHODS This study uses control group post test only with male Sprague dawley rats.Diabetic rats was induced by high fructose diet(HFD)and single dose streptozotocin 25mg·kg-1 bw intra peritoneal.The rat was administrated orally with water extract of U.lobataleaves in concentrations of 250,500 and 1000mg·kg-1 bw for 4 weeks.After scarifying,kidney organ were collected and then superoxyde dismutase(SOD)kidney level,malondialdehyda(MDA)and tumor necrosis factor-alpha(TNF-α)were examined.The data was analyzed using ANOVA test continued with LSD test(P<0.05).RESULTS The oral administration of U.lobataleaves extract 250,500 and 1000mg·kg-1 bw were able to increase SOD kidney level about 30%,60% and 90% respectively compared to diabetic group(P<0.05),while the MDA kidney level was decreased by 30%,60% and 70%(P<0.05)respectively.The supplementation of water extract from U.lobatain dose of 250,500 and 1000mg·kg-1 bw were also decrease TNF-αkidney level approximately 30%,40% and 60% compared to control group(P<0.05).In diabetic groups,SOD kidney level was decreased compared to normal group(P<0.05)while the MDA and TNF-αwere increased(P<0.05).CONCLUSION U.lobata leaves extract could inhibit nephropathy diabetic complication by increasing of SOD kidney level,decreasing of MDA kidney level,and TNF-α.This effect may be related to active compounds that act as an antioxidant and anti-inflammatory in U.lobata extract.展开更多
基金supported by National Nature Science Foundation of China(81770847)CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-3-007,2016-I2M-1-010)National Key Research and Development Plan(2016YFC1000905)
文摘OBJECTIVE Diabetic nephropathy(DN)has been one of the most common complications of diabetes and the leading cause of end-stage renal disease.Glomerular hyperfiltrationis central in earlystage of DN and leads to the progression of renal architectonic and functional abnormalities.Salvianolic acid A(SalA)has been proved to protect diabetic complications such as hepatic fibrosis and neuropathy.The present study was designed to investigate the effects of SalA on glomerular endothelial dysfunctionand diabetic nephropathy.METHODS Primary glomerular endothelial cells were subjected to assess permeability under injury of advanced glycation end-products(AGEs).AGEs-induced changes of Rho A/ROCK pathway and cytoskeleton rearrangement were assessed bywestern blotandimmunofluorescence.The beneficial effects of SalA on diabetic nephropathy were investigated in a rat model induced by high-fat and high-glucose diet combined with low dose of streptozocin(35 mg·kg^(-1),ip).Renal function and architectonic changes were evaluated by biochemical assay and PAS staining.RESULTS SalA 3μMameliorated AGEs-induced glomerular endothelial permeability(P<0.05)and suppressed rearrangement of cytoskeleton through inhibiting AGE-RAGE-Rho A/ROCK pathway.SalA1 mg·kg^(-1)markedly reduced endothelium loss(P<0.01)and glomerular hyperfiltration(P<0.05)in diabetic kidney.Subsequently,SalA 1 mg·kg^(-1) suppressed glomerular hypertrophy and mesangial matrix expansion,eventually reduced 24 h-urinary albumin and ameliorated renal function by decreasing blood urine nitrogen(BUN),serum creatinine(Scr)and serum n-acetyl-β-d-glucosaminidase(NAG).AGEs-RAGE-Nox4-induced oxidative stress was suppressed by the treatment of SalA 1 mg·kg^(-1).CONCLUSION SalA ameliorated AGEs-induced glomerular endothelial hyperpermeability,and effectively protected against early-stage diabetic nephropathy by reducing hyperfiltration and alleviating renal structural deterioration through inhibiting AGEs and its downstream pathway.Thus,SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.
文摘Diabetic nephropathy(DN)is one of the most common complications of diabetes.It is an important cause of diabetes disability and death.DN is a systemic metabolic syndrome.In its pathogenesis,the interaction of various cell activities and a large number of cytokine biological activities,the activation of signal pathways and so on are involved in the development of DN.At present,the clinical treatment of DN is mainly Western medicine,but it has limitations such as strong toxicity,high side effects and poor compliance.Therefore,the discovery of natural anti-DN substances has also become an important means to treat DN.Mulberry leaves are the dry leaves of Morus alba L.It is not only a traditional Chinese medicine,but also a dual-purpose medicinal material for medicine and food.It has the effects of dispelling wind and clearing heat,cooling blood and brightening eyes,tonifying and so on.Mulberry leaf polysaccharide(MLP)is a kind of high molecular compound in mulberry leaves.It has many pharmacological effects,such as hypoglycemic,antioxidant,anti-stress,anti-virus and so on.Therefore,the pharmacological effects of mulberry leaf polysaccharides on diabetic nephropathy are reviewed in this paper,so as to provide references for further research and application.The pathogenesis of DN is complex,and the mechanism of renal injury has not been completely clarified.The current studies believe that DN is closely related to heredity,abnormal glucose metabolism,abnormal lipid metabolism,microcirculation disorder,cytokine action,oxidative stress and so on.Relevant studies show that the pharmacological effects of mulberry leaf polysaccharide in the prevention and treatment of DN mainly include:①Effect on transforming factor-β1(TGF-β1):TGF-β1 has become an important cytokine involved in the formation of renal fibrosis by regulating cell proliferation and differentiation and the production of extracellular matrix(ECM).MLP can significantly inhibit TGF-β1 protein,and then inhibit the synthesis of extracellular matrix by renal interstitial fibroblasts and inhibit the realization of fibrosis.②Effect on insulin receptor substrate(IRS-1):IRS-1 is an important signal molecule at the beginning of IR signal transduction.The decrease of IRS-1 gene expression or the decrease of expression can affect the effective transmission of IR signal and lead to the development and deterioration of diabetes. MPL can significantly increase the expression of IRS-1 mRNA in liver tissue of DN rats, so as to prevent and treat DN. ③ Effect on the expression of resistin protein in adipose tis sue. Resistin is a secretory polypeptide derived from adipose tissue and is specifically expressed in white adipose tissue and is closely related to type 2 diabetes mellitus (T2DM). Experimental studies show that MLP can effectively reduce the expression of resistin protein in white adipose tissue of T2DM rats, indicating that MLP may reduce the level of IR by inhibiting the expression of resistin in adipose tissue, thereby reducing the insulin resistance state of T2DM rats, so as to achieve the goal of treating diabetes. ④ Effect on adiponectin receptor 1 (AdipoR1): adiponectin can improve insulin resistance, reduce blood glucose and lipid. AdipoR1 is mainly expressed in skeletal muscle and kidney. Studies have shown that AdipoR1 is closely related to the occurrence and development of DN. The results showed that MLP could reduce the blood glucose and blood lipid level and up regulate the expression of AdipoR1 mRNA in DN rats, suggesting that MLP may delay the occurrence and development of DN. This article reviewed the pharmacological effects of mulberry leaf polysaccharides on diabetic nephropathy, and provided a useful basis for further development and utilization of mul berry leaf polysaccharides in the treatment of DN.
基金The project supported by Fundamental Research Funds for the Central Universities(21615463)
文摘OBJECTIVE To investigate possible protective effect of berberine,an isoquinoline alkaloid,is the major active constituent of Rhizoma coptidis and Cortex phellodendri,on high-fat diet/streptozotocin-induced early diabetic nephropathy in rats and various mechanisms underlie this effect.METHODS The diabetic rat model was generated by a single intraperitoneal injection of streptozotocin(STZ,50 mg·kg-1).Diabetic rats were randomlyassigned into the following five groups:control,DN,losartan(30 mg·kg-1·d-1),berberine(100,200 mg·kg-1·d-1).Berberine and losartan were given intragastricly for nine weeks.At the end of the experiment,urine of each group was collected in a 24 h period.Rats were weighed and then sacrificed.Plasma and kidneys were collected.The levels of blood glucose,creatinine(Cr),triglycerides(TG),total cholesterol(TCH)and malondialdehyde(MDA)in serum were determined using commercial kits according to the manufacturer′s instructions.Transforming growth factor(TGF)-β1and intracellular adhesion molecule-1(IAM-1)mR NA levels were evaluated by RT-PCR.The renal histopathology was observed by light microscopy.Further biochemical analysis of IKKβ1 and p65(nucleus/cytoplasm)was provided using Western blotting techniques.RESULTS Our study has demonstrated that berberine has various pharmacological activities.The DN rats had significantly higher kidney/body weight ratio(17.4±1.4)mg·g-1,and berberine treatment could reduce this ratio change 13.6±0.6 and(11.6±0.8)mg·g-1,respectively;glucose control still remains the only disease-modifying therapy for diabetic complications,FBG was also recorded in the experiment.The findings reveal that the DN group showed a significantly higher glucose level(28.67±2.78)mmol·L-1.Treatment with8 weeks of berberine improved these parameters except blood glucose〔(18.67±2.59)mmol·L-1and 16.45±1.80 vs(28.67±2.78)mmol·L-1:plasma levels of urea nitrogen(15.67±2.48)mmol·L-1and 14.45±2.40 vs(12.26±2.40)mmol·L-1〕;plasma levels of 24 h urine albuminuria〔30.48±1.56 and 25.72±2.24 vs(15.26±0.12)μg·d-1〕;based on these results,berberine supposed to improve renal functions in diabetic rats.Berberine also ameliorated the inflammatory changes of DN in diabetic animals;levels of TG,TCH and MDA in berberine-treatment rats were significantly lower compared with those in the DN group:TG〔2.78±0.24 and 2.45±0.36 vs(5.20±0.60)mmol·L-1〕;TCH〔4.26±0.46 and 3.74±0.68 vs(6.26±0.50)mmol·L-1〕;MDA〔4.94±1.19 and 4.28±0.64 vs(4.28±0.64)nu·mL-1〕.Chronic inflammation,as is observed in diabetes,is associated with increased production of TGF-β1and IAM-1.Compared with the renal tissues of DN group,TGF-β1and IAM-1 gene expressions in berberine treated groups were reduced at the dose levels(100 and 200 mg·kg-1).And TGF-β1and IAM-1levels in berberine treated groups were reduced in a dosedependent manner:Relative expression of TGF-β1mR NA level(3.56±0.28 and 3.12±0.14 vs 5.12±0.44);Relative expression of IAM-1 mR NA leve(l1.78±0.56 and 1.42±0.24vs 4.36±0.35).Research finds that the NF-κB signaling pathway is activated in the renal tissue of diabetic mice and berberine inhibits activation of the NF-κB pathway:staining score for IKKβ1(4.34±0.26 and 3.82±0.24 vs 6.23±0.76),staining score for p65(2.34±0.26 and 1.74±0.78 vs 6.23±0.24)in nucleus and staining score for p65(7.21±0.13 and8.15±0.45 vs 4.23±0.54)in cytoplasm.CONCLUSION In this field,berberine suppresses the increased expression of p65 in the nucleus and decreases it in cytoplasm,which leads to the inhibition of the NF-κB pathway.These changes will result in decreasing the transcription and translation of many inflammatory mediators,such as TGF-β1and IAM-1.Additionally,these changes decrease the number of inflammatory cells and mononuclear macrophage infiltration into glomeruli and renal interstitium.These results indicated that berberine can protect the kidney of STZ-diabetic rats by reducing the expression of TGF-β1and IAM-1 in the renal tubulointerstitium.And we propose that berberinemayfunction as an effective therapeutic agent for diabetic nephropathy and attenuate the progression of renal injury.
基金The project supported by Ministry Education of Indonesia
文摘OBJECTIVE To investigate the effect of Urena lobataleaves extract on the inhibition of nephropathy diabetic complication.METHODS This study uses control group post test only with male Sprague dawley rats.Diabetic rats was induced by high fructose diet(HFD)and single dose streptozotocin 25mg·kg-1 bw intra peritoneal.The rat was administrated orally with water extract of U.lobataleaves in concentrations of 250,500 and 1000mg·kg-1 bw for 4 weeks.After scarifying,kidney organ were collected and then superoxyde dismutase(SOD)kidney level,malondialdehyda(MDA)and tumor necrosis factor-alpha(TNF-α)were examined.The data was analyzed using ANOVA test continued with LSD test(P<0.05).RESULTS The oral administration of U.lobataleaves extract 250,500 and 1000mg·kg-1 bw were able to increase SOD kidney level about 30%,60% and 90% respectively compared to diabetic group(P<0.05),while the MDA kidney level was decreased by 30%,60% and 70%(P<0.05)respectively.The supplementation of water extract from U.lobatain dose of 250,500 and 1000mg·kg-1 bw were also decrease TNF-αkidney level approximately 30%,40% and 60% compared to control group(P<0.05).In diabetic groups,SOD kidney level was decreased compared to normal group(P<0.05)while the MDA and TNF-αwere increased(P<0.05).CONCLUSION U.lobata leaves extract could inhibit nephropathy diabetic complication by increasing of SOD kidney level,decreasing of MDA kidney level,and TNF-α.This effect may be related to active compounds that act as an antioxidant and anti-inflammatory in U.lobata extract.
