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Aim To observe the effect of total flavonoid from Mori folium(TFMF) on renal interstitial fibrosis in type 1 diabetic mice and its possible mechanism.Methods Diabetic mice were induced by intraperitoneal injection of streptozotocin(STZ) dissolved in 0.01 mol·L-1 citrate buffer(pH 4.5) at 150 mg·kg-1 body weight after 12 h of food deprivation.Forty model mice were divided randomly into four groups: model group, and low-(0.25 g·kg-1), moderate-(0.5 g·kg-1), high-dose groups(1 g·kg-1) fed with TFMF once daily.In addition, eight normal mice were used as normal group.After 12 weeks, the fasting blood glucose(FBG), serum creatinine(Cr), blood urea nitrogen(BUN) and microalbuminuria(mAlb) were measured.Masson staining, Sirius red staining and collagen type Ⅳ immunohistochemical staining were used to detect the expression of collagen protein in the cortex, while laminin staining to assess the degree of glomerular and renal tubular basement membrane thickening.The protein expressions related to epithelial-mesenchymal transition and PI3K/Akt/mTOR in the renal cortex of mice were detected by Western blot.Results The moderate and high dose of TFMF could significantly decrease the levels of FBG, Cr, BUN and mAlb in diabetic mice, meanwhile decreasing the expression of α-SMA protein by inhibiting the activation of PI3K/Akt/mTOR signaling pathway, which led to the amelioration of the pathological alterations of renal tissue.Conclusions The moderate and high dose of TFMF can reduce the level of renal interstitial fibrosis in type 1 diabetic mice, and its mechanism may be related to the inhibition of activation of PI3K/Akt/mTOR signaling pathway.
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Objective To prepare naloxone hydrochloride nasal spray and evaluate the ciliotoxicity and pharmacokinetics of the formulation. Methods The stability of naloxone hydrochloride was studied in pH3.5-5.5. Penetration promoting effects of absorp-tion enhancers on the naloxone hydrochloride were evaluated. Nasal ciliotoxicity studies were carried out using isolated toad palate. Rats were treated with naloxone hydrochloride solution by intramuscular injection of nasal drops to evaluate the pharmacokinetics. Results Naloxone hydrochloride solution was stable in pH3.5-5.5. Disodium ethylenediaminetetraacetic acid(0.2%,W/V)had the best penetration promoting effect on naloxone hydrochloride. Naloxone hydrochloride nasal spray did not exhibit obvious nasal ciliotox-icity compared to the negative control. The nasal spray had a faster therapeutic effect and its bioavailability was similar to that of the in-tramuscular injection. Conclusion Naloxone hydrochloride nasal spray prepared in this research is stable with no obvious nasal cilio-toxicity,has faster therapeutic effect,and good bioavailability,so may have a broad application prospect.
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The present study aimed to explore the neuroprotective effect and possible mechanisms of rhGLP-1 (7–36) against transient ischemia/reperfusion injuries induced by middle cerebral artery occlusion (MCAO) in type 2 diabetic rats. First, diabetic rats were established by a combination of a high-fat diet and low-dose streptozotocin (STZ) (30 mg/kg, intraperitoneally). Second, they were subjected to MCAO for 2 h, then treated with rhGLP-1 (7–36) (10, 20, 40 µg/kg i.p.) at the same time of reperfusion. In the following 3 days, they were injected with rhGLP-1 (7–36) at the same dose and route for three times each day. After 72 h, hypoglycemic effects were assessed by blood glucose changes, and neuroprotective effects were evaluated by neurological deficits, infarct volume and histomorphology. Mechanisms were investigated by detecting the distribution and expression of the nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) in ischemic brain tissue, the levels of phospho-PI3 kinase (PI3K)/PI3K ratio and heme-oxygenase-1 (HO-l), as well as the activities of superoxide dismutase (SOD) and the contents of malondialdehyde (MDA). Our results showed that rhGLP-1 (7–36) significantly reduced blood glucose and infarction volume, alleviated neurological deficits, enhanced the density of surviving neurons and vascular proliferation. The nuclear positive cells ratio and expression of Nrf2, the levels of P-PI3K/PI3K ratio and HO-l increased, the activities of SOD increased and the contents of MDA decreased. The current results indicated the protective effect of rhGLP-1 (7–36) in diabetic rats following MCAO/R that may be concerned with reducing blood glucose, up-regulating expression of Nrf2/HO-1 and increasing the activities of SOD.
Subject(s)
Animals , Rats , Blood Glucose , Brain , Diet, High-Fat , Hypoglycemic Agents , Infarction , Infarction, Middle Cerebral Artery , Malondialdehyde , Neurons , Neuroprotective Agents , Phosphotransferases , Reperfusion , Reperfusion Injury , Streptozocin , Superoxide DismutaseABSTRACT
Aim To observe the effects of tetrahydro-biopterin ( BH4 ) on nitric oxide ( NO ) production in the kidney of type 2 diabetic nephropathy ( DN) mice, and to find a new target for the treatment of type 2 DN. Methods The 12 week-old db/db mice developed in-to DN phase were divided into 2 groups:DAHP group, subjected to intraperitoneal injection of 150 mg·kg-1 DAHP (n=8);DN group, subjected to intraperitone-al injection of same dose of normal saline containing 5% DMSO ( n = 6 ) . The age-matched db/m mice ( NS group) were subjected to intraperitoneal injection of same dose of normal saline containing 5% DMSO ( n =6 ) . Three groups of mice were treated for 7 days. Then the fasting blood-glucose, serum creatinine, u-rine protein and activity of iNOS were determined by chemical colorimetry. And the iNOS protein in renal cortex was determined by immunohistochemisty and western blot, respectively. BH4 was measured by HPLC method. NO level was determined by Griess method. Results The levels of fasting blood-glucose, serum creatinine, 24h urine volume, 24h urine pro-tein, BH4 , iNOS and NO in DN group were signifi-cantly higher than those in NS group;The levels of ser-um creatinine, urine volume, urine protein, BH4 , iN-OS and NO in DAHP group were significantly lower than those in DN group. Conclusion In the kidney of type 2 DN mice, the increased BH4 contributes to over-production of NO by the increased iNOS expression, and resultes in the increase of urine volume and urine protein.
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BACKGROUND:Our previous study has already manifested that Chinese medicine Xiaokening can effectively prevent and treat the early diabetic nephropathy. OBJECTIVE:To compare the effect of rhein and archen on the apoptosis of mesangial cells of rats cultured with high glucose. METHODS:Mesangial cells were stimulated by different concentrations of rhein and archen (20, 40 and 80 μmol/L). Morphology of apoptotic cells was observed by hematoxylin-eosin staining. Karyon apoptosis was examined by fluorescence staining of DAPI. cellapoptosis rate was detected by flow cytometry. RESULTS AND CONCLUSION:The outcome of hematoxylin-eosin staining and DAPI staining indicated that the effect of rhein was much stronger than that of archen on the apoptosis of mesangial cells in the rats cultured with high glucose. Comparison of the apoptosis rate also indicated that the rhein had a stronger effect on the earlier and the later stage apoptotic rate of mesangial cells than archen. Both rhein and archen with different concentrations can induce apoptosis of mesangial cells, but the effect of rhein is much stronger.
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To investigate the protective effects of bendazac lysine (BDL) on diabetic nephropathy (DN) in vitro and in vivo experiments. METHODS: After rat mesangial cells were cultured in 3 concentrations of BDL for 36 h, the percentages of S phase of cells were determined by flowcytometry; the transforming growth factor β1 (TGF-β1) mRNA level was assayed by reverse transcription PCR; and two main components of extracellular matrix (ECM), collagen Ⅳ and laminin, were determined by radioimmunoassay. Streptozotocin (STZ) induced diabetic rats were administered BDL at doses of 100, 200, 400 mg/kg for 8 weeks. The physical behavior and HbAlC levels of rats were observed. RESULTS: In the presence of high glucose and H2O2, the percentages of S phase of cells were lowered, and TGF-β1 mRNA level, collagen Ⅳ and laminin level were significantly increased. When compared with those in the high glucose group, the percentages of S phase of cells were significantly raised, and the levels of TGF-β1 mRNA, collagen Ⅳ and laminin were statistically decreased. The physical behavior of high BDL treated rats restored to be vibrant, vigorous and weight gaining, and the HbAlC level was significantly reduced. CONCLUSION: BDL has the protective effects against damage caused by DN, and is a potential drug candidate worth further study in preventing and treating DN.
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AIM: To compare pharmacokinetics and relative bioavailability of telmisartan capsule (T) and telmisartan tablet(R). METHODS: 20 male healthy Chinese volunteers were enrolled in a randomized two-way crossover designs with a single-oral dose study(80 mg once per day for each preparation). The plasma telmisatan concentration was determined by HPLC- fluorescence detector. Plasma levels of telmisatan were followed up to 96 h. Area under the telmisartan concentration time curve was calculated by variance analysis and the bioequivalent was determined by two one-side t-test. RESULTS: A two-compartment model was adopted in telmisartan plasma concentration-time data analysis. The pharmacokinetic parameters of T and R in single-dose study including Cmax (μg·L-1), Tmax (h), T1/2β (h), MRT(h), AUC0-92(μg·h·L-1) were as following: 456±253 and 760±314, 1.61±0.71 and 1.08±0.36, 22.39±6.29 and 21.08±5.24, 27.02±6.23 and 24.27±5.79, 3454±1050 and 3635±1300, respectively. Statistically significant differences were observed between the parameter values of the two products in Cmax and Tmax; whereas there was no statistically significant difference between AUC0-∞μg·h·L-1 (3601±1095 and 3767±1399). The relative bioavailability for T was 97.28%±12.74%. CONCLUSION: The test telmisartan capsule is bioequivalent to the reference tablet.
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Aim To study the anticonvulsive and antiepileptic mechanism of ?-asarone.Methods ?-asarone was intraperitoneally injected (ip) in mice and acute epileptic mouse models were made after 30 min.Change of ATPase,index of antioxidation,and variation of amino acid (AA) contents in brain of epileptic mice were used to investigate ?-asarone′s anticonvulsive and antiepileptic mechanism.Results For ?-asarone treated epileptic mice,when compared with model group,glutamate/gamma-aminobutyric acid (Glu/GABA) was greatly decreased (P
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Aim To investigate the effects of co-administration of Astragalus Saponin Ⅰ(ASI)and bendazac lysine(BDL)on hypertrophy of cultured rat mesangial cells and its mechanism.Methods The levels of collagen Ⅳ and laminin,the percentages of cells in S phase,the relative quantity of transforming growth factor ?1(TGF-?1) mRNA and indexes of oxidative status were assayed after the cells were incubated in different agents for 36 h.Results The percentage of S phase cells in high glucose group(HG) was greatly decreased while those of vitamin E group(VE) and co-administration groups were increased.The relative quantity of TGF-?1 mRNA and the collagen Ⅳ level in co-administration groups were significantly decreased,and the levels of total anti-oxidative capability(T-AOC),activity of catalase(CAT),GSH-PX,and SOD were greatly increased.Furthermore,the significant differences were found between low ASI(AL)group,low BDL(BL) group and co-administration of low ASI and low BDL(AL+BL) group for TGF-?1 mRNA,T-AOC and GSH-PX;the high ASI group(AH),high BDL group(BH) and co-administration of high ASI and high BDL group(AH+BH) for TGF-?1 mRNA and collagen Ⅳ,respectively. Conclusion Co-administration of ASI and BDL has synergetic effects on regulating TGF-?1,collagen Ⅳ,and radical oxidative stress,therefore,is beneficial to protecting rat mesangial cells against hypertrophy.
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Diabetic nephropathy is one of the leading causes of the end-stage renal failure, and its major pathologic feature is the renal fibrosis. Transforming growth factor-?_1 is a key factor in the progression of the disease. Two signal pathways, Smads and MAPK following the factor, are closely connected with extracellular matrix accumulation which leads to renal fibrosis. Smads and MAPK also have a cross talk in extracellular matrix accumulation. The relationship between the two signal pathway and ECM accumulation offers us a new therapeutic strategy for renal fibrosis of diabetes.