Assessment of peripheral tissue perfusion disorder in streptozotocin-induced diabetic rats using dynamic contrast-enhanced MRI

Purpose

To assess peripheral tissue perfusion disorder in streptozotocin (STZ)-induced diabetic rats by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Materials and Methods

A rat diabetes model was produced by intravenous injection of STZ. Diabetic rats were sustainably treated with either saline or insulin using an Alzet osmotic pump. Hind paw tissue perfusion was measured by signal intensity (SI) enhancement after gadolinium diethylenetriaminepentaacetic acid injection in DCE-MRI study and quantified using the initial area under the SI-time curve (IAUC). Peripheral tissue uptake of [¹⁴C]iodoantipyrine (IAP) was also determined as a marker of tissue blood flow for comparison with the IAUC value indicating tissue perfusion.

Results

STZ caused hyperglycemia at 1 and 2 weeks after injection. Treatment with insulin significantly alleviated hyperglycemia. At 2 weeks after STZ injection, peripheral tissue perfusion was clearly reduced in the diabetic rats and its reduction was significantly improved in the insulin-treated diabetic rats. Tissue perfusion evaluated by DCE-MRI was similar to the tissue blood flow measured by [¹⁴C]IAP uptake.

Conclusion

Our findings demonstrated that DCE-MRI can assess peripheral tissue perfusion disorder in diabetes. DCE-MRI could be suitable for noninvasive evaluation of peripheral tissue perfusion in both preclinical and clinical studies. It may also be useful for developing novel drugs to protect against diabetic vascular complications.     

生物医学光子学在糖尿病视网膜病变中的应用进展

随着我国社会经济的发展及国人饮食、生活习惯的改变,糖尿病的发病率呈逐年上升趋势。糖尿病视网膜病变(Diabetic Retinopathy,DR)作为糖尿病最为常见的并发症,已成为视力下降甚至致盲的主要原因之一。通过对其早期诊断和及时治疗,超过50%的患者的视力损伤及致盲可得到预防。因此,研究DR的诊断和治疗方法具有重要的临床意义。由于眼部的结构及光学特性,生物医学光子学技术在DR的临床诊断和治疗中已得到了非常广泛的应用并且具有巨大的发展前景。本文综述了目前临床上用于DR诊断和治疗的主要生物医学光子学技术的原理及其最新应用进展,并分析对比了各个技术的特点,最后总结并展望了生物医学光子学技术在临床DR诊断和治疗的发展趋势。     

Bousigonine A and B,bis- and tri-indole alkaloids from Bousigonia mekongensis and their preventing high glucose-induced podocyte injury activity

Bousigonine A (1), an unprecedented eburnamine-voaphylline type dimeric indole alkaloid, and Bousigonine B (2), the first example of eburnamine-eburnamine-aspidospermine type trimeric indole alkaloid were isolated from Bousigonia mekongensis. Their structures were elucidated mainly by spectroscopic analysis and compared to published data. Their preventing high glucose-induced podocyte injury activity were evaluated for the first time, and compound 1 exhibited significant effect with EC₅₀ value of 2.5 μM.     

HPLC同时检测血清和尿样中肌酐、假尿苷、尿酸

用反相高效液相色谱法同时测定了３９例糖尿病患者的血清和尿样中的假尿嘧啶核苷、肌酐和尿酸,并与２４ｈ尿白蛋白排泄量进行了比较分析。发现血清假尿嘧啶核苷是糖尿病肾病早期诊断的一种新颖而敏感的指标,有助于连续监测肾脏的功能状态以了解病程的转归。     

Comparative pharmacokinetic study of six lignans in normal and diabetic rats after oral administration of Saururus chinensis extract by LC–MS/MS

Saururus chinensis (SC) possesses significant anti-diabetic activity and lignans were its major bioactive compounds. In this study, a rapid and sensitive ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) method was established for simultaneous quantification of six lignans, namely (-)-(7R,8R)-machilin D ( 1 ), verrucesin ( 2 ), rel-(7S,8S,7′R,8′R)-3,3′,4,4′,5,5′-hexamethoxy-7.O.7′,8.8′-lignan ( 3 ), manassantin A ( 4 ), manassantin B ( 5 ), and saucerneol F ( 6 ) in rat’s plasma. It was validated with acceptable linearity (r ≥ 0.9922), accuracy (80.42–95.17%), precision (RSD ≤ 12.08%), and extraction recovery (80.36–93.45%). The method was successfully applied to the comparative pharmacokinetic study of the six lignans in normal and diabetic rats after oral administration of SC extract. Results showed that the areas under the plasma concentration-time curve (AUC_{0 → t} and AUC_{0 → ∞}) of (-)-(7R,8R)-machilin D, rel-(7S,8S,7′R,8′R)-3,3′,4,4′,5,5′-hexamethoxy-7.O.7′,8.8′-lignan, manassantin B, and saucerneol F in diabetic rats were significantly increased, and the plasma clearance (CL) of (-)-(7R,8R)-machilin D in diabetic rats was significantly decreased. However, the AUC_{0 → t} and AUC_{0 → ∞} of verrucesin were significantly decreased, and its CL was significantly increased in diabetic rats compared with those in normal rats. These results indicated that there were remarkable differences in the pharmacokinetic parameters between the normal and diabetic rats. The pharmacokinetic studies might be beneficial for the clinical use of SC as hypoglycemic agent.     

Synthesis,characterization, antioxidant and anti‐diabetic activities of a novel protein–vanadium complex

The protein–vanadium complex was successfully synthesized and systematically characterized using electron paramagnetic resonance, Fourier transform‐infrared spectroscopy and thermogravimetric analysis. The antioxidant activity analysis indicated that it had better radical scavenging activity on 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH), 2,2′‐azinobis (3‐ethylbenzothiazoline)‐6‐sulfonic acid (ABTS) and O₂^? compared with the free protein and vanadate. Additionally, the complex exhibited high anti‐diabetic activity against Saccharomyces cerevisiae α‐glucosidase and rat intestinal maltase with IC₅₀ values of 258.53 and 72.41 μg/ml, respectively. Kinetics study showed that the complex was a mixed inhibition type against S. cerevisiae α‐glucosidase and uncompetitive inhibition type against rat intestinal maltase. These indicated that the complex with antioxidant and anti‐diabetic potential could be used for lowering blood glucose that might be caused by insufficient secretion of insulin in the body or excess fat storage. Our findings provide a new protein–vanadium complex for further use in diabetes mellitus or obesity.     

Effects of Tang Luo Ning on diabetic peripheral neuropathy in rats revealed by LC–MS metabolomics approach

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes with limited therapies. Tang Luo Ning (TLN), a traditional Chinese medicine compound, has been proved to be effective in the treatment of DPN in clinical and experimental studies. However, the potential metabolic mechanism of TLN for the treatment of DPN is still unclear. Here the therapeutic effect of TLN on DPN was studied, and HPLC-IT-TOF/MS was used to explore the metabolic changes related to DPN and to explore the mechanism of TLN on DPN induced by high glucose. Furthermore, metabolic pathway analysis was used to explore the metabolic changes induced by DPN and TLN. As a result, TLN could improve the peripheral nerve function of DPN rats, and TLN could reduce the demyelination of the sciatic nerve in DPN rats. Metabolomics analysis showed that 14 potential biomarkers (citrate, creatine, fumarate, glyceric acid, glycine, succinate, etc.) of both DPN and TLN treatment were identified. Pathway analysis showed that the changes in these metabolites were mainly related to the citrate cycle (TCA cycle); glycine, serine, and threonine metabolism; and glyoxylate and dicarboxylate metabolism.     

Fourier-transform-infrared-spectroscopy based metabolomic spectral biomarker selection towards optimal diagnostic differentiation of diabetes with and without retinopathy

Abstract

The purpose of this study is to identify Fourier transform infrared (FTIR) spectroscopy-based serum metabolomic spectral biomarkers using chemometrics for the diagnosis of Diabetic Retinopathy. FTIR spectroscopy was performed on 85 human serum samples [30 type 2 diabetes patients each without retinopathy and with retinopathy along with 25 normal healthy individuals as control]. Difference between mean spectra (DBMS), forward feature selection (FFS), and Mann–Whitney’s U tests were applied for spectral biomarker selection. Classification of disease conditions was achieved using analysis of different combinations of spectral features with linear, quadratic, and cubic Support Vector Machine at 10-fold cross validation. Twelve spectral signatures extracted by FFS could differentiate diabetes and diabetic retinopathy with 90% sensitivity, 92.7% specificity, and 90.5% overall accuracy. Two peaks (1042, 1114.18?cm^?1) were associated with carbohydrate and polysaccharide content and five peaks (1114.18, 1165, 1211.18, 1402.70, 1451.14, 1657?cm^?1) represented aberrations in total lipid content. Four peaks (1114.18, 1117, 1147, 1165?cm^?1) were associated with protein phosphorylation and three peaks (1527, 1544.71, 1591.10?cm^?1) with Amide II group. Again, lipidic signatures were strongly corroborated with glycosylated hemoglobin levels in diabetic retinopathy and diabetic subjects. Spectral signatures also revealed an elevated level of β-sheet containing proteins in serum in diabetic retinopathy condition. The method was validated through spectral biomarker selection by the DBMS technique. Thus, this method has the capability of diagnostic cost minimization for detection of diabetic retinopathy by label-free spectral biomarker identification.     

1 H NMR‐based metabolomics study for identifying urinary biomarkers and perturbed metabolic pathways associated with severity of IgA nephropathy: a pilot study

The severity of IgA nephropathy (IgAN), the most common primary glomerulonephritis, is judged on the basis of histologic and clinical features. A limited number of studies have considered molecular signature of IgAN for this issue, and no reliable biomarkers have been presented non‐invasively for use in patient evaluations. This study aims to identify metabolite markers excreted in the urine and impaired pathways that are associated with a known marker of severity (proteinuria) to predict mild and severe stages of IgAN. Urine samples were analysed using nuclear magnetic resonance from biopsy‐proven IgAN patients at mild and severe stages. Multivariate statistical analysis and pathway analysis were performed. The most changed metabolites were acetoacetate, hypotaurine, homocysteine, L‐kynurenine and phenylalanine. Nine metabolites were positively correlated with proteinuria, including mesaconic acid, trans‐cinnamic acid, fumaric acid, 5‐thymidylic acid, anthranilic acid, indole, deoxyguanosine triphosphate, 13‐cis‐retinoic acid and nicotinamide riboside, while three metabolites were negatively correlated with proteinuria including acetoacetate, hypotaurine and hexanal. ‘Phenylalanine metabolism’ was the most significant pathway which was impaired in severe stage in comparison to mild stage of IgAN. This study indicates that nuclear magnetic resonance is a versatile technique that is capable of detecting metabolite biomarkers in combination with advanced multivariate statistical analysis. Copyright © 2017 John Wiley & Sons, Ltd.     

Delaying of cataract through intervention of Hemidesmus indicus in STZ induced diabetic rats

Hemidesmus indicus (L.) R. Br. was extensively used as hypoglycaemic agent and significance of this plant on secondary complications of diabetes remained unknown. The present study was to investigate the anti-cataractous activity of H. indicus against streptozotocin (STZ)-induced diabetic cataract in rodent model. Root extracts have been prepared and tested for inhibition of rat lens aldose reductase (AR) activity. In addition, its pharmacological potential has been investigated in STZ-induced diabetic cataract. Methanol extract of H. indicus-inhibited AR activity in vitro decreased the blood glucose levels, inhibited the AR activity and delayed the onset and progression of cataract in a dose-dependent manner in in vivo and the antioxidant markers have been normalised. Our results demonstrate that H. indicus has decrease the osmotic stress by inhibiting the AR activity and prevented the loss of antioxidants and delayed the progression of diabetic cataract in STZ-induced diabetic rats.