Islet cell function in gold thioglucose-induced obesity in mice

Summary Blood insulin, blood glucose and the biosynthesis and release of insulin have been studied in mice made obese with a single injection of gold thioglucose. In such mice, blood glucose levels were normal, though serum insulin rose in parallel with the development of obesity. When compared with controls, insulin secretion and synthesis were increased in isolated islets of Langerhans from obese mice, over a wide range of glucose concentrations. However, in obese animals, insulin biosynthesis was augmented above control levels at 2 mmol/l glucose, whilst the increase in insulin secretion accompanying obesity only became evident at glucose concentrations > 5 mmol/l. After 2 min incubation, cyclic AMP rose more in islets from obese mice than in controls, though cyclic AMP levels did not significantly differ in either group after 10 min incubation with glucose. Glucose oxidation was also increased in islets of Langerhans from obese mice. It seems possible that changes in glucose oxidation, as well as in cyclic AMP levels, contribute to the alteration in the B cell response in this type of obesity.     

DRD2 Dopamine Receptor Genotype, Linkage Disequilibrium, and Alcoholism in American Indians and Other Populations

We defined interpopulation differences in the frequency of the dopamine D2 receptor DRD2/Taq1 A1 allele, which has previously been associated with alcoholism. Frequencies of the A1 allele in unrelated subjects were 0.18 to 0.20 (se = 0.02 to 0.03) in several Caucasian populations previously assessed, 0.38 (±0.05) in American Blacks ( n = 44), 0.63 (±0.07) in Jemez Pueblo Indians ( n = 23), and 0.80 (± 0.04) in Cheyenne Indians ( n = 52). The existence of large interpopulation differences in the frequency of the Taq1 alleles suggests that associations to disease status could readily be generated or masked if disease and control groups were uneven in ethnic composition. To address the possibility that the 4-fold higher frequency of the A1 allele in Cheyenne Indians was related to an increased vulnerability to alcoholism in that population, 47 Cheyenne Indians were psychiatrically interviewed and blind-rated. However, there was no significant difference between interviewed controls (0.73 ± 0.06, n = 24), subjects with alcoholism and/or drug abuse (0.74 ± 0.06, n = 23) and noninterviewed population controls (0.87 ± 0.05, n = 20). Legitimate association of the DRD2/Taq1 allele to alcoholism would presumably require it to be in linkage disequilibrium (nonrandom association) with a functional mutation at DRD2 or elsewhere. The level of disequilibrium would vary between populations and could place an upper bound on the strength of an association. To provide a model for the extent and variation of disequilibrium at DRD2, the level of linkage disequilibrium between the Taq1 RFLP and a second DRD2 polymorphism, the SSCP variant in the immediate 3'region of the gene, was determined in three populations. The normalized disequilibrium values were 0.36 In U.S. Caucasians ( n = 48), 0.34 in Finns ( n = 86), and 0.78 in Cheyenne Indians ( n = 34).     

“Atypical” multidrug resistance in human ovarian cancer cell line A2780 selected for resistance to doxorubicin (A2780 DX3)

Human ovarian cancer cells A2780, selected for resistance to doxorubicin (A2780-DX3), are crossresistant to various other topoisomerase-II-targeted drugs but not to vinblastine. The parental cell line was very sensitive to doxorubicin-, mitoxantrone- or etoposide (VP16)-induced DNA single-strand breaks, under deproteinizing conditions. In contrast, little or no DNA strand breakage was seen in resistant A2780-DX3 cells, even at very high concentrations, indicating a good correlation, with cytotoxicity. No significant alterations in cellular drug uptake were observed in DX3 cells. Further studies showed that the nuclei isolated from resistant cells were also resistant to mitoxantroneor VP16-induced single-strand breaks, indicating that nuclear modifications in resistant cells are responsible for this resistance. Catalytic activity in crude nuclear extracts from wild-type and DX3 cells was almost equal. However, an assay that specifically measures generation of 5-protein-linked breaks in³²P-labeled 3 DNA revealed that, DNA cleavage activity in nuclear extract from the DX3 cell line is profoundly resistant to a stimulation by VP16. These data indicate that stimulation of topoisomerase-II-mediated DNA cleavage is responsible for topoisomerase-II-targeted drugcytotoxicity rather than loss of normal topoisomerase catalytic function. These data support the hypothesis that A2780-DX3 cells display an atypical multidrug resistance.Abbreviations MDR multidrug resistance - SSB Single-strand break     

The pathogenesis of tumour hypoglycaemia: Blocks of hepatic glucose release and of adipose tissue lipolysis

Summary Earlier findings on the pathogenesis of tumour hypoglycaemia [15] were confirmed and extended in a second patient with this disease. — A block of hepatic glucose release was found to be the main cause of hypoglycaemia in both patients suffering from large tumours of non-endocrine origin. The free fatty acid level failed to increase upon hypoglycaemia. Low free fatty acid levels correlated with an increased rate of glucose assimilation and glucose oxidation. — Immunoreactive, suppressible and nonsuppressible ILA measuredin vitro andin vivo were normal. — However, the serum of patient Z.B. inhibited lipolysis of adipose tissuein vitro to a greater extent than serum of normal subjects. This difference was no longer present after dialysis of the sera and the antilipolytic activity was now found in the diffusate. — The block of hepatic glucose release may be overcome by a pharmacological dose of intravenous glucagon. The block of hepatic glucose release is of paramount importance for the development of hypoglycaemia since the pharmacological blocking of lipolysis alone does not lead to hypoglycaemia, although it may increase glucose assimilation and glucose oxidation. — An attempt is being made to characterize further the antilipolytic substance which is present in increased amounts in the serum of patients with tumour hypoglycaemia.This work was supported by grants from the Schweizerische Nationalfonds (3336) and from the U.S. Public Health Service (AM 5387).     

Mechanistic insights of the controlled release capacity of polar functional group in transdermal drug delivery system: the relationship of hydrogen bonding strength and controlled release capacity

BackgroundHydrogen bonding interaction was considered to play a critical role in controlling drug release from transdermal patch. However, the quantitative evaluation of hydrogen bonding strength between drug and polar functional group was rarely reported, and the relationship between hydrogen bonding strength and controlled release capacity of pressure sensitive adhesive (PSA) was not well understood. The present study shed light on this relationship.MethodsAcrylate PSAs with amide group were synthesized by a free radical-initiated solution polymerization. Six drugs, i.e., etodolac, ketoprofen, gemfibrozil, zolmitriptan, propranolol and lidocaine, were selected as model drugs. In vitro drug release and skin permeation experiments and in vivo pharmacokinetic experiment were performed. Partial correlation analysis, fourier-transform infrared spectroscopy and molecular simulation were conducted to provide molecular details of drug-PSA interactions. Mechanical test, rheology study, and modulated differential scanning calorimetry study were performed to scrutinize the free volume and molecular mobility of PSAs.ResultsRelease rate of all six drugs from amide PSAs decreased with the increase of amide group concentrations; however, only zolmitriptan and propranolol showed decreased skin permeation rate. It was found that drug release was controlled by amide group through hydrogen bonding, and controlled release extent was positively correlated with hydrogen bonding strength.ConclusionFrom these results, we concluded that drugs with strong hydrogen bond forming ability and high skin permeation were suitable to use amide PSAs to regulate their release rate from patch.     

中药治疗肝损伤的药理研究进展

肝损伤主要由化学物质、酒精、药物等因素造成,进一步可能发展肝硬化和肝癌等重大肝病,是威胁人体健康的重要因素。近年来,由于中药具有多靶点和低毒副作用的优势,受到人们的广泛关注。因此本文综述了化学性肝损伤、免疫性肝损伤、酒精性肝损伤和药物性肝损伤的发病机制,及近年来中药作为抗肝损伤药物的药理作用及其机制,以期为抗肝损伤中药药物研发提供思路。     

MiR-142-3p enhances chemosensitivity of breast cancer cells and inhibits autophagy by targeting HMGB1

MiR-142-3p has been reported to act as a tumor suppressor in breast cancer. However, the regulatory effect of miR-142-3p on drug resistance of breast cancer cells and its underlying mechanism remain unknown. Here, we found that miR-142-3p was significantly downregulated in the doxorubicin (DOX)-resistant MCF-7 cell line (MCF-7/DOX). MiR-142-3p overexpression increased DOX sensitivity and enhanced DOX-induced apoptosis in breast cancer cells. High-mobility group box 1 (HMGB1) is a direct functional target of miR-142-3p in breast cancer cells and miR-142-3p negatively regulated HMGB1 expression. Moreover, overexpression of HMGB1 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by miR-142-3p up-regulation. In conclusion, miR-142-3p overexpression may inhibit autophagy and promote the drug sensitivity of breast cancer cells to DOX by targeting HMGB1. The miR-142-3p/HMGB1 axis might be a novel target to regulate the drug resistance of breast cancer patients.     

Phospholipid membrane-decorated deep-penetrated nanocatalase relieve tumor hypoxia to enhance chemo-photodynamic therapy

Hypoxia is a serious impediment to current treatments of many malignant tumors. Catalase, an antioxidant enzyme, is capable of decomposing endogenous hydrogen peroxide (H₂O₂) into oxygen for tumor reoxygenation, but suffered from in vivo instability and limited delivery to deep interior hypoxic regions in tumor. Herein, a deep-penetrated nanocatalase-loading DiIC₁₈ (5, DiD) and soravtansine (Cat@PDS) were provided by coating catalase nanoparticles with PEGylated phospholipids membrane, stimulating the structure and function of erythrocytes to relieve tumor hypoxia for enhanced chemo-photodynamic therapy. After intravenous administration, Cat@PDS preferentially accumulated at tumor sites, flexibly penetrated into the interior regions of tumor mass and remarkably relieved the hypoxic status in tumor. Notably, the Cat@PDS + laser treatment produced striking inhibition of tumor growth and resulted in a 97.2% suppression of lung metastasis. Thus, the phospholipids membrane-coated nanocatalase system represents an encouraging nanoplatform to relieve tumor hypoxia and synergize the chemo-photodynamic cancer therapy.     

Transporters (OATs and OATPs) contribute to illustrate the mechanism of medicinal compatibility of ingredients with different properties in yuanhuzhitong prescription

Various medicinal ingredients with different tastes are combined according to the theory of compatibility in Chinese materia medica to achieve a better efficacy, while the mechanism was not very clear. Here, the authors studied the interaction between ingredients and human transporters such as the kidney transporters OAT1 and OAT3, the liver transporters OATP1B1 and OATP1B3, and the intestine transporter OATP2B1 to discern the compatibility mechanism of ingredients with different tastes in the Yuanhuzhitong preparation (YHP) comprising Corydalis yanhusuo (CYH) and Angelica dahurica (AD), which could relieve pain by restraining the central system. The results show that tetrahydropalmatine (TDE), the major component of CYH, could be transported by OAT3 into kidney, OATP1B1 and OATP1B3 into liver, while imperatorin (IPT) and isoimperatorin (ISP), the two key components of AD, and AD extract showed strong inhibition to OAT1 and OAT3. What's more, AD extract also exerted strongly inhibition to human transporters OATP1B1 and OATP1B3. It was also detected that IPT, ISP, and AD extract significantly downregulated the expression of Oatp1a1, Oatp1a4, and Oatp1b2 of liver in mice. The in vivo results show that the concentration of TDE in liver and kidney significantly decreased, while the TDE concentration in blood and brain were both significantly enhanced in the presence of IPT, ISP, and AD extract. These results suggest that the ingredients in AD with pungent taste could enhance the exposure of TDE in blood and brain by inhibiting the uptake of TDE in liver and kidney. That is to say, TDE with bitter taste could “flood up” into the central nervous system to play its therapeutic effect by the cut-off of that into liver and kidney in the presence of ingredients within AD. This paper not only proves the meridian distribution of CYH in liver and kidney with the role of OAT3, OATP1B1, and OATP1B3, but also illustrates how to improve the efficacy of CYH by reasonable compatibility with AD. This study may offer a valuable clue to illustrate the mechanism of compatibility theory.