Forsythoside B alleviates osteoarthritis through the HMGB1/TLR4/NF-κB and Keap1/Nrf2/HO-1 pathways.

Osteoarthritis (OA) is a joint pain and dysfunction syndrome resulting from severe joint degeneration. Inflammation and degeneration of the articular cartilage are two main features of OA and have tight interactions during OA progression. Conventional treatment with nonsteroidal anti-inflammatory drugs has been widely utilized clinically, whereas the side effects have restricted their application. Forsythoside B has been found with anti-inflammatory effects and antiapoptosis in inflammatory diseases, whereas in OA it remains poorly understood. Interleukin (IL)-1ß (10 ng/mL) was taken to induce an OA cell model on HC-A chondrocytes and an OA rat model was constructed for in vivo experiments. Forsythoside B was adopted to treat HC-A chondrocytes and OA rats. As shown by the data, Forsythoside B hampered IL-1ß-elicited rat chondrocyte apoptosis, oxidative stress, and facilitated proliferation. The profiles of inflammatory factors, NOD-like receptor family pyrin domain containing 3 inflammasomes, Kelch-like epichlorohydrin-associated protein-1 (Keap1), and nuclear factor-κB (NF-κB) phosphorylation were suppressed by Forsythoside B, whereas the nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels were promoted. Further, Forsythoside B mitigated cartilage damage and degeneration. Moreover, the oxidative stress and inflammation mediators in the cartilage tissue of OA rats were remarkably abated. Collectively, Forsythoside B hinders the NF-κB and Keap1/Nrf2/HO-1 pathways to curb IL-1ß-elicited OA rat oxidative stress and inflammation both in vivo and ex vivo, ameliorating OA development. All over, this study provides an underlying strategy for treating OA, which might help the clinical treatment of OA patients.

Baicalein Alleviates Arsenic-induced Oxidative Stress through Activation of the Keap1/Nrf2 Signalling Pathway in Normal Human Liver Cells.

BACKGROUND: Oxidative stress is a key mechanism underlying arsenicinduced liver injury, the Kelch-like epichlorohydrin-related protein 1 (Keap1)/nuclear factor E2 related factor 2 (Nrf2) pathway is the main regulatory pathway involved in antioxidant protein and phase II detoxification enzyme expression. The aim of the present study was to investigate the role and mechanism of baicalein in the alleviation of arsenic-induced oxidative stress in normal human liver cells. METHODS: Normal human liver cells (MIHA cells) were treated with NaAsO2 (0, 5, 10, 20 µM) to observe the effect of different doses of NaAsO2 on MIHA cells. In addition, the cells were treated with DMSO (0.1%), NaAsO2 (20 µM), or a combination of NaAsO2 (20 µM) and Baicalein (25, 50 or 100 µM) for 24 h to observe the antagonistic effect of Baicalein on NaAsO2. Cell viability was determined using a Cell Counting Kit- 8 (CCK-8 kit). The intervention doses of baicalein in subsequent experiments were determined to be 25, 50 and 100µM. The intracellular content of reactive oxygen species (ROS) was assessed using a 2',7'-dichlorodihydrofluorescein diacetate (DCFHDA) probe kit. The malonaldehyde (MDA), Cu-Zn superoxide dismutase (Cu-Zn SOD) and glutathione peroxidase (GSH-Px) activities were determined by a test kit. The expression levels of key genes and proteins were determined by real-time fluorescence quantitative polymerase chain reaction (qPCR) and Western blotting. RESULTS: Baicalein upregulated the protein expression levels of phosphorylated Nrf2 (p-Nrf2) and nuclear Nrf2, inhibited the downregulation of Nrf2 target genes induced by arsenic, and decreased the production of ROS and MDA. These results demonstrate that baicalein promotes Nrf2 nuclear translocation by upregulating p-Nrf2 and inhibiting the downregulation of Nrf2 target genes in arsenic-treated MIHA cells, thereby enhancing the antioxidant capacity of cells and reducing oxidative stress. CONCLUSION: Baicalein alleviated arsenic-induced oxidative stress through activation of the Keap1/Nrf2 signalling pathway in normal human liver cells.

Development of a cellulose-based scaffold for sustained delivery of curcumin.

Due to the unique properties of cellulose-based materials, they are attractive to be developed in industrial pharmaceutics and biomedical fields. Carboxymethyl-diethyl amino ethyl cellulose scaffold (CM-DEAEC) has been synthesized in the current work as a smart novel derivative of cellulose with a great functionality in drug delivery systems. The scaffolds were well cross-linked with 2% (v/v) epichlorohydrin (ECH), loaded with curcumin (Cur), and then were analyzed by FT-IR, XRD, SEM, and mechanical strength. While developing the ideal delivery platform, curcumin (an important chemotherapeutic agent) was chosen due to its hydrophobicity and poor bioavailability. Thus, we developed a novel scaffold for efficient loading and controlled releasing of curcumin. The swelling ratio of 136%, high curcumin entrapment efficiency (up to 83.7%), sustained in vitro drug release profile, and appropriate degradability in three weeks confirmed significant properties of the CM-DEAEC scaffold. More than 99% antibacterial activity has been observed by the cross-linked curcumin loaded CM-DEAEC scaffolds. Cytotoxicity studies using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 4',6-diamidino-2-phenylindole (DAPI) staining showed that cross-inked curcumin loaded CM-DEAEC scaffolds did not show any toxicity using L929 cells. All experiments were compared with CMC scaffolds and better characteristics of the novel scaffold for drug delivery have been confirmed.

Interconnected Microdomain Structure of a Cross-Linked Cellulose Nanocomposite Revealed by Micro-Raman Imaging and Its Influence on Water Permeability of a Film.

Substantial adsorption of water vapor triggered by hydrogen-bonding interactions between water molecules and cellulose chains (or nanoplates) is hard to avoid in nanocomposite films, although the addition of nanoplates can improve the oxygen (or carbon dioxide) barrier property. In the present work, an effective strategy is raised to decline adsorption by weakening hydrogen-bonding interactions via chemical cross-linking by epichlorohydrin (ECH) without sacrificing the homogeneous dispersion of nanoplates. The generated microdomain structure of the chemical cross-linking reaction via ECH is explicitly revealed by micro-Raman imaging. Unambiguously, Raman maps of scanning elucidate the distribution and morphology of physical and chemical cross-linking domains quantitatively. The chemical cross-linking domains are nearly uniformly located in the matrix at a low degree of cross-linking, while the interconnected and assembled networks are formed at a high degree of cross-linking. ECH boosts the formation of chemical cross-linking microdomains, bringing out the terrific water vapor barrier property and alleviating the interfacial interactions in penetration, consequently magnifying the water contact angle and holding back the water vapor permeability. Our methodology confers an effective and convenient strategy to obtain remarkable water vapor-resistant cellulose-based films that meet the practical application in the packaging fields.

[THE CELLULAR COMPOSITION OF THE EPITHELIUM OF THE VILLUS OF THE MUCOUS MEMBRANE OF THE DUODENUM OF RATS IN THE CONDITIONS OF EPICHLOROHYDRIN AND DRUG INFLUENCE].

Purpose of the research is to study the nature of the disorders of the villi of the duodenal mucous membrane (MM) in conditions of long-acting ECH as well as to substantiate experimentally the effectiveness of the use of the extract of Echinacea purpurea (EP) and thiotriazoline for the purpose of these disorders correction. The withdrawal of the rats from the experiment was carried out on the 1st, 7th, 15th, 30th and 60th day after the completion of the administration of ECH, EP extract and thiotriazoline. Histological processing of duodenum fragments was performed according to the standard method. The cell composition of the villus epithelium of duodenal MM was evaluated using a laboratory microscope of the MC 100 (Micros, Austria) and the Microvisible software (version 1.11.10). The determination of the significance of differences was carried out according to the Mann-Whitney U criterion. Differences were considered significant at p<0.05. Prolonged action of ECH led to a decrease in the number of cells in one villus of duodenal MM. This decrease persisted after the end of the administration of this chemical. There was a decrease in the number of columnar epithelial cells, goblet exocrinocytes and argyrophil endocrinocytes. In rats that did not receive ECH, administration of an EP extract was accompanied by a short-term increase in the number of columnar epithelial cells in one villus of duodenal MM. The administration of thiotriazolin to rats that did not receive ECH caused a short-term increase in the number of cells in one villus of duodenal MM and the number of columnar epithelial cells in the one villus of duodenal MM. The use of EP extract on the background of inhalations of ECH reduced the degree of decrease in the number of cells in one villus of duodenal MM and the number of columnar epitheliocytes in one villus of duodenal MM, reduced the degree and duration of reduction in the number of goblet exocrinocytes in one villus of duodenal MM, reduced the duration of reduction in the number of argyrophil endocrinocytes in one villus of duodenal MM. The use of thiotriazolin during the administration of ECH led to a decrease in the degree and duration of a decrease in the number of cells in one villus of duodenal MM and the number of columnar epithelial cells in one villus of duodenal MM, and also prevented the occurrence of a decrease in the number of goblet exocrinocytes and argyrophil endocrinocytes in one villus of duodenal MM.

Impacts of epichlorohydrin-dimethylamine on coagulation performance and membrane fouling in coagulation/ultrafiltration combined process with different Al-based coagulants.

Two kinds of aluminum-based coagulants and epichlorohydrin-dimethylamine (DAM-ECH) were used in the treatment of humic acid-kaolin simulated water by coagulation-ultrafiltration (C-UF) hybrid process. Coagulation performance, floc characteristics, including floc size, compact degree, and strength were investigated in this study. Ultrafiltration experiments were conducted by a dead-end batch unit to implement the resistance analyses to explore the membrane fouling mechanisms. Results showed that DAM-ECH aid significantly increased the UV254 and DOC removal efficiencies and contributed to the formation of larger and stronger flocs with a looser structure. Aluminum chloride (Al) gave rise to better coagulation performance with DAM-ECH compared with poly aluminum chloride (PACl). The consequences of ultrafiltration experiments showed that DAM-ECH aid could reduce the membrane fouling mainly by decreasing the cake layer resistance. The flux reductions for PACl, Al/DAM-ECH (dosing both Al and DAM-ECH) and PACl/DAM-ECH (dosing both PACl and DAM-ECH) were 62%, 56% and 44%, respectively. Results of this study would be beneficial for the application of PACl/DAM-ECH and Al/DAM-ECH composite coagulants in water treatment processes.

Effect of colestimide on the concentrations of polychlorinated dibenzo-p-dioxins, polychlorinated dizenzofurans, and polychlorinated biphenyls in blood of Yusho patients.

BACKGROUND: Oral colestimide was reported to lower the concentration of PCDDs, PCDFs, and PCB in the blood of humans. A pilot study showed that the arithmetic mean total TEQ concentrations of PCDDs, PCDFs, and PCBs in the blood of subjects after the trial decreased approximately 20 % compared to pre-trial levels, suggesting that colestimide could decrease human dioxin levels. We designed the current clinical trial study based on this information. In this study, we examined whether colestimide could reduce the individual congener concentrations of PCDDs, PCDFs, and PCBs in the blood of Yusho patients. METHODS: Out of the 36 Yusho patients who participated in the clinical trial, 26 patients self-administered colestimide 3 g/day orally for 6 months. The concentrations of PCDDs, PCDFs and PCBs in the blood of 26 Yusho patients before the trial were compared with those after the trial. RESULTS: The arithmetic mean total TEQ concentrations of PCDDs, PCDFs, non-ortho PCBs, and mono-ortho PCBs in the blood of the 26 Yusho patients before and after the clinical trial were 42-303 (mean: 130, median: 120) and 43-283 (mean: 132, median: 118) pg TEQ/g lipid, respectively. The sums of the concentrations of 58 PCB congeners measured in the blood of Yusho patients before and after the trial were 321-2643 (mean: 957, median: 872) and 286-2007 (mean: 975, median: 806) ng/g lipid, respectively, indicating that the concentrations of PCDDs, PCDFs, and PCBs after the trial were almost the same as those before the trial. Among congeners of PCDDs, PCDFs, dioxin-like PCBs, and non-dioxin-like PCBs, most congeners of these compounds did not show a statistically significant decrease after the trial. CONCLUSION: Colestimide may not be beneficial in reducing the high blood levels of dioxin-like compounds in Yusho patients.

Intestinal Bile Acid Composition Modulates Prohormone Convertase 1/3 (PC1/3) Expression and Consequent GLP-1 Production in Male Mice.

Besides an established medication for hypercholesterolemia, bile acid binding resins (BABRs) present antidiabetic effects. Although the mechanisms underlying these effects are still enigmatic, glucagon-like peptide-1 (GLP-1) appears to be involved. In addition to a few reported mechanisms, we propose prohormone convertase 1/3 (PC1/3), an essential enzyme of GLP-1 production, as a potent molecule in the GLP-1 release induced by BABRs. In our study, the BABR colestimide leads to a bile acid-specific G protein-coupled receptor TGR5-dependent induction of PC1/3 gene expression. Here, we focused on the alteration of intestinal bile acid composition and consequent increase of total TGR5 agonistic activity to explain the TGR5 activation. Furthermore, we demonstrate that nuclear factor of activated T cells mediates the TGR5-triggered PC1/3 gene expression. Altogether, our data indicate that the TGR5-dependent intestinal PC1/3 gene expression supports the BABR-stimulated GLP-1 release. We also propose a combination of BABR and dipeptidyl peptidase-4 inhibitor in the context of GLP-1-based antidiabetic therapy.

Bile acid sequestrants: glucose-lowering mechanisms and efficacy in type 2 diabetes.

Bile acids are synthesized in the liver from cholesterol and have traditionally been recognized for their role in absorption of lipids and in cholesterol homeostasis. In recent years, however, bile acids have emerged as metabolic signaling molecules that are involved in the regulation of lipid and glucose metabolism, and possibly energy homeostasis, through activation of the bile acid receptors farnesoid X receptor (FXR) and TGR5. Bile acid sequestrants (BASs) constitute a class of drugs that bind bile acids in the intestine to form a nonabsorbable complex resulting in interruption of the enterohepatic circulation. This increases bile acid synthesis and consequently reduces serum low-density lipoprotein cholesterol. Also, BASs improve glycemic control in patients with type 2 diabetes. Despite a growing understanding of the impact of BASs on glucose metabolism, the mechanisms behind their glucose-lowering effect in patients with type 2 diabetes remain unclear. This article offers a review of the mechanisms behind the glucose-lowering effect of BASs, and the efficacy of BASs in the treatment of type 2 diabetes.

Salicylic acid and some of its derivatives as antibacterial agents for viscose fabric.

Salicylic acid and three of its derivatives were used to provide antibacterial properties to viscose fabrics. The four bactericides used were bonded to the viscose fabrics using epichlorohydrin or polymer binders. Optimization of the salicylic acid and its derivatives as well as the concentration of polymers was reported. The ability of the polymer binders to attract and bind the four bactericides was observed. The overall results show that the antibacterial reactivity of salicylic acid and its derivatives are in the following order 5-bromosalicylic acid>salicylic acid>5-chlorosalicylic acid>4-chlorosalicylic acid. Using epichlorohydrin as a binding agent, unfortunately, inhibits the bactericidal activity of the four bactericides. The FTIR study concludes that the reaction between salicylic acid as well as its derivatives with epichlorohydrin takes place through the phenolic group of the acids. The unexpected deterioration in the bactericidal properties of salicylic acid and its derivatives as a result of the treatment with epichlorohydrin could be due to the nature of interaction between the epichlorohydrin molecule and the acids molecules. PVP and PU show superior ability to sustain the four bactericides used even after 10 washing cycles.

Effect of cross-linking and enzymatic hydrolysis composite modification on the properties of rice starches.

Native rice starch lacks the versatility necessary to function adequately under rigorous industrial processing, so modified starches are needed to meet the functional properties required in food products. This work investigated the impact of enzymatic hydrolysis and cross-linking composite modification on the properties of rice starches. Rice starch was cross-linked with epichlorohydrin (EPI) with different concentrations (0.5%, 0.7%, 0.9% w/w, on a dry starch basis), affording cross-linked rice starches with the three different levels of cross-linking that were named R1, R2, and R3, respectively. The cross-linked rice starches were hydrolyzed by α-amylase and native, hydrolyzed, and hydrolyzed cross-linked rice starches were comparatively studied. It was found that hydrolyzed cross-linked rice starches showed a lower the degree of amylase hydrolysis compared with hydrolyzed rice starch. The higher the degree of cross-linking, the higher the capacity to resist enzyme hydrolysis. Hydrolyzed cross-linked rice starches further increased the adsorptive capacities of starches for liquids and decreased the trend of retrogradation, and it also strengthened the capacity to resist shear compared to native and hydrolyzed rice starches.

Hypoglycemic effects of colestimide on type 2 diabetic patients with obesity.

Recent studies have shown colestimide, a bile acid-binding resin, to also exert a glucose-lowering effect via amelioration of insulin resistance. To evaluate the effects of colestimide on glucose metabolism and to elucidate the underlying mechanism, we conducted a 6-month, open-label pilot study on 43 type 2 diabetic patients with obesity (BMI ≥ 25). The subjects were randomized to either treatment with colestimide 4g/day (T group, n=23) or continuation of their current therapy (C group, n=20). In the T group patients, mean HbA1c and fasting glucose improved markedly (from 7.71 ± 0.32% to 6.97 ± 0.20%; from 147.4 ± 7.3mg/dL to 127.0 ± 5.0mg/dL, respectively), while obesity-related parameters, i.e. body weight, waist circumference, and visceral fat and subcutaneous fat as determined by umbilical slice abdominal CT, showed no significant changes. Fractionation analyses of serum bile acids revealed significantly increased cholic acids (CA) and decreased chenodeoxycholic acids (CDCA) in the T group patients. However, no correlation was observed between these changes and ΔHbA1c. According to logistic regression analysis, baseline HbA1c was the only variable predicting the decrease of HbA1c (>0.5%) among sex, age, BMI, total cholesterol, ΔCA and ΔCDCA. The index of insulin resistance, i.e. HOMA-R, did not improve, and the index of ß cell function, i.e. HOMA-ß, actually increased significantly. These results suggests that, in obese patients with type 2 diabetes, the mechanism underlying improved glycemic control with colestimide treatment involves enhanced ß cell activity rather than improved insulin resistance.

Glucose-lowering effect of colestimide is associated with baseline HbA1c in type 2 diabetic patients with hypercholesterolemia.

We previously reported that colestimide, an anion exchange resin, improved glycemic control in patients with type 2 diabetes. However, the factors associated with the decrease of HbA1c remain unclear. In present study, we retrospectively compared glycemic control between groups receiving colestimide (n=71), atorvastatin (n=99), pravastatin (n=85), and pitavastatin (n=95) until 3 months after the start of treatment. In the colestimide group, fasting plasma glucose decreased significantly from 169 ± 59 to 138 ± 29 mg/dL after 3 months (P<0.01), and glycated hemoglobin (HbA1c) declined from 8.1 ± 1.0% to 7.4 ± 0.8% (an 8% reduction, P<0.01). Fasting plasma glucose and HbA1c did not change in the pravastatin and pitavastatin groups. On the other hand, both parameters increased significantly in the atorvastatin group. Multivariate analysis revealed that baseline HbA1c was the main determinant of the decrease of HbA1c in the colestimide group while age, sex, BMI, and baseline lipid levels were not correlated with the effect of colestimide treatment. The decrease of HbA1c showed a positive correlation with baseline HbA1c (r=0.60, P<0.0001), and patients with a larger change of HbA1c (>8.4%) displayed a better response to colestimide. In conclusion, since patients with type 2 diabetes often have hyperlipidemia as well, colestimide therapy may have a clinically useful dual action in such patients. Baseline HbA1c has the most important independent influence on the glucose-lowering effect of colestimide.

Colestimide, an anion exchange resin agent, can decrease the number of LDL particles without affecting their size in patients with hyperlipidemia.

OBJECTIVES: Recent studies have demonstrated that not only plasma low-density lipoprotein (LDL) levels, but also the number of small dense LDL particles are involved in the development of arteriosclerosis. Anion exchange resins can reduce plasma LDL levels and affect LDL particle size via increasing triglycerides. In the present study, the effects of short-term colestimide administration on LDL particle size were investigated. METHODS: Obese patients with primary hyperlipidemia (n=21) were administered 3000 mg/day of colestimide for 1 month and fasting blood was obtained before and after the treatment. LDL particle size and number were measured by nuclear magnetic resonance (NMR) lipoprofile using magnetic resonance spectroscopy. RESULTS: Levels of plasma LDL cholesterol decreased from 155.5 mg/dl to 128.1 mg/dl (p<0.001) and levels of apolipoprotein B decreased from 139.2 mg/dl to 120.6 mg/dl (p<0.001) by colestimide administration. Levels of high-density lipoprotein (HDL) cholesterol and triglyceride were unaltered. LDL particle size did not change, whereas LDL particle numbers decreased from 1920.3 nmol/l to 1568.8 nmol/l (p<0.01). CONCLUSIONS: Short-term administration of colestimide to patients with hyperlipidemia reduced LDL particle numbers. LDL particle size was not changed.

Lack of relationship between blood glucose-lowering activity of colestimide and serum cholecystokinin (CCK) concentrations in patients with type 2 diabetes.

Colestimide has been reported to lower blood glucose levels in patients with type 2 diabetes and hypercholesterolemia. We investigated the mechanism of the hypoglycemic activity of colestimide by examining changes in serum cholecystokinin (CCK) and insulin concentrations before and after its 2-week oral administration. A total of seven type 2 diabetes inpatients with hypercholesterolemia received colestimide after their blood glucose levels had stabilized. We daily measured plasma glucose levels and serum lipid concentrations, calculated Body Mass Index (BMI), and determined whole-day changes in serum immunoreactive insulin (IRI) and CCK concentrations in all study subjects. We daily measured plasma glucose levels, as well as serum IRI and CCK concentrations at 10 time points for measurement. Plasma glucose levels, as well as serum IRI and CCK concentrations before and after the 2-week oral administration of colestimide were compared. The means of total cholesterol levels and BMI decreased significantly after administration. At time points for measurement (10 : 00 and 12 : 00), plasma glucose levels decreased significantly after administration (P=0.026 and P=0.009, respectively). Diurnal changes in serum IRI and CCK concentrations were not observed after administration, except for the IRI concentration at 20: 00. The effect of colestimide on CCK may not explain the mechanism of its blood glucose-lowering activity in patients with type 2 diabetes and hypercholesterolemia.

Sterol regulatory element-binding protein-2- and liver X receptor-driven dual promoter regulation of hepatic ABC transporter A1 gene expression: mechanism underlying the unique response to cellular cholesterol status.

ABC transporter A1 (ABCA1) mediates and rate-limits biogenesis of high density lipoprotein (HDL), and hepatic ABCA1 plays a major role in regulating plasma HDL levels. HDL generation is also responsible for release of cellular cholesterol. In peripheral cells ABCA1 is up-regulated by the liver X receptor (LXR) system when cell cholesterol increases. However, cholesterol feeding has failed to show a significant increase in hepatic ABCA1 gene expression, and its expression is up-regulated by statins (3-hydroy-3-methylglutaryl-CoA reductase inhibitors), suggesting distinct regulation. In this study we investigated the mechanism of regulation of the rat hepatic ABCA1 gene and identified two major ABCA1 transcripts and two corresponding promoter regions. Compactin activated the novel liver-type promoter in rat hepatoma McARH7777 cells by binding the sterol regulatory element-binding protein-2 (SREBP-2). In contrast, compactin repressed the previously identified peripheral-type promoter in an LXR-responsive element-dependent but not E-box-dependent manner. Thus, compactin increased the liver-type transcript and decreased the peripheral-type transcript. The same two transcripts were also dominant in human and mouse livers, whereas the intestine contains only the peripheral-type transcript. Treatment of rats with pravastatin and a bile acid binding resin (colestimide), which is known to activate SREBP-2 in the liver, caused a reduction in the hepatic cholesterol level and the same differential responses in vivo, leading to increases in hepatic ABCA1 mRNA and protein and plasma HDL levels. We conclude that the dual promoter system driven by SREBP-2 and LXR regulates hepatic ABCA1 expression and may mediate the unique response of hepatic ABCA1 gene expression to cellular cholesterol status.

Fluvastatin alters platelet aggregability in patients with hypercholesterolemia: possible improvement of intraplatelet redox imbalance via HMG-CoA reductase.

BACKGROUND: Hypercholesterolemia enhances platelet aggregability. Statins have beneficial effects on cardiovascular events. The purpose of this study is to investigate whether statins inhibit platelet aggregation and, if so, the mechanisms. METHODS AND RESULTS: Twelve patients with hypercholesterolemia were prospectively randomized in a crossover design to receive either fluvastatin (20 mg/d) or colestimide (3000 mg/d) for 12 weeks. The subjects were switched to the opposite arm for additional 12 weeks. Before and after first and second treatments, experiments were performed. Eleven age-matched volunteers with normal lipid profiles served as controls. ADP-induced platelet aggregation, platelet-derive nitric oxide (PDNO) release, intraplatelet levels of GSH and GSSG, and intraplatelet nitrotyrosine production during platelet aggregation were measured. Fluvastatin and colestimide equally lowered total and low density lipoprotein cholesterol levels in hypercholesterolemia. Platelet aggregation was greater in hypercholesterolemia than in normocholesterolemia before treatment and was altered by fluvastatin. PDNO release, intraplatelet glutathione level, and GSH/GSSG ratio were lower in hypercholesterolemia than in normocholesterolemia before treatment and were increased by fluvastatin. Intraplatelet nitrotyrosine formation was greater in hypercholesterolemia than in normocholesterolemia, and decreased by fluvastatin. Colestimide did not have such effects. In vitro application of fluvastatin dose-dependently inhibited platelet aggregation. Furthermore, in vitro application of fluvastatin dose-dependently inhibited platelet nitrotyrosine expressions and the inhibitory effects by fluvastatin were reversed by preincubation with geranylgeranylpyrophosphate. CONCLUSIONS: Fluvastatin altered platelet aggregability in hypercholesterolemic patients in a cholesterol-lowering independent manner, which was partly mediated by the improvement of intraplatelet redox imbalance.

Effect of colestimide therapy for glycemic control in type 2 diabetes mellitus with hypercholesterolemia.

Colestimide is a new anion-exchange resin used to lower serum cholesterol in Japan. Because of its excellent compliance, colestimide can replace cholestyramine. To clarify the effect of colestimide on glycemic controls, colestimide (3 g/day) or pravastatin (10 mg) was given orally to patients with type 2 diabetes treated with oral hypoglycemic agents or insulin who had low-density lipoprotein (LDL) cholesterol levels exceeding 3.6 mmol/l. In the colestimide groups, fasting plasma glucose concentrations had decreased significantly from 8.5 +/- 1.4 to 7.7 +/- 1.5 mmol/l at 3 months (P<0.05), as had glycated hemoglobin (HbA1c) from 7.7 +/- 0.7% to 6.8 +/- 0.5%, for an 8% reduction (P<0.01). Fasting plasma glucose and HbA1c did not change in the pravastatin group. Total cholesterol and LDL-cholesterol decreased significantly (P<0.01) with either medication, with similar reduction rates for both drugs. Doses of oral hypoglycemic agents and insulin did not change during the study, and body weight remained stable. Considering that patients with type 2 diabetes often have hyperlipidemia, colestimide therapy may have a clinically useful dual action in such patients.

Biosorption of lead ion by chemically-modified biomass of marine brown algae Laminaria japonica.

In this paper, marine brown algae Laminaria japonica was chemically-modified by crosslinking with epichlorohydrin (EC(1), EC(2)), or oxidizing by potassium permanganate (PC), or only washed by distilled water (DW). They were used for equilibrium sorption uptake studies with lead. As can be seen from the experimental results that biosorption equilibriums were rapidly established in about 2h. The lead adsorption was strictly pH dependent, and maximum removal of lead on biosorbents were observed at pH 5.3. The effects solid/liquid ratio on lead biosorption was also investigated. The maximum lead uptakes were 1.67 mmol g(-1), 1.62 mmol g(-1), 1.54 mmol g(-1) and 1.21 mmol g(-1), respectively for EC(1), EC(2), PC and DW. The order of maximum lead uptakes for different pretreated and raw alga was EC(1)>EC(2)>PC>DW. A comparison of different isotherm models revealed that the combination of Langmuir and Freundlich (L-F) isotherm model fitted the experimental data best.