Research communications in molecular pathology and pharmacology最新文献

A high-sucrose diet induces insulin resistance and dyslipidemia in normal rats. The purpose of the present study was to investigate effects of a high-sucrose diet to glycolipid metabolism in Zucker Diabetic Fatty (ZDF) rat. Male ZDF rats were fed with a high-sucrose (68%) diet from 6 to 18 weeks of age. In biochemical analyses, the glucose levels did not change as compared with those in standard diet-fed rats, but the total cholesterol levels were elevated during the experimental period. In pathological analyses, the relative liver weight increased by about 2-fold as compared with that in standard diet-fed rats, and severe fatty change was observed by high-sucrose feeding. A high-sucrose diet induces fatty liver, but not deterioration of diabetes mellitus in ZDF rats. High sucrose-fed rats are considered to be very useful to determine the relationship between hepatic insulin resistance and diabetes mellitus.

Gas chromatography mass/spectrometry quantitative analysis of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THCCOOH), the major metabolite of delta-9-tetrahydrocannabinol (THC) found in urine following marijuana use, was performed on serial urine specimens collected from an inpatient adolescent population of marijuana users. Creatinine normalization of THCCOOH was used to compensate for dilute or concentrated urine specimens. The urinary terminal elimination rate constant and terminal half-life was calculated for each subject. The mean urinary elimination rate constant for THCCOOH normalized to creatinine was 0.08433 days(-1) (range 0.05408-0.16544) reflecting a 8.22 day terminal half-life. A half-life of 1.15 days was observed for the initial decline phase of THCCOOH corrected by creatinine suggesting that reuse of marijuana can be detected after this phase ends. The creatinine normalized THCCOOH level was a better indicator for predicting reuse of marijuana than urinary concentrations of THCCOOH. The Mean Residence Time (MRT) of THCCOOH/Cr (5.7 days) correlated well with the length of time a subject will have detectable urinary THCCOOH concentrations (20.8 days).

A quantitative trait locus (QTL) responsible for intramuscular fat accumulation in Musculus longissimus of Otsuka Long-Evans Tokushima Fatty (OLETF) rat, Imfm, was previously mapped to the approximately 10-cM genomic region between D1Rat166 and D1Rat90 on chromosome 1 using Imfm congenic strain. In this study, we refined the Imfm region to a approximately 2.3-cM genomic region between D1Rat225 and D1Rat90, using 12 informative recombinants selected from 176 (Imfm congenic x F344) F, x Imfm congenic backcross progenies. Among 46 genes located within the approximately 2.3-cM region, pancreatic lipase gene, Pnlip, that is a possible candidate for obesity QTL, Nidd6/of, was thought to be the most prominent and physiologically relevant positional candidate for the Imfm QTL. It was previously showed that Pnlip possesses an OLETF allele-specific increase of mRNA levels in the pancreas, and that the OLETF allele is longer in variable number of tandem repeat (VNTR) within the 5'-flanking region than normal alleles. We found complete cosegregation of the Imfm QTL with Pnlip VNTR in the 12 informative recombinants, suggesting that Pnlip is also a possible candidate for the Imfm QTL.

Sivelestat sodium hydrate (sivelestat) is a selective inhibitor of polymorphonuclear leukocyte elastase (PMN-E). We administered sivelestat to patients with septic acute lung injury (ALI) to examine its usefulness. The primary endpoints in the study were the duration of artificial ventilation and pulmonary oxygenation ability, and the secondary endpoints were mortality and the concentrations of PMN-E, SP-D, TNF-alpha and IL-8 in blood. In the sivelestat group, the duration of artificial ventilation, pulmonary oxygenation ability, and the blood PMN-E, SP-D, TNF-alpha and IL-8 concentrations decreased significantly. Administration of sivelestat was found to reduce alveolar dysfunction and improve respiratory function, and it was suggested that early administration might be useful.

Endothelins (ETs) are a multifunctional large family of polypeptides. There are three well recognized members in this family (ET-1, ET-2, and ET-3) of which ET-1 appears to be the most important. They have been shown to play an important role in the pathogenesis of many life threatening diseases of humans and animals. They also perform a wide variety of physiological roles. The most important property of ETs is smooth muscle contraction, which allows them to play an important role in the pathogenesis of many vascular, gastrointestinal, urogenital and airway diseases. Another important feature of ETs is their influence on the immune system. Many animal and human studies have shown that antagonists of ET receptors can remarkably alleviate many disease symptoms. ETs produce their effect by acting via two established types of receptors namely ET-A and ET-B, which are present in various type of cells in the body. These receptors have varied and sometimes opposite functions. Pulmonary vascular endothelium is the richest source of ET in the body. Lung is the primary organ of ET metabolism and clearance. It has been reported that ETs play a pivotal role in the pathogenesis of asthma, chronic obstructive pulmonary disease, bronchiolitis obliterans and other important airway diseases. Many of these obstructive airway diseases are characterized by bronchoconstriction, mucous hyperplasia, airway remodeling and inflammation. ET is involved in all of these symptoms. In spite of its involvement in many diseases, the exact role of ET in the pathogenesis of these diseases remains unclear. The purpose of this review is to give the reader an insight regarding the importance of multitude and diverse roles played by ETs in various airway diseases.

Monascus purpureus-fermented rice (MR), a preparation which has been shown to be hypolipidemic and antiatherogenic in rabbits and hamsters was fed to quail maintained on a high fat diet to determine if it could influence lipidemia and hepatic steatosis. MR was fed at two levels (0.8 or 1.6 g/kg/d), and compared with a lipoptropic preparation (dongbaogantai 0.6 g/kg/d) and an established hypolipidemic compound (lovastatin 6 mg/kg/d). All the test compounds lowered serum lipids and liver cholesterol levels. Dongbaogantai inhibited hepatic steatosis to the greatest extent (78%), lovastatin inhibited steatosis by 29% and the low and high doses of MR by 25 and 43%, respectively. These serum cholesterol lowering agents have been shown to reduce hepatic steatosis induced by dietary means.

CYP 3A4 plays a vital role in the metabolism of many drugs including immunosuppressants. An association between a transition of A --> G at position -290 of the 5'-regulatory region of the CYP 3A4 gene and an effect on the level of transcription has been reported. The CYP 3A4-G variant frequency varies substantially in different populations. In addition it has been demonstrated in association with several disease conditions, including clinical grades of prostate cancer, breast cancer, secondary leukemia, hypercholesterolemia and diabetes. We sought to determine the frequency distributions, in African American (AFAM) and Caucasian (CAU) populations as well as patients with multiple complex diseases, such as those that had undergone cardiac or renal transplantation. Sequence-specific primers and PCR were used to determine genotype variation in 206 AFAM and 108 CAU individuals. CYP 3A4-G genotype was present with a higher frequency in AFAM individuals as compared with CAU (83% vs. 3%, p < 0.0001, RR = 3.9). The homozygous AA allele was predominantly present in CAU (97%) but only 17% in AFAM (p < 0.0001, RR = 2.5). In contrast, the homozygous GG allele was only detected in AFAM group (14.6%). The frequency distribution of homozygous GG and AA alleles were inversely present in male vs. female patients with CTx or RTx. Pre-transplantation clinical conditions demonstrated that hypertension (HTN), hyperlipidemia and to a lesser extent diabetes (DM) were present in CTx and RTx patients with homozygous GG alleles. In addition, 75% of AFAM patients with homozygous GG genotype experienced multiple rejection episodes with severity grades of 3A after cardiac transplantation, and 31.5% of homozygous GG patients with RTx suffered from rejections (p < 0.05; RR = 2.4). In conclusion, CYP 3A4 genotype demonstrated a remarkable interindividual variation between AFAM and CAU populations, and furthermore CTx patients with homozygous GG genotype were at higher risk of developing rejection as compared with RTx patients. This indicates an underlying heterogeneity with regard to the disease characteristics as well as the therapy regimen.

Inhibitory effects on glycogenolysis have been reported for glibenclamide in the presence of insulin after stimulation of glycogenolysis by glucagon. Inhibition of oxidative phosphorylation, which has been equally reported for this drug, however, should stimulate glycogenolysis. The present work aimed to find an answer to the question of how glibenclamide affects glycogen catabolism in the liver of fed rats undergoing substrate- and hormone-free perfusion. The experimental system was the isolated perfused liver of ad libitum fed rats. Metabolites in the outflowing perfusate were assayed enzymatically. Oxygen uptake was measured polarographically. Glibenclamide (25-500 microM) stimulated glucose production and lactate release, with a clear correlation between concentrations and effects. Maximal stimulations were 132 and 127% for lactate production and glucose release, respectively. At low glibenclamide concentrations (up to 100 microM) both oxygen uptake and pyruvate production were stimulated, but at higher concentrations inhibition took place. Uric acid production was stimulated by glibenclamide. All effects of glibenclamide are probably due to decreases in oxidative phosphorylation. Stimulation of glucose release is the opposite of what should be expected for a hypoglycemic drug and it also contrasts with some reports of diminishing effects in the presence of glucagon plus insulin. This means that the stimulatory action on glycogenolysis that was seen as a net effect under the specific conditions of the present work could be counterbalancing inhibitory effects in vivo. This combination of events could eventually diminish the effectiveness of the drug as a hypoglycemic agent in the fed state.

Nickel(II) compounds are carcinogenic metals which induce genotoxicity and oxidative stress through the generation of reactive oxygen species. In search of new molecular pathways toward understanding the molecular mechanism of nickel(II)-induced carcinogensis, we performed mRNA differential display analysis using total RNA extracted from nickel(II) acetate-treated normal rat kidney cells (NRK-52E). Cells were exposed for 2 months to 160 and 240 microM nickel(II) concentrations. cDNAs corresponding to mRNAs for which expression levels were altered by nickel(II) were isolated, sequenced, and followed by a GenBank Blast homology search. Specificity of differential expression of cDNAs was determined by RT-PCR. Two of them (SH3BGRL3 and FHIT) were down-regulated and one (metallothionein) was up-regulated by nickel(II) treatment. The expression of these mRNAs were nickel(II) concentration-dependent. Overall, although the fundamental questions related to function of these genes in nickel(II)-mediated carcinogenicity are not answered, our study suggests that they can be interesting candidates for studies of molecular mechanisms of nickel(II) carcinogenesis.