MicroRNA-181a-mediated downregulation of AC9 protein decreases intracellular cAMP level and inhibits ATRA-induced APL cell differentiation.

AC9 is one of the adenylate cyclase (AC) isoforms, which catalyze the conversion of ATP to cAMP, an important second messenger. We previously found that the integration of cAMP/PKA pathway with nuclear receptor-mediated signaling was required during all-trans retinoic acid (ATRA)-induced maturation of acute promyelocytic leukemia (APL) cells. Here we showed that AC9 could affect intracellular cAMP level and enhance the trans-activity of retinoic acid receptor. Knockdown of AC9 in APL cell line NB4 could obviously inhibit ATRA-induced differentiation. We also demonstrated that miR-181a could decrease AC9 expression by targeting 3'UTR of AC9 mRNA, finally controlling the production of intracellular cAMP. The expression of miR-181a itself could be inhibited by CEBPα, probably accounting for the differential expression of miR-181a in NB4 and ATRA-resistant NB4-R1 cells. Moreover, we found that AC9 expression was relatively lower in newly diagnosed or relapsed APL patients than in both complete remission and non-leukemia cases, closely correlating with the leukemogenesis of APL. Taken together, our studies revealed for the first time the importance of miR-181a-mediated AC9 downregulation in APL. We also suggested the potential value of AC9 as a biomarker in the clinical diagnosis and treatment of leukemia.

Artificial selection of the melanocortin receptor 1 gene in Chinese domestic pigs during domestication.

Black coat colour is common in Chinese indigenous domestic pigs, but not among their wild ancestors, and it is thus presumed to be a 'domestication trait.' To determine whether artificial interference contributes to morphological diversification, we examined nucleotide variation from 157 Chinese domestic pigs and 40 wild boars in the melanocortin receptor 1 (MC1R) gene, which has a key role in the coat pigmentation of Sus scrofa. Compared with a pseudogene GPIP, our results showed that the joint effects of demography and selection have resulted in markedly low genetic diversity of MC1R in Chinese domestic pigs. Coalescent simulation and selection tests further suggest that the fixation of two non-synonymous substitutions associated with black colour is the result of artificial selection. In contrast, a much higher genetic diversity and only a single non-synonymous substitution were found among the wild boars, suggesting a strong functional constraint. Moreover, our conclusion is consistent with the preference for black colour in the ancient Chinese sacrificial culture. This case provides an interesting example of a molecular evaluation of artificial livestock selection and its associated cultural impact in ancient China.

Prevalence of diabetes and its risk factors in China, 1994. National Diabetes Prevention and Control Cooperative Group.

OBJECTIVE: To determine the prevalence of diabetes and impaired glucose tolerance (IGT) and its risk factors in the Chinese population. RESEARCH DESIGN AND METHODS: This study was a population-based cross-sectional study of 224,251 residents aged 25-64 years in 19 provinces and areas, including cities and rural areas of the north, south, east, and middle part of China. RESULTS: Using the 1985 World Health Organization criteria, the prevalence of diabetes and IGT was 2.5 and 3.2%, respectively, in 213,515 subjects aged 25-64 years. Two thirds (70.3%) of the cases had newly recognized diabetes. The prevalence of diabetes in China is about three times higher than it was 10 years ago. On average, subjects with diabetes are older, have higher personal annual incomes, and more often have a family history of diabetes. They also have higher mean BMI, waist-to-hip ratio (WHR), systolic blood pressure, diastolic blood pressure, and a greater prevalence of hypertension. They perform less physical activity and have less education than people with normal oral glucose tolerance test results. Multiple logistic stepwise regression analysis shows that age, BMI (or WHR), family history of diabetes, hypertension, less physical activity, and higher annual income are independent risk factors of NIDDM, and that low education is also an independent risk factor of NIDDM in people with higher personal annual income. CONCLUSIONS: The prevalence of diabetes in China is increasing with economic development and changes from traditional to modernized lifestyle, especially where people had lower level of education and socioeconomic development. Therefore, Chinese people should attempt to retain certain features of their traditional lifestyle (physical activity, healthy food, moderate body weight). Increased knowledge of risk factors for diabetes may help to prevent a further rapid increase in the prevalence of diabetes in China.

Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study.

OBJECTIVE: Individuals with impaired glucose tolerance (IGT) have a high risk of developing NIDDM. The purpose of this study was to determine whether diet and exercise interventions in those with IGT may delay the development of NIDDM, i.e., reduce the incidence of NIDDM, and thereby reduce the overall incidence of diabetic complications, such as cardiovascular, renal, and retinal disease, and the excess mortality attributable to these complications. RESEARCH DESIGN AND METHODS: In 1986, 110,660 men and women from 33 health care clinics in the city of Da Qing, China, were screened for IGT and NIDDM. Of these individuals, 577 were classified (using World Health Organization criteria) as having IGT. Subjects were randomized by clinic into a clinical trial, either to a control group or to one of three active treatment groups: diet only, exercise only, or diet plus exercise. Follow-up evaluation examinations were conducted at 2-year intervals over a 6-year period to identify subjects who developed NIDDM. Cox's proportional hazard analysis was used to determine if the incidence of NIDDM varied by treatment assignment. RESULTS: The cumulative incidence of diabetes at 6 years was 67.7% (95% CI, 59.8-75.2) in the control group compared with 43.8% (95% CI, 35.5-52.3) in the diet group, 41.1% (95% CI, 33.4-49.4) in the exercise group, and 46.0% (95% CI, 37.3-54.7) in the diet-plus-exercise group (P < 0.05). When analyzed by clinic, each of the active intervention groups differed significantly from the control clinics (P < 0.05). The relative decrease in rate of development of diabetes in the active treatment groups was similar when subjects were stratified as lean or overweight (BMI < or > or = 25 kg/m2). In a proportional hazards analysis adjusted for differences in baseline BMI and fasting glucose, the diet, exercise, and diet-plus-exercise interventions were associated with 31% (P < 0.03), 46% (P < 0.0005), and 42% (P < 0.005) reductions in risk of developing diabetes, respectively. CONCLUSIONS: Diet and/or exercise interventions led to a significant decrease in the incidence of diabetes over a 6-year period among those with IGT.

Relative bioavailability of two oral formulations of navelbine in cancer patients.

A study was carried out in 14 cancer patients to assess the relative bioavailability of two oral formulations of navelbine. A single 130 mg oral dose of the drug was given according to a randomized two-way crossover design as two capsules: one contained the drug in powder (formulation A, reference); another contained the drug in solution (formulation B). A 7 d washout period separated each dose. Navelbine was rapidly absorbed after administration of either formulation and exhibited a biphasic concentration decay pattern. The peak plasma level was reached within 2 h of administration in most patients. Formulation B resulted in better navelbine absorption with respect to peak plasma concentration (Cmax) and area under the plasma concentration-time curves (AUC) than did formulation A as ascertained by analysis of variance (ANOVA). The relative bioavailabilities (solution versus powder) were, respectively, 286.0% and 268.0% as estimated from experimental (0-72 h) and extrapolated (0-infinity) AUC.

[Relationship between obesity and risk factors of coronary heart disease in nondiabetics].

We analysed the data of 395 nondiabetic obese (BMI 25-42.2, impaired glucose tolerance, IGT, 257 and normal glucose tolerance, NGT, 138) and 482 nonobese subjects (BMI 15.9-24.9, IGT 170 and NGT 312). The blood pressure, plasma glucose, insulin, triglyceride and total cholesterol in obese were higher than that in nonobese, while HDL-c level was lower after controlling for age and sex (P < 0.001). This difference remained to be significant even after the adjustment of age, sex, insulin and 2-hours plasma glucose. Therefore, it was suggested that obesity was easy of access to coronary heart disease risk factors independent of hyperglycemia and hyperinsulinemia.

Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions.

Vinblastine biotransformation was investigated by using a human liver microsomes library. The drug was converted into one major metabolite (M) upon incubation with the microsomes. A large interindividual variation in vinblastine metabolism was observed among the samples tested, with a 4.4 ratio between the lowest and the highest metabolic rates. The biotransformation of vinblastine followed Michaelis-Menten kinetics (Km = 6.82 +/- 0.27 microM and Vmax = 0.64 +/- 0.06 nmol/min/mg protein). The involvement of the cytochrome P450 3A subfamily in vinblastine metabolism was demonstrated by the following body of evidence: (a) the competitive inhibition of vinblastine biotransformation by cytochrome P450 3A specific probes with Ki values of 0.17, 22.5, 14.8, and 35.3 microM for ketoconazole, erythromycin, troleandomycin, and vindesine, respectively; (b) the immunoinhibition of vinblastine metabolism by polyclonal anti-cytochrome P450 3A antibodies; (c) the highly significant correlation between the level of cytochrome P450 3A determined by Western blots and vinblastine metabolism (r = 0.759, P < 0.001); (d) the highly significant correlation between erythromycin N-demethylase activity (mediated by cytochrome P450 3A) and vinblastine metabolism (r = 0.83, P < 0.001); (e) the significant correlation between the CYP3A4 mRNA level and vinblastine metabolism (r = 0.60, P < 0.1). Although vincristine and navelbine (members of the Vinca alkaloid family) also inhibit the metabolism of vinblastine, suggesting the involvement of the cytochrome subfamily in their respective metabolisms, other anticancer drugs currently associated with vinblastine in chemotherapy (etoposide, Adriamycin, lomustine, and teniposide) also interfere with vinblastine biotransformation. These metabolic drug interactions may alter the antitumor activity and/or toxicity of the drug during anticancer chemotherapy.

[A new insulin-sensitivity index for the population-based study].

This paper suggests a new simple insulin-sensitivity index, the reverse of fasting plasma glucose and insulin product, which is significantly correlated with the insulin-sensitivity index determined by euglycemic insulin clamp technique (insulin mediated glucose disposal rate, M value) in 320 subjects of Americans including two races (r > 0.7, P = 0.0001). The analysis of 874 cases Chinese showed that the insulin-sensitivity (IS) evaluated by this new index in Chinese was similar to that determined by insulin clamp in Americans: If the IS in subjects with normal glucose tolerance defined as 1.0, then the IS in subjects with impaired glucose tolerance in Chinese and in Americans was 0.61, 0.62 (Pima Indians), 0.71 (Caucasians) and in diabetic Chinese and Americans was 0.57 and 0.53 (Pima Indians and Caucasians) respectively. Thus, it indicated this new index is fit for the evaluation of IS in Chinese population.

[Effects of sex hormones on plasma lipoproteins in middle older age non-diabetes, diabetes and coronary heart disease].

We has observed the effects of sex hormones on plasma lipoproteins by analysing 165 patients of non-diabetes mellitus (NDM), diabetes mellitus (DM) and coronary heart disease (CHD) in the elder than 45 years. Of these subjects, NDM were 54, DM 47, CHD 48 and DM with CHD 16. The result statistically showed that is a significant difference in high density lipoprotein cholesterol (HDL-C) and Apolipoprotein A1 (Apo-A1) between male and female subjects in NDM group and general population (P = 0.0001, 0.003 and P = 0.009, 0.002 respectively), but this statistically significant difference could not be observed between male and female patients in groups of DM, CHD and DM with CHD. After adjusting multiple factors of age, body mass index (BMI), estradiol (E2), fasting plasma insulin (FINS), fasting blood glucose (FBS) by the stepwise procedure analysis, the levels of HDL-C and Apo-A1 have significantly negative association with the level of testosterone (T) (P = 0.0012 and 0.0040), however, have no association with E2. Total cholesterol (TC) and triglyceride (TG) have no association with T and E2. The result suggests that T should be an independent risk factor which reduces HDL-C level.

[Incidence of NIDDM in Daqing and forecasting of NIDDM in China in 21st century].

Based on the survey of the prevalence of NIDDM in 110 660 people aged 25-74 in 1986, the incidence of NIDDM was investigated in 1990 in 36 471 people (M/F 18,801:17,670) who had normal glucose tolerance and/or plasma glucose concentration less than 6.7 mmol/L 2-hour after breakfast (carbohydrate 80 g) four years ago in Daqing, Heilongjiang province, northeast China. 103 male and 88 female diabetics were diagnosed among the 36 471 subjects from June 1986 to June 1990. This result showed that the annual incidence of NIDDM in this area is 131/100,000 (137 in males, 125 in females), and is 130/100,000 standardized to the 1982's chinese population (95% confidence interval, 94-168/100,000). We may estimate that there would be 754 thousand new diabetics per year in 25-74 years old Chinese if the total population were 1.3 billion in China in the 21st century.

Human liver microsomal cytochrome P450 3A isozymes mediated vindesine biotransformation. Metabolic drug interactions.

Vindesine biotransformation was investigated using a bank of human liver microsomes. The drug was converted into one major metabolite (M) upon incubation with the microsomes. Large interindividual variations were observed: vindesine biotransformation rates ranged from 1.2 to 12.9 pmol/min/mg protein. Vindesine metabolic processes followed Michaelis-Menten kinetics: Km = 24.7 +/- 9.4 microM, Vmax = 1.5 +/- 0.8 nmol/min/mg protein. The involvement of human cytochrome P450 3A isozymes in vindesine metabolism was demonstrated by: (1) competitive inhibition of vindesine biotransformation by compounds known to be specifically metabolized by human cytochrome P450 3A. Apparent Ki values were 3.6, 17.9 and 19.8 microM for quinidine, troleandomycin and erythromycin, respectively; (2) immunoinhibition of vindesine metabolism by polyclonal anti-P450 3A antibody; (3) significant correlation between immunoquantified P450 3A and vindesine biotransformation (r = 0.800, P < 0.001); and (4) significant correlation between erythromycin N-demethylase activity, which was supported by P450 3A in humans, and vindesine biotransformation (r = 0.853, P < 0.001). Other vinca alkaloids also exerted an inhibitory effect on vindesine biotransformation with apparent Ki values of 3.8, 10.6 and 19.2 microM for vinblastine, vincristine and navelbine, respectively, suggesting a possible involvement of the same cytochrome subfamily in their hepatic metabolism. Moreover, a number of anticancer drugs currently associated with the vinca alkaloids, such as teniposide, etoposide, doxorubicin, lomustine, folinic acid and mitoxantrone, significantly inhibited vindesine biotransformation.

Impaired glucose tolerance and its relationship to ECG-indicated coronary heart disease and risk factors among Chinese. Da Qing IGT and diabetes study.

OBJECTIVE: To determine the prevalence of IGT and diabetes and identify the occurrence of CVD and its risk factors. RESEARCH DESIGN AND METHODS: This study was a population-based, cross-sectional study of 110,660 residents, 25-74 yr of age of DaQing, Hei Long Jiang Province, China. RESULTS: Using 1985 WHO criteria, 577 (5.5/1000) subjects with IGT and 630 (6.0/1000) with newly diagnosed diabetes were identified. In addition, 190 (1.7/1000) with previously known diabetes were identified. Hypertension, obesity, and abnormal albumin excretion were twice as frequent in those with IGT as in 279 men and 240 women of similar age and sex distribution who had normal OGTTs. Plasma cholesterol and TGs were higher, and HDL cholesterol was lower in subjects with IGT than in nondiabetic subjects. Those with IGT had a prevalence of electrocardiographically recognized CHD 9.5-fold greater than the normoglycemic subjects. Subjects with IGT had higher plasma insulin concentrations, but the 1-h insulin-glucose ratio after the 75-g glucose load was lower. In a forward stepwise multiple logistic regression analysis, IGT itself remained an independent factor associated with CHD after adjustment for age, sex, cigarette smoking, plasma cholesterol, BP, and obesity. CONCLUSIONS: Therefore, in China, IGT may occur with almost as high a frequency as diabetes and is accompanied by an increased frequency of CVD and its risk factors. Estimates from this study indicate that > 12.0% of all ECG-indicated CHD in the Da Qing population occurs in individuals with IGT and NIDDM. The IGT subjects identified in this survey form the cohort for a long-term follow-up and intervention study.

[Associations between plasma insulin and high blood pressure].

We studied the relationship between plasma insulin level and hypertension in 510 cases with normal glucose tolerance and impaired glucose tolerance. In nonobese group (BMI < 25kg/m2), plasma insulin was higher in those with hypertension than those with normal blood pressure (P < 0.0001). There was no correlation between diastole blood pressure and plasma insulin; multiple regression analysis showed that fasting plasma insulin was significantly associated with systolic blood pressure after controlling age, BMI and plasma glucose level (beta = 0.27, P = 0.0078). The result suggested that age, BMI and plasma insulin level were independent risk factors of hypertension. In obese group (BMI > 25kg/m2), blood pressure was significantly associated with age and BMI, there was no association between blood pressure and plasma insulin level.

Coronary heart disease and diabetic retinopathy in newly diagnosed diabetes in Da Qing, China: the Da Qing IGT and Diabetes Study.

In 1986, 110,660 of 281,589 residents aged 25-74 years in Da Qing, Hei Long Jiang Province of China, were surveyed. Based on the results of a 75-g oral glucose tolerance test, 630 subjects were found to have previously undiagnosed diabetes according to 1985 WHO criteria. Among them, 600 diabetics aged 35-74 years (288 men, 312 women) and 410 non-diabetics of similar age with normal glucose tolerance (207 men, 203 women) were examined to determine the prevalence of retinopathy and coronary heart disease (CHD) and to evaluate associated characteristics. Retinal examinations of 423 newly diagnosed diabetics showed that 15.4% had several microaneurysms and/or small intraretinal haemorrhage, 5.5% soft exudates, 7.1% hard exudates, and 2.3% proliferative retinopathy. Among 220 non-diabetics, 13.6% had one or two microaneurysms and/or small intraretinal haemorrhage, and only 1.4% had a few soft exudates; half of the non-diabetics with retinopathy had hypertension. CHD, according to Minnesota coding (1.1-1.3, 5.1-5.3 and 7.1) of resting electrocardiograms, was ten times more frequent in the diabetics (3.59%) than in the controls (0.32%), after adjusting for age and sex. Multiple regression analysis showed that plasma glucose concentration was a risk factor for retinopathy after adjusting for age, sex, body mass index (BMI), smoking and blood pressure. Two-hour plasma glucose concentration (after adjusting for age, sex, BMI, smoking and blood pressure) and blood pressure (after adjusting for age, sex BMI, smoking and 1-h or 2-h plasma glucose level) were associated with CHD among the diabetics and non-diabetics and among the diabetics alone. Thus, both micro- and macrovascular complications occur frequently in previously undiagnosed Chinese diabetics and the frequency of CHD is markedly increased compared to the low frequency among Chinese non-diabetics.

Cloning of apoprotein AI gene and observation on DNA polymorphism of apoprotein AI/CIII gene-loci in genomic library from a liver of Chinese.

For the research on the structure and function of the HDL apoproteins, we have successfully constructed a complete genomic library, in self-prepared EMBL3 lambda vector and the packaging extracts of lysogenic strains BHB2688, BHB2690, from a Chinese fetal liver, which will be widely used in the research on the structure and function of apoproteins. In this study, a DNA sequence polymorphism, revealed by digestion of human DNA with the restriction endonuclease Sst1 and hybridization with an apoprotein AI cDNA probe, has been shown to be located at apoAI/CIII gene-loci. Three gene related fragments (5.7 Kb, 4.0 Kb and 3.0 Kb) were detected. The 5.7 Kb fragment is common and the polymorphism is demonstrated by the presence of either a 4.0 Kb fragment (S1 allele) or the 3.0 Kb fragment (S2 allele). Individuals were genotyped S1S1 or S1S2. Our result showed that the frequency of genotype S1S2 was higher in hypertriglyceridemic subjects than that in normolipidemic subjects.

Lack of sex differences in high density lipoproteins in Pima Indians. Studies of obesity, lipase activities, and steroid hormones.

To investigate the reasons for the lack of sex differences in high density lipoproteins (HDL) observed in population studies of the Pima Indians, we selected 18 lean (9 men, 9 women, body mass index (BMI) less than 27) and 22 obese (12 men, 10 women, BMI greater than 27) Pima Indians for an inpatient study of HDL composition. We measured lipase activities and steroid hormone concentrations, both of which have previously been implicated in the control of HDL. The lean women had higher concentrations of HDL and HDL2 than did either the obese women or the lean or obese men. Lean women had significantly lower hepatic lipase activities and significantly higher concentrations of estradiol compared to obese women. Lean women also had different HDL2 composition, as indicated by the molar ratio of HDL2 cholesterol/A-I. Significant negative correlations between HDL and obesity measured by either BMI or percent body fat were observed in both sexes, but the slope of the relationship was steeper in women. Significant negative associations were observed between HDL or HDL2 concentrations and hepatic lipase in both sexes, and there were significant positive associations between HDL2 and plasma estradiol in women. The data suggest that obesity in this population has a stronger negative influence on HDL concentrations in women, possibly through changes in estradiol and hepatic lipase activities. Since there are so few lean women in the Pima population, the net result is that HDL levels in women in the population as a whole do not differ from those of men.