Ancient Mitogenomes Reveal the Origins and Genetic Structure of the Neolithic Shimao Population in Northern China.

Shimao City is considered an important political and religious center during the Late Neolithic Longshan period of the Middle Yellow River basin. The genetic history and population dynamics among the Shimao and other ancient populations, especially the Taosi-related populations, remain unknown. Here, we sequenced 172 complete mitochondrial genomes, ranging from the Yangshao to Longshan period, from individuals related to the Shimao culture in northern Shaanxi Province and Taosi culture in southern Shanxi Province, Middle Yellow River basin. Our results show that the populations inhabiting Shimao City had close genetic connections with an earlier population in the Middle Neolithic Yangshao period of northern Shaanxi Province, revealing a mostly local origin for the Shimao Society. In addition, among the populations in other regions of the Yellow River basin, the Shimao-related populations had the closest maternal affinity with the contemporaneous Taosi populations from the Longshan period. The Shimao-related populations also shared more affinity with present-day northern Han populations than with the minorities and southern Han in China. Our study provides a new perspective on the genetic origins and structure of the Shimao people and the population dynamics in the Middle Yellow River basin during the Neolithic period.

[The way to identify the man-made-lime in Neolithic in China].

Archaeological studies indicated that the "Baihuimian" building material has been excavated widely in the Neolithic Age, which was not only hard, but also of beauty and cleanly. Archaeologist concluded that the "Baihuimian" may be the earliest man-made-lime in China. So, the infrared spectroscopy was used to analyze the "Baihuimian" and "Baitiaoshi" from Taosi site. The results indicated that the ratio of upsilon2 to upsilon4 is markedly different between "Baihuimian" and "Baitiaoshi" by infrared spectroscopy which shows that there is a big difference in the disorder parameter of calcium carbonate crystal, suggesting calcined "Baihuimian" is identified depending on infrared spectroscopy. Thereby, it offers a simpler and more efficient method to study the origin of lime. Meanwhile, the temper of "Baihuimian" was also analyzed by microscope and infrared spectroscopy methods, respectively, which proves that the mixed materials (admixture) in "Baihuimian" is cellulose.

[Spectral analysis of ceramic-painting pigments from Taosi site].

Based on the analysis of Raman, IR spectroscopy and XRD methods, the structure of the different pigments and bond in red pigment in the ceramic from Taosi site in Xiangfeng county, Shanxi province was analyzed. It is very prominent that both red and white pigments have been well preserved. The red pigment was identified as HgS, while white pigment is CaCO3, and the bond in red pigment is CaCO3, which was made from white lime, and the reasons for its formation is because of carbon dioxide in air, which was absorbed by white lime over long history. Moreover, it was indicated that the Raman and IR spectra are more effective for identifying the ancient pigments in very few quantities than XRD. Furthermore, the fact that quartz was unfound in vermilion, suggested that the technique for synthetic vermilion might have been known in 4 000 years ago in Taosi site.

Induction of cyp3a in primary cultures of human hepatocytes by ginkgolides a and B.

1. The present study was designed to determine the effects of ginkgolide A, ginkgolide B and quercetin on CYP3A protein expression and enzyme activity in primary cultures of human hepatocytes. 2. Hepatocytes were pretreated with ginkgolide A, ginkgolide B and quercetin (at 1, 3, 10 and 30 micromol/L) for 48 h and then exposed to testosterone (250 micromol/L) for 30 min. Rifampin (10 micromol/L) and phenobarbital (2 mmol/L) were used as positive controls. The CYP3A activity was measured by the amount of 6beta-hydroxytestosterone in the culture medium and CYP3A protein in hepatocyte lysate was semiquantified by immunoblotting. 3. Compared with the vehicle control, ginkgolides A and B, at 30 micromol/L, significantly induced CYP3A protein expression (2.1- and 2-fold, respectively; both P < 0.01) and markedly induced CYP3A-mediated testosterone 6beta-hydroxylation (2.5-fold each; P < 0.05 for ginkgolide A; P > 0.05 for ginkgolide B). Quercetin had no apparent induction. 4. Ginkgolide A and ginkgolide B can induce CYP3A protein expression and enzyme activity in primary cultures of human hepatocytes at higher doses.

Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor gamma.

Adiponectin is a protein hormone involved in maintaining energy homeostasis in metabolically active tissues. It enhances glucose and lipid metabolism via activation of AMP-dependent kinase (AMPK) in skeletal muscle and liver. Energy homeostasis is vital for the heart to work as a pump. In this study, we investigated whether adiponectin and its receptors are expressed in adult ventricular cardiomyocytes. We observed adiponectin transcript and protein in cultured ventricular cardiomyocytes isolated from adult rat, by quantitative real-time PCR, ELISA assays, Western blots, and immunofluorescent staining. In addition, we detected adiponectin receptor (AdipoR1 and AdipoR2) expression in the heart. AdipoR1 was expressed in rat myocardium at a level of approximately 50% of that in skeletal muscle; whereas adipoR2 was expressed at a similar level to that in liver. Rosiglitazone, a Peroxisome proliferator activated receptor gamma (PPARgamma) activator, substantially elevated expression of adiponectin in cultured cardiomyocytes and its secretion into cultured media. Rosiglitazone also increased adipoR1 and adipoR2 expression in cardiomyocytes. Treatment of recombinant globular adiponectin in cultured cardiomyocytes increased fatty acid oxidation and glucose uptake via activation of AMPK, suggesting a role for adiponectin in cardiac energy metabolism. Together, these data establish the existence of a local cardiac-specific adiponectin system that is regulated by PPARgamma. Moreover, these findings indicate a role for adiponectin on normal myocardial energy homeostasis, in part, through the activation of AMPK.

Effects of individual ginsenosides, ginkgolides and flavonoids on CYP2C19 and CYP2D6 activity in human liver microsomes.

1. The effects of four individual ginsenosides (Rb1, Rb2, Rc and Rd), two ginkgolides (A and B) and one flavonoid (quercetin) on CYP2C19-dependent S-mephenytoin 4 cent-hydroxylation and CYP2D6-mediated bufuralol 1 cent-hydroxylation were evaluated in human liver microsomes. 2. Increasing concentrations of each test compound were added to microsomal incubation mixtures containing a well-characterized marker substrate (S-mephenytoin for CYP2C19 or bufuralol for CYP2D6) to determine their IC(50) values (compound concentration yielding 50% inhibition of a marker enzyme activity), which were estimated by graphical inspection. 3. For CYP2C19, the IC(50) values were 46, 46 and 62 micromol/L for ginsenoside Rd, quercetin and ginsenoside Rb2, respectively, whereas only ginsenoside Rd had an IC(50) value of 57 micromol/L for CYP2D6. 4. The data suggest that the tested compounds are not likely to inhibit the metabolism of the concurrent use of a given drug whose primary route of elimination is through CYP2C19 or CYP2D6.

Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy.

Fatty acid oxidation (FAO) is a primary energy source for meeting the heart's energy requirements. Peroxisome proliferator-activated receptor-delta (PPAR-delta) may have important roles in FAO. But it remains unclear whether PPAR-delta is required for maintaining basal myocardial FAO. We show that cre-loxP-mediated cardiomyocyte-restricted deletion of PPAR-delta in mice downregulates constitutive expression of key FAO genes and decreases basal myocardial FAO. These mice have cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy and congestive heart failure with reduced survival. Thus, chronic myocardial PPAR-delta deficiency leads to lipotoxic cardiomyopathy. Together, our data show that PPAR-delta is a crucial determinant of constitutive myocardial FAO and is necessary to maintain energy balance and normal cardiac function. We suggest that PPAR-delta is a potential therapeutic target in treating lipotoxic cardiomyopathy and other heart diseases.

The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes.

Herbal medicines are widely consumed by patients in different clinical settings in the United States and all over the world. In this study, 7 herbal components ginsenosides Rb1, Rb2, Rc, and Rd (from ginseng quercetin) ginkgolides A and B (from ginkgo biloba) were investigated for their inhibitory effects on hepatic CYP2C9 and CYP3A4 catalytic activities in human liver microsomes. Tolbutamide 4-methylhydroxylation and testosterone 6beta-hydroxylation were used as index reactions of CYP2C9 or CYP3A4 catalytic activities, respectively. The metabolites of both reactions were measured by high-performance liquid chromatography and used as indicators of whether enzymes were inhibited or unaffected by these agents. Herbal components were studied at various concentrations (0.1, 1, 10, 100, 200 micromol/L). The herbal compounds investigated were capable of inhibiting CYP2C9 and CYP3A4 catalytic activities, but the potencies differed. Quercetin showed marked inhibitory effects on both tolbutamide 4-methylhydroxylation and testosterone 6beta-hydroxylation with IC(50) values of 35 and 38 micromol/L, respectively. Ginsenoside Rd also had significant inhibitory potency on both CYP2C9- and CYP3A4-mediated index reactions with IC(50) values of 105 and 62 micromol/L, respectively. Ginsenosides Rb1, Rb2, and Rc had limited inhibitory activities on both enzyme reaction systems, whereas the effects of ginkgolides A and B appeared negligible. It is concluded that the components of ginseng and ginkgo biloba screened are capable of inhibiting CYP2C9- and CYP3A4-mediated metabolic reactions. Our findings suggest that quercetin and ginsenoside Rd have the potential to interact with conventional medicines that are metabolized by CYP2C9 and CYP3A4 in vivo.

Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes.

OBJECTIVE: To screen the inhibitory effects of H1-antihistamines on hepatic bufuralol 1'-hydroxylation and on tolbutamide 4-methylhydroxylation in human liver microsomes. METHODS: Bufuralol 1'-hydroxylation and tolbutamide 4-methylhydroxylation were used as index reactions for CYP2D6 and CYP2C9, respectively. The metabolites of both reactions were measured using high-performance liquid chromatography and were used as indicators of whether CYP2D6 or CYP2C9 activities were inhibited or unaffected by the agents. RESULTS: All five H1-antihistamines studied showed a concentration-dependent inhibition of CYP2D6-mediated bufuralol 1'-hydroxylation with 50% inhibitory concentration (IC50) values of 32-109 microM. Cyclizine and promethazine showed inhibitory effects on tolbutamide 4-methylhydroxylation with IC20 values of 85 microM and 88 microM, respectively. Tripelennamine, chlorpheniramine, and diphenhydramine showed no inhibitory effects on CYP2C9. CONCLUSION: All five H1-antihistamines studied inhibited CYP2D6 markedly, but only cyclizine and promethazine inhibited CYP2C9 at concentrations above that usually seen in plasma. Promethazine and chlorpheniramine inhibited CYP2D6 at concentrations that are very close to their therapeutic plasma concentrations. Further studies in humans, especially in poor metabolizers of CYP2D6, will be required to confirm these findings.

Comparison of Plasma Protein Binding of Basic Drugs in Black and White Individuals.

Interethnic difference in drug disposition is an important contributing factor to interindividual variation in drug response. Since interethnic differences in the protein binding of drugs may contribute to variation in drug disposition between ethnic groups, we conducted a study in 10 black Americans (A) and mean (plus minusSE) age 26 plus minus 6 years and weight 80 plus minus 9 kg matched against 10 white Americans (C) with a mean age of 28 plus minus 6 years and weight 81 plus minus 9 kg, all within 10% of ideal body weight. Serum alpha-1-acid glycoprotein (AGP) and albumin concentrations were measured using the auramine-O and bromcresol green methods, respectively. Verapamil, propranolol, lidocaine, disopyramide and diazepam binding in plasma were measured with the equilibrium-dialysis method, involving the determination of free and unbound drug concentrations. The unbound fraction of diazepam (A = 1.1 plus minus 0.1%; C = 1.1 plus minus 0.1%), verapamil (A = 9.5 plus minus 0.8%; C = 9.8 plus minus 0.4%), propranolol (A = 14.2 plus minus 1.0%; C = 12.6 plus minus 0.7%), lidocaine (A = 28.5 plus minus 2.1%; C = 25.7 plus minus 1.1%) and diphenhydramine (A = 42.9 plus minus 10.2; C = 30.4 plus minus 7.01%) showed no significant ethnic differences (unpaired t-test). Disopyramide measured at 7 different concentrations (1.0--20.0 &mgr;g/ml) was similar in both groups, as were the plasma concentrations of AGP (A = 100 plus minus 20 mg 100 ml; C = 120 plus minus 20 mg 100 ml) and albumin (A = 4.3 plus minus 0.1 g 100 ml; C = 4.5 plus minus 0.1 g 100 ml). It is therefore concluded that there are no interethnic differences in the protein binding of basic drugs between black Americans and white Americans and that it is not a major contributing factor to any possible interethnic variation in the disposition of responsiveness of these drugs.