To establish a model for the prediction of initial standard and maintenance doses of warfarin for the Han Chinese population based on gene polymorphism: a multicenter study.

PURPOSE: The purpose of this paper is to study the correlation between demographic and clinical factors and warfarin dose of patients in Chinese Han population taking warfarin and study gene polymorphisms impact of related gene loci (CYP2C9*3, VKORC1-1639G > A) on warfarin doses, to establish a model to predict initial standard dose and maintenance dose based on CYP2C9*3, VKORC1-1639G > A genotype. METHODS: The study collects the data of patients in our hospital and other subcenters which incorporates 2160 patients to establish the initial dose model and 1698 patients for the stable dose model, and sequences 26 multigene sites in 451 patients. Based on the patient's dosage, clinical data, and demographic characteristics, the genetic and non-genetic effects on the initial dose and stable dose of warfarin are calculated by using statistical methods, and the prediction model of initial standard dose and maintenance dose can be established via multiple linear regression. RESULTS: The initial dose of warfarin (mg/day) was calculated as (1.346 + 0.350 × (VKORC1-1639G > A) - 0.273 × (CYP2C9*3) + 0.245 × (body surface area) - 0.003 × (age) - 0.036 × (amine-iodine) + 0.021 × (sex))2. This model incorporated seven factors and explained 55.3% of the individualization differences of the warfarin drug dose. The maintenance dose of warfarin (mg/day) was calculated as (1.336 + 0.299 × (VKORC1-1639G > A) + 0.480 × (body surface area) - 0.214 × (CYP2C9*3) - 0.074 × (amine-iodine) - 0.003 × (age) - 0.077 × (statins) - 0.002 × (height))2. This model incorporated six factors and explained 42.4% of the individualization differences in the warfarin drug dose. CONCLUSION: The genetic and non-genetic factors affecting warfarin dose in Chinese Han population were studied systematically in this study. The pharmacogenomic dose prediction model constructed in this study can predict anticoagulant efficacy of warfarin and has potential application value in clinical practice.

Anti-influenza A Virus Effects and Mechanisms of Emodin and Its Analogs via Regulating PPARα/γ-AMPK-SIRT1 Pathway and Fatty Acid Metabolism.

The peroxisome proliferator-activated receptor (PPAR) α/γ-adenosine 5'-monophosphate- (AMP-) activated protein kinase- (AMPK-) sirtuin-1 (SIRT1) pathway and fatty acid metabolism are reported to be involved in influenza A virus (IAV) replication and IAV-pneumonia. Through a cell-based peroxisome proliferator responsive element- (PPRE-) driven luciferase bioassay, we have investigated 145 examples of traditional Chinese medicines (TCMs). Several TCMs, such as Polygonum cuspidatum, Rheum officinale Baillon, and Aloe vera var. Chinensis (Haw.) Berg., were found to possess high activity. We have further detected the anti-IAV activities of emodin (EMO) and its analogs, a group of common important compounds of these TCMs. The results showed that emodin and its several analogs possess excellent anti-IAV activities. The pharmacological tests showed that emodin significantly activated PPARα/γ and AMPK, decreased fatty acid biosynthesis, and increased intracellular ATP levels. Pharmaceutical inhibitors, siRNAs for PPARα/γ and AMPKα1, and exogenous palmitate impaired the inhibition of emodin. The in vivo test also showed that emodin significantly protected mice from IAV infection and pneumonia. Pharmacological inhibitors for PPARα/γ and AMPK signal and exogenous palmitate could partially counteract the effects of emodin in vivo. In conclusion, emodin and its analogs are a group of promising anti-IAV drug precursors, and the pharmacological mechanism of emodin is linked to its ability to regulate the PPARα/γ-AMPK pathway and fatty acid metabolism.

Regulatory action of charred Gossamer urocteae on the functions of mouse oral fibroblasts.

OBJECTIVE: To explore the influence of charred Gossamer urocteae (CGU) on the functions of primary cultured mouse oral fibroblasts and reveal its mechanism in wound healing. METHODS: CGU was extracted with different solvents and ethanol extract (EE), ethyl acetate fraction (EF), n-butanol fraction (BF) and aqueous fraction (AF) were obtained. The effects of different fractions on the proliferation, matrix metalloproteinase-2,9 (MMP-2,9) activities, synthesis of collagen and tissue inhibitor of metalloproteinase 1 (TIMP-1) in the mouse oral fibroblasts were determined by MTT, gelatin zymography, chloramine-T method, and enzyme-linked immunosorbent assay (ELISA) respectively. RESULTS: EE, EF and BF at high concentrations could significantly inhibit proliferation of fibroblasts (P<0.05 or P<0.01), and at low concentrations EF and BF could promote proliferation of fibroblasts, and BF and AF could significantly inhibit collagen synthesis (P<0.05 or P<0.01). EE, EF and AF at high concentrations could significantly increase the MMP-9 activity, and BF and AF could significantly inhibit synthesis of TIMP-1. CONCLUSION: CGU at high concentrations can inhibit the proliferations of fibroblasts and synthesis of collagen, and in healing of wound, CGU at high concentrations possibly has the functions of anti-fibrosis and anti-scar, and the mechanism to promote degradation of collagen is possibly related to the increase in MMP-9 activity and the inhibition of TIMP-1 synthesis.

[Regulation of calculus bovis on the function of mice oral fibroblasts].

To explore the influence of calculus bovis on the function of primary cultured mice oral fibroblasts, we determined the effects of calculus bovis on the fibroblast proliferation, collagen production, matrix metalloproteinases-2, -9 activities and tissue inhibitor of metalloproteinase-1 production by MTT assay, chloramine T method, gelatin zymography and enzyme-linked immunosorbent assays respectively. The results showed that calculus bovis could significantly inhibit the proliferation of fibroblasts and collagen synthesis in a concentration dependent manner, could significantly (P<0.05) suppress matrix metalloproteinases-2 activity and very significantly (P<0.01) inhibit the production of tissue inhibitor of metalloproteinase-1. In conclusion, the major function of calculus bovis in the process of ulcer healing is not to promote tissue regeneration, the mechanism that calculus bovis inhibits collagen synthesis may be partly due to its ability to very significantly (P<0.01) suppress the production of tissue inhibitor of metalloproteinase-1.

Influence of borneol on primary mice oral fibroblasts: a penetration enhancer may be used in oral submucous fibrosis.

BACKGROUND: Borneol, a widely used food and cosmetics additive, has analgesic, anti-inflammatory, antibacterial and penetration enhancing effects. We try to use it as a penetration enhancer for a formula which we have used to treat oral submucous fibrosis (OSF). To assess its safety, we investigate its effects on primary mice oral fibroblasts. METHODS: Primary mice oral fibroblasts were cultured, the effects of borneol on fibroblasts proliferation, cytotoxicity, collagen production, matrix metalloproteinases-2,9 (MMP-2,9) activities and tissue inhibitors of metalloproteinase 1 (TIMP-1) production were tested by methyl thiazolyl tetrazolium assay, lactic dehydrogenase activity assay, chloramine T method, gelatin zymography and enzyme-linked immunosorbent assay, respectively. RESULTS: Borneol, from 18.75 to 300 microg/ml, could significantly (P < 0.05) decrease the growth of fibroblasts and very significantly (P < 0.01) inhibit collagen production in a concentration dependant manner. From 18.75 to 150 microg/ml, borneol had no cytotoxicity on mice oral fibroblasts. Moreover borneol could significantly (P < 0.05) decrease MMP-2 activity, and very significantly (P < 0.01) inhibit TIMP-1 production. CONCLUSIONS: This study indicates that borneol has anti-fibrosis activity and the mechanism may partly be relevant to its inhibiting effects on fibroblasts mitosis, collagen and TIMP-1 production. It can be safely used as a penetration enhancer for our formula to treat OSF.

[Molluscicidal activity of endophyte JJ18 from Pseudolarix kaempferi inoculated to beach soil].

Endophyte JJ18 from Pseudolarix kaempferi was inoculated on solid medium (A), sterile soil (B), and non-sterile soil (C), respectively. The molluscicidal efficacy of fermented products of soil extract was detected according to the immersion test method recommended by WHO, the survival time of JJ18 was observed. Control groups included non-sterile soil (D), ionic water without chloride ion (E) and niclosamide (F). The acute toxicity of A-D group against Artemia salina was determined with artificial seawater as control. After immersing for 24 h, 48 h and 72 h, the snail mortality of group B [(36.67+/-7.56)%, (63.33+/-4.65)%, and (90+/-0)%] was significantly higher than those of group D [(30+/-6.87)%, (33.33+/-5.68)%, and (56.67+/-8.55)%] (P<0.05, P<0.01). Endophyte JJ18 survived in soil for at least 30 days. The mortality of Artemia salina in group B [(25.24+/-3.74)%] was significantly lower than that of group A[(57.15+/-8.90)%] (P<0.01).