A pharmacogenetics-based dosing algorithm has been developed for improvement in the time to reach the stable dosing of warfarin. This model may be useful in helping the clinicians to prescribe warfarin with greater safety and efficiency.

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1. Metformin is an activator of AMP-activated protein kinase (AMPK). Recent studies suggest that pharmacological activation of AMPK inhibits cardiac hypertrophy. In the present study, we examined whether long-term treatment with metformin could attenuate ventricular hypertrophy in a rat model. The potential involvement of nitric oxide (NO) in the effects of metformin was also investigated. 2. Ventricular hypertrophy was established in rats by transaortic constriction (TAC). Starting 1 week after the TAC procedure, rats were treated with metformin (300 mg/kg per day, p.o.), N(G)-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg per day, p.o.) or both for 8 weeks prior to the assessment of haemodynamic function and cardiac hypertrophy. 3. Cultured cardiomyocytes were used to examine the effects of metformin on the AMPK-endothelial NO synthase (eNOS) pathway. Cells were exposed to angiotensin (Ang) II (10⁻⁶ mol/L) for 24 h under serum-free conditions in the presence or absence of metformin (10⁻³ mol/L), compound C (10⁻⁶ mol/L), L-NAME (10⁻⁶ mol/L) or their combination. The rate of incorporation of [³H]-leucine was determined, western blotting analyses of AMPK-eNOS, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) were undertaken and the concentration of NO in culture media was determined. 4. Transaortic constriction resulted in significant haemodynamic dysfunction and ventricular hypertrophy. Myocardial fibrosis was also evident. Treatment with metformin improved haemodynamic function and significantly attenuated ventricular hypertrophy. Most of the effects of metformin were abolished by concomitant L-NAME treatment. L-NAME on its own had no effect on haemodynamic function and ventricular hypertrophy in TAC rats. 5. In cardiomyocytes, metformin inhibited AngII-induced protein synthesis, an effect that was suppressed by the AMPK inhibitor compound C or the eNOS inhibitor L-NAME. The improvement in cardiac structure and function following metformin treatment was associated with enhanced phosphorylation of AMPK and eNOS and increased NO production. 6. The findings of the present study indicate that long-term treatment with metformin could attenuate ventricular hypertrophy induced by pressure overload via activation of AMPK and a downstream signalling pathway involving eNOS-NO.

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Objectives: To investigate the specific role of Toll-like receptor 4 (TLR4) in the regulation of the intestinal mucosa-associated microbiota by vitamin A (VA). Methods: Both TLR4 -/- (knockout, KO) and wild-type (WT) female mice were randomly fed a VA normal (VAN) or VA deficient (VAD) diet for 4 weeks to establish the following four mouse model groups: TLR4 -/- mice fed a VAN diet (KO VAN), TLR4 -/- mice fed a VAD diet (KO VAD), WT mice fed a VAN diet (WT VAN), and WT mice fed a VAD diet (WT VAD). Then, the mice from each experimental group were mated with male mice with the same genetic background. The pups in the KO VAD and WT VAD groups were subsequently fed the VAD diet after weaning, while the pups in the KO VAN and WT VAN groups were fed the VAN diet continuously after weaning. The serum retinol levels of 7-week-old offspring were determined using high-performance liquid chromatography, and colons were collected from mice in each group and analyzed via 16S rRNA gene sequencing using an Illumina MiSeq platform to characterize the overall microbiota of the samples. Results: The abundance and evenness of the colon mucosa-associated microbiota were unaffected by dietary VA and TLR4 KO. VAD decreased the abundance of Anaerotruncus ( Firmicutes ), Oscillibacter ( Firmicutes ), Lachnospiraceae _ NK4A136 _ group ( Firmicutes ) and Mucispirillum ( Deferribacteres ) and increased the abundance of Parasutterella ( Proteobacteria ). TLR4 KO decreased the abundance of Bacteroides ( Bacteroidetes ) and Alloprevotella ( Bacteroidetes ). However, the abundance of Allobaculum ( Firmicutes ), Ruminiclostridium_9 ( Firmicutes ), Alistipes ( Bacteroidetes ), and Rikenellaceae_RC9 ( Bacteroidetes ) impacted the interaction between VA and TLR4. Conclusion: TLR4 may play a pivotal role in regulation of the intestinal mucosa-associated microbiota by VA to maintain the intestinal microecology.

Proteasome inhibitors are involved in cell cycle control, growth and inflammatory signaling, and transcriptional regulation of mitotic cells. A recent study has suggested that specific proteasome inhibitor MG132 may suppress cardiomyocyte hypertrophy in vitro. However, the underlying molecular mechanisms are not clear. In this study, we investigated the effects of long-term MG132 treatment on cardiac hypertrophy and the related molecular mechanisms in vivo. MG132 (0.1 mg/kg/day) was intraperitoneally injected to rats with abdominal aortic banding (AAB) for 8 weeks. Results showed that treatment with MG132 significantly attenuated left ventricular (LV) myocyte area, LV weight/body weight, and lung weight/body weight ratios, decreased LV diastolic diameter and wall thickness, and increased fractional shortening in AAB rats. AAB induced the phosphorylation of ERK1/2, JNK1, and p38 in cardiac myocytes. The elevated phosphorylation levels of ERK1/2 and JNK1 in AAB rats were significantly reversed by MG132 treatment. In conclusion, our results suggested that long-term treatment with MG132 attenuates pressureoverload-induced cardiac hypertrophy and improves cardiac function in AAB rats through regulation of ERK1/2 and JNK1 signaling pathways.