Polymorphism of ORM1 Is Associated with the Pharmacokinetics of Telmisartan

Background

The pharmacokinetics (PKs) and pharmacodynamics (PDs) of telmisartan varies among the individuals, and the main causes remain unknown. The aim of this study was to evaluate the impact of ORM1, as well as ABCC2, ABCB1, ABCG2 and SLCO1B3 polymorphisms, on the disposition of the drug and BP change after taking 40 mg telmisartan in 48 healthy Chinese males.

Method

A total of 48 healthy males were included in this trial. Every volunteer ingested a single dose of 40 mg telmisartan, and the plasma drug concentration and blood pressure (BP) were measured up to 48 h.

Result

In this study, the area under the plasma concentration-time curve (AUC) in the heterozygotes of ORM1 113AG was higher than that in the wild-type homozygotes, AUC_(0–48) (113AA vs. 113AG, 1,549.18±859.84 ng·h/ml vs. 2,313.54±1,257.71 ng·h/ml, P = 0.033), AUC_(0–∞) (113AA vs. 113AG, 1,753.13±1,060.60 ng·h/ml vs. 2,686.90±1,401.87 ng·h/ml, P = 0.016), and the change(%) of the diastolic blood pressure (DBP) from the baseline BP value also showed a significant difference between the ORM1 113AG and 113AA genotypes at 5 h after taking telmisartan (P = 0.026). This study also showed that the allele of ABCC2 C3972T would affected the disposition of telmsiartan and the DBP change significantly after taking the drug. However, the common SNPs of ABCG2 C421, ABCB1 C3435T, and SLCO1B3 T334G showed no impacts on the PKs of telmisartan or BP change(%) in our trial.

Conclusion

The ORM1 A113G polymorphism was associated with the PKs variability after taking telmsiartan, as well as ABCC2 C3972T. The heterozygotes of ORM1 113AG showed a larger AUC and a notable BP change(%) from the baseline compared with the wild-type.

Trial Registration

Chinese Clinical Trial Registry ChiCTR-TNC-10000898     

Transcriptome and weighted correlation network analyses provide insights into inflorescence stem straightness in Paeonia lactiflora

Plant Molecular Biology - Lack of structural components results in inflorescence stem bending. Differentially expressed genes involved in lignin and hemicellulose biosynthesis are vital; genes...     

Inhibition of ROS-Activated p38MAPK Pathway is Involved in the Protective Effect of H2S Against Chemical Hypoxia-Induced Inflammation in PC12 Cells

We have demonstrated the neuroprotection of hydrogen sulfide (H₂S) against chemical hypoxia-induced injury by inhibiting p38MAPK pathway. The present study attempts to evaluate the effect of H₂S on chemical hypoxia-induced inflammation responses and its mechanisms in PC12 cells. We found that treatment of PC12 cells with cobalt chloride (CoCl₂, a hypoxia mimetic agent) enhanced IL-6 secretion, nitric oxide (NO) generation and expression levels of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). L-canavanine, a selective iNOS inhibitor, partly blocked CoCl₂-induced cytotoxicity, apoptosis and mitochondrial insult. In addition, 7-Nitroindazole (7-NI), an inhibitor of nNOS, also partly attenuated the CoCl₂-induced cytotoxicity. The inhibition of p38MAPK by SB203580 (a selective p38MAPK inhibitor) or genetic silencing of p38MAPK by RNAi (Si-p38) depressed not only CoCl₂-induced iNOS expression, NO production, but also IL-6 secretion. In addition, N-acetyl-l-cysteine, a reactive oxygen species (ROS) scavenger, conferred a similar protective effect of SB203580 or Si-p38 against CoCl₂-induced inflammatory responses. Importantly, pretreatment of PC12 cells with exogenous application of sodium hydrosulfide (a H₂S donor, 400 μmol/l) for 30 min before exposure to CoCl₂ markedly attenuated chemical hypoxia-stimulated iNOS and nNOS expression, NO generation and IL-6 secretion as well as p38MAPK phosphorylation in PC12 cells. Taken together, we demonstrated that p38MAPK-iNOS pathway contributes to chemical hypoxia-induced inflammation and that H₂S produces an anti-inflammatory effect in chemical hypoxia-stimulated PC12 cells, which may be partly due to inhibition of ROS-activated p38MAPK-iNOS pathway.     

Relationship between leptin receptor and polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, which is involved in the multi-system disease, and its etiology is still not clearly understood. It is currently considered that not only the genetic factors but also the environment factors play a crucial role in the pathogenesis of PCOS. Obesity plays an important role through the insulin, leptin and endocannabinoid system in the pathological process of PCOS, leading to more severe clinical manifestations. The aim of our present study is to investigate whether there is association between single nucleotide polymorphisms (SNPs) of Gln223Arg and Pro1019Pro in the leptin receptor gene (LEPR) and PCOS in a Korean population. Interestingly, a significant association was found between the Pro1019Pro in LEPR gene and PCOS, and a highly significant association was found between the Gln223Arg in LEPR gene and PCOS (P = 0.033, OR = 1.523, 95% confidence interval and P < 0.0001, OR = 0.446, 95% confidence interval). Moreover, genotype combination and haplotype analyses indicate that Gln223Arg and Pro1019Pro polymorphisms of LEPR are significantly associated with the risk of PCOS.     

A functional polymorphism in interleukin-1α (IL1A) gene is associated with risk of alopecia areata in Chinese populations

Alopecia areata (AA) is an inflammatory hair loss disorder with a major genetic component, which may cause great psychosocial distress for those affected. Studies have shown that interleukin-1 (IL-1) is a very potent inducer of hair loss and a significant human hair growth inhibitor. The 4-bp insertion/deletion (Indel) polymorphism (rs3783553) within the 3′ untranslated regions of IL1A gene has been suggested to be associated with risk of various types of cancers, possibly through regulating expression of IL-1α levels. In the current study, we estimated the susceptibility to AA associated with rs3783553 in two independent case–control panels of Eastern and Southern Chinese populations, totally containing 313 AA cases and 626 healthy controls. Logistic regression analysis showed that the heterozygote and the homozygote 4-bp ins/ins confer a significantly lower risk of AA in both panels and total subjects [odds ratio (OR) = 0.55, 95% confidence interval (C.I.) = 0.41–0.75, P = 6.24 × 10^− 5; OR = 0.47, 95% C.I. = 0.28–0.76, P = 0.001, respectively]. Stratification analysis based on age onset showed that the protective roles of ins/del and ins/ins genotype against developing AA was more obvious in AA patients with early age onset (< 30 years) under dominant model (OR = 0.48, 95% C.I. = 0.29–0.77, P = 0.001). The results of luciferase assay showed that rs3783553 could influence expression of IL-1α in a miR-122 dependant manner. Taken together, our results suggested that the IL1A 4-bp indel polymorphism may be a marker for genetic susceptibility to patchy (mild) AA in Chinese populations, likely through miR-122 mediated regulation.     

Molecular cloning and expression of Hedychium coronarium farnesyl pyrophosphate synthase gene and its possible involvement in the biosynthesis of floral and wounding/herbivory induced leaf volatile sesquiterpenoids

Farnesyl pyrophosphate synthase (FPPS EC 2.5.1.10) catalyzes the production of farnesyl pyrophosphate (FPP), which is a key precursor for many sesquiterpenoids such as floral scent and defense volatiles against herbivore attack. Here we report a new full-length cDNA encoding farnesyl diphosphate synthase from Hedychium coronarium. The open reading frame for full-length HcFPPS encodes a protein of 356 amino acids, which is 1068 nucleotides long with calculated molecular mass of 40.7 kDa. Phylogenetic tree analysis indicates that HcFPPS belongs to the plant FPPS super-family and has strong relationship with FPPS from Musa acuminata. Expression of the HcFPPS gene in Escherichia coli yielded FPPS activity. Tissue-specific and developmental analyses of the HcFPPS mRNA and corresponding volatile sesquiterpenoid levels in H. coronarium flowers revealed that the HcFPPS might play a regulatory role in floral volatile sesquiterpenoid biosynthesis. The emission of the FPP-derived volatile terpenoid correlates with strong expression of HcFPPS induced by mechanical wounding and Udaspes folus-damage in leaves, which suggests that HcFPPS may have an important ecological function in H. coronarium vegetative organ.     

极性蛋白与上皮肿瘤恶性转变

细胞极性是指细胞形态、蛋白分布以及细胞功能的不对称性,它是细胞发育、维持项一底极性、损伤修复及组织完整性等生理过程所必需的,主要是由极性蛋白调控。一旦极性蛋白之间的平衡失调,则会破坏细胞极性,诱导肿瘤发生、增殖及迁移。研究表明,极性蛋白的异常表达及错误定位均与肿瘤紧密相关。上皮细胞肿瘤发生及恶性转变过程通常伴有细胞极性丢失以及组织结构紊乱的现象,尤其是经历上皮间充质转变的上皮肿瘤细胞更易侵袭周围基质,最终引发转移。作者就目前有关极性蛋白在肿瘤方面的研究作一综述,重点阐述极性蛋白在肿瘤转移中的功能,并对相关问题进行讨论。