Effects of black cohosh on the plasminogen activator system in vascular smooth muscle cells

Objective

The rhizome of the Cimicifuga racemosa plant (commonly known as black cohosh) has been used for menopausal complaints. Studies regarding the cardiovascular effects of black cohosh are lacking. We investigated the effect of black cohosh on the plasminogen activator system in cultured vascular smooth muscle cells (VSMCs).

Methods

VSMCs were isolated from rat aortae. Expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) proteins were evaluated by Western blot analysis and enzyme-linked immunosorbent assay, respectively. The activities of PAI-1 and t-PA in the conditioned media were assessed by fibrin overlay zymography. A 40% 2-propanol extract of black cohosh was used.

Results

Black cohosh extract (BcEx) stimulated the protein expression of PAI-1, but it did not affect that of t-PA. Vitamin E, a potent antioxidant, inhibited the BcEx-induced increase in PAI-1 expression, while ICI 182,780, an estrogen receptor antagonist, had no effect. Fibrin overlay zymography revealed that BcEx increased the activity of PAI-1 in the conditioned media, while concurrently decreasing that of free t-PA by inducing a binding to PAI-1.

Conclusions

BcEx induces PAI-1 protein expression in the VSMCs likely via an oxidant mechanism. It also stimulates the enzyme activity of PAI-1 and reduces that of free t-PA. These findings suggest that black cohosh might exert a negative influence on fibrinolysis.     

Day/Night Rhythm of Hemostatic Factors in Obstructive Sleep Apnea

Study Objectives:

To investigate the hypothesis that day/night patterns of prothrombotic activity differ between patients with obstructive sleep apnea (OSA) and individuals with no OSA.

Design:

Prothrombotic markers'' day/night rhythms recorded over one 24-h period.

Setting:

General clinical research center.

Patients:

38 untreated OSA patients as verified by polysomnography (apnea-hypopnea index ≥10/h sleep) and 22 non-OSA controls.

Measurements and Results:

Blood samples were collected every 2 h to measure plasma levels of fibrinolysis-inhibiting plasminogen activator inhibitor (PAI)-1 and the primary fibrin degradation product D-dimer. Day/night variation in hemostasis factors was examined using a cosinor analysis. Mesor (mean) PAI-1 over the 24-h period was higher (P = 0.015), and mesor of D-dimer was lower (P = 0.001) in patients with OSA than in the non-OSA controls. These group differences stayed significant when controlling for age and gender. After further adjustment for body mass index, mean arterial pressure, and smoking, the relationship between OSA and PAI-1 became non-significant, but the relationship between OSA and D-dimer continued to be significant (P = 0.006). In the fully adjusted analysis, the amplitude (peak) for D-dimer was lower in OSA patients than in non-OSA controls (P = 0.048). The acrophase (time of the peak) for PAI-1 and D-dimer did not significantly differ between groups.

Conclusions:

The relatively higher average level of PAI-1 and lower average level of D-dimer across the 24-h in OSA patients might reflect decreased fibrinolytic capacity and fibrin degradation, respectively. The findings provide some evidence for a prothrombotic state in OSA, but were only partially independent of metabolic variables.

Citation:

von Käanel R; Natarajan L; Ancoli-Israel S; Mills PJ; Loredo JS; Dimsdale JE. Day/night rhythm of hemostatic factors in obstructive sleep apnea. SLEEP 2010;33(3):371-377.     

The association of SERPINE2 gene with COPD in a Chinese Han population

Purpose

Polymorphisms of several candidate genes have been studied and associated with the development of chronic obstructive pulmonary disease (COPD). One such candidate is the SERPINE2 (Serpin peptidase inhibitor, clade E member 2) gene.

Materials and Methods

To assess whether the SERPINE2 gene is associated with COPD in a Chinese Han population. Samples were collected from a Chinese Han population and analyzed for the association of single nucleotide polymor phisms (SNPs) or haplotypes of SERPINE2 gene with COPD in a case-control study. Three SNPs including rs840088 G/A in intron 1, rs1438831 A/G in 5'' upstream sequence and rs3795879 G/A in intron 3 were detected using the polymerase chain reaction (PCR)-based restriction fragment length polymorphism technique in 409 COPD subjects and 411 controls. Genotyping of the SREPINE2 polymorphisms at positions rs840088, rs1438831and rs3795879 was performed.

Results

We found that none of the rs840088G/A, rs1438831G/A and rs3795879 G/A polymorphisms were associated with the disease. The p-values were 0.630, 0.208 and 0.398 respectively.

Conclusion

Our data suggested that there was no significant association between SERPINE2 polymorphism and COPD susceptibility in the Chinese Han population.     

Reduced monocyte adhesion to aortae of diabetic plasminogen activator inhibitor-1 knockout mice

Objective and design

To determine the requirement of plasminogen activator inhibitor-1-knockout (PAI-1) for monocyte adhesion in animals and cells under diabetic conditions.

Methods and subjects

Monocyte adhesion assay, enzyme-linked immunosorbent assay, and Western blotting were used in analyzing samples from PAI-1-knockout (PAI-1-KO) mice or cultured human umbilical vein endothelial cells (HUVEC).

Treatments

Diabetes in PAI-1-KO and wild-type mice was induced by intraperitoneal injection of streptozotocin (STZ). HUVEC was transfected with short interference RNA (siRNA) against PAI-1, tumor necrosis factor-α (TNFα), or toll-like receptor (TLR4), and then was treated with glycated low-density lipoproteins (glyLDL).

Results

The adhesion of monocytes to aortic intima was reduced in PAI-1-KO mice, which was associated with decreased levels of TNFα and monocyte chemotactic protein-1 (MCP-1) in plasma and cardiovascular tissue, and increased abundances of urokinase plasminogen activator (uPA) and uPA receptor (uPAR) in cardiovascular tissue compared to wild-type mice. Significant reductions in monocyte adhesion, inflammatory, and fibrinolytic regulators were detected in cardiovascular tissue or plasma in diabetic PAI-1-KO mice compared to wild-type diabetic mice. Transfection of PAI-1, TNFα or TLR4 siRNA to HUVEC inhibited glyLDL-induced monocyte adhesion to EC. PAI-1 siRNA inhibited the abundances of TLR4 and TNFα in EC.

Conclusion

The findings suggest that PAI-1 is required for diabetes-induced monocyte adhesion via interactions with uPA/uPAR, and it also regulates TLR4 and TNFα expression in vascular EC. Inhibition of PAI-1 potentially reduces vascular inflammation under diabetic condition.

     

Is there a relationship between endothelial nitric oxide synthase gene polymorphisms and ankylosing spondylitis?

OBJECTIVE:

Nitric oxide is produced by endothelial nitric oxide synthase, and its production can be influenced by polymorphisms of the endothelial nitric oxide synthase gene. Because candidate genes responsible for susceptibility to ankylosing spondylitis are mostly unknown and available data suggest that there may be problems related to the nitric oxide pathway, such as endothelial dysfunction and increased asymmetric dimethylarginine, this study aimed to assess the association of common endothelial nitric oxide synthase gene polymorphisms with ankylosing spondylitis.

METHODS:

One hundred ninety-four unrelated Turkish ankylosing spondylitis patients and 113 healthy without apparent cardiovascular disease, hypertension or diabetes mellitus were included. All individuals were genotyped by PCR-RFLP for two single-nucleotide polymorphisms, namely 786T>C (rs2070744, promoter region) and 786 Glu298Asp (rs1799983, exon 7). Variable numbers of tandem repeat polymorphisms in intron 4 were also studied and investigated by direct electrophoresis on agarose gel following polymerase chain reaction analysis. The Bath ankylosing spondylitis metrology index of the patients was calculated, and human leukocyte antigen B27 was studied.

RESULTS:

All studied polymorphisms satisfied Hardy-Weinberg equilibrium. Sex distributions were similar between the patient and control groups. No significant differences were found in the distributions of allele and genotype frequencies of the studied endothelial nitric oxide synthase polymorphisms between patients and controls. There were no correlations between endothelial nitric oxide synthase polymorphisms, disease duration, Bath ankylosing spondylitis metrology index or human leukocyte antigen B27.

CONCLUSION:

The results presented in this study do not support a major role of common endothelial nitric oxide synthase polymorphisms in Turkish ankylosing spondylitis patients.     

Etanercept Promotes Bone Formation via Suppression of Dickkopf-1 Expression in Rats with Collagen-Induced Arthritis

Background

Various clinical reports suggest etanercept (ETN) has some efficacy in bone formation in rheumatoid arthritis (RA). To examine this effect, we investigated the gene expression of cytokines relevant to osteoblast/osteoclast differentiation, and evaluated histomorphometric findings in mature rats with collagen-induced arthritis (CIA).

Methods

Total RNA was extracted from knee joints with CIA after ETN or placebo administration. Subsequently, realtime-PCR was carried out to quantify the mRNAs encoding Wnt-1, Dickkopf-1 (DKK-1), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegelin (OPG) and TNF (tumor necrosis factor)-alpha. In histomorphometric analysis, the infiltrating pannus volume and pannus surface, and the following items in contact with pannus surface were measured: osteoclast number, osteoid surface, osteoid volume and labeling surface. These were evaluated in the distal femur with CIA with or without ETN administration.

Results

TNF-alpha, RANKL and OPG mRNA expressions, linked to osteoclastogenesis, were not significantly different with or without ETN administration. ETN administration significantly increased Wnt-1 mRNA expression, the osteoblast promoter, and decreased DKK-1 mRNA expression, the Wnt signal inhibitor. In histomorphometric analysis, pannus volume, pannus surface and osteoclast number, parameters of bone destruction, were not significantly different among groups. Osteoid volume, osteoid surface and labeling surface, parameters of bone formation, increased significantly with ETN administration.

Conclusion

Our results suggest that ETN suppresses DDK-1 expression, and, as a result, Wnt expression is promoted and osteoblastogenesis becomes more active, independent of the regulation of osteoclast activity. Marked bone formation is attributed to the fact that ETN directly promotes osteoblastogenesis, not as a result of suppressing osteoclastogenesis.     

EGFR Polymorphism as a Predictor of Clinical Outcome in Advanced Lung Cancer Patients Treated with EGFR-TKI

Purpose

Mutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of the efficacy of treatment with EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR gene were associated with clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with EGFR-TKI.

Materials and Methods

A polymorphic dinucleotide repeat in intron 1 [CA simple sequence repeat in intron 1(CA-SSR1)] in intron 1 and single nucleotide polymorphisms (SNP-216) in the promoter region of the EGFR gene were evaluated in 71 NSCLC patients by restriction fragment length polymorphism and DNA sequencing. The relationship between genetic polymorphisms and clinical outcomes of treatment with EGFR-TKIs was evaluated.

Results

SNP-216G/T polymorphisms were associated with the efficacy of EGFR-TKI. The response rate for the SNP-216G/T tended to be higher than that for G/G (62.5% vs. 27.4%, p=0.057). The SNP-216G/T genotype was also associated with longer progression-free survival compared with the GG genotype (16.7 months vs. 5.1 months, p=0.005). However, the length of CA-SSR1 was not associated with the efficacy of EGFR-TKI.

Conclusion

SNP-216G/T polymorphism was a potential predictor of clinical outcomes in NSCLC patients treated with EGFR-TKI.     

Insulin-like growth factor 1 gene (CA)n repeats and a variable number of tandem repeats of the insulin gene in Brazilian children born small for gestational age

OBJECTIVE:

To investigate the influence of (CA)n repeats in the insulin-like growth factor 1 gene and a variable number of tandem repeats of the insulin gene on birth size in children who are small or adequate-sized for gestational age and to correlate these polymorphisms with serum insulin-like growth factor 1 levels and insulin sensitivity in children who are small for gestational age, with and without catch-up growth.

PATIENTS AND METHODS:

We evaluated 439 infants: 297 that were adequate-sized for gestational age and 142 that were small for gestational age (66 with and 76 without catch-up). The number of (CA)n repeat in the insulin-like growth factor 1 gene and a variable number of tandem repeats in the insulin gene were analyzed using GENESCAN software and polymerase chain reaction followed by enzymatic digestion, respectively. Clinical and laboratory data were obtained from all patients.

RESULTS:

The height, body mass index, paternal height, target height and insulin-like growth factor 1 serum levels were higher in children who were small for gestational age with catch-up. There was no difference in the allelic and genotypic distributions of both polymorphisms between the adequate-sized and small infants or among small infants with and without catch-up. Similarly, the polymorphisms were not associated with clinical or laboratory variables.

CONCLUSION:

Polymorphisms of the (CA)n repeats of the insulin-like growth factor 1 gene and a variable number of tandem repeats of the insulin gene, separately or in combination, did not influence pre- or postnatal growth, insulin-like growth factor 1 serum levels or insulin resistance.     

Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension

Background

Inositol polyphosphate phosphatase‐like 1 (INPPL1, SHIP2) is a negative regulator of insulin signalling and has previously been found to be associated with hypertension, obesity and type 2 diabetes in a cohort of families with diabetes in the UK presenting features of metabolic syndrome. In particular, a haplotype of three genetic polymorphisms (rs2276047, rs9886 and an insertion/deletion polymorphism in intron 1) was found to be strongly associated with increased susceptibility to hypertension.

Objective and methods

To assess if INPPL1 variants play a direct role in the development of essential hypertension, we genotyped the three previously associated INPPL1 polymorphisms in a cohort of 712 families with severe hypertension from the BRIGHT study transmission disequilibrium test cohort.

Results

We found no evidence of significant association between hypertension and any of the three INPPL1 polymorphisms or haplotypes (p>0.1).

Conclusion

These results suggest that INPPL1 variants may be involved in mechanisms causing hypertension in metabolic syndrome patients specifically.     

Frequencies of glutathione s-transferase (GSTM1, GSTM3 AND GSTT1) polymorphisms in a Malaysian population

Introduction

Glutathione S-transferase (GST) is a xenobiotic metabolising enzyme (XME), which may modify susceptibility in certain ethnic groups, showing ethnic dependent polymorphism. The aim of this study was to determine GSTM1, GSTM3 and GSTT1 gene polymorphisms in a Malaysian population in Kuala Lumpur.

Material and methods

Blood or buccal swab samples were collected from 137 Form II students from three schools in Wilayah Persekutuan Kuala Lumpur. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Results

Glutathione-S-transferase GSTM3 gene frequencies were 89% for AA, 10% for AB and 1% for BB. The gene frequencies for deleted GSTM1 and GSTT1 were 66% and 18% respectively.

Conclusions

This study suggested that the Malay population is at risk for environmental diseases and provides the basis for gene-environment association studies to be carried out.     

Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia

Background

Mutilating sensory neuropathy with spastic paraplegia is a very rare disease with both autosomal dominant and recessive modes of inheritance. We previously mapped the locus of the autosomal recessive form to a 25 cM interval between markers D5S2048 and D5S648 on chromosome 5p. In this candidate interval, the Cct5 gene encoding the epsilon subunit of the cytosolic chaperonin‐containing t‐complex peptide‐1 (CCT) was the most obvious candidate gene since mutation in the Cct4 gene encoding the CCT delta subunit has been reported to be associated with autosomal recessive mutilating sensory neuropathy in mutilated foot (mf) rat mutant.

Methods

A consanguineous Moroccan family with four patients displaying mutilating sensory neuropathy associated with spastic paraplegia was investigated. To identify the disease causing gene, the 11 coding exons of the Cct5 gene were screened for mutations by direct sequencing in all family members including the four patients, parents, and six at risk relatives.

Results

Sequence analysis of the Cct5 gene revealed a missense A492G mutation in exon 4 that results in the substitution of a highly conserved histidine for arginine amino acid 147. Interestingly, R147 was absent in 384 control matched chromosomes tested.

Conclusion

This is the first disease causing mutation that has been identified in the human CCT subunit genes; the mf rat mutant could serve as an animal model for studying these chaperonopathies.     

Circulating levels of vascular endothelial markers in obstructive sleep apnoea syndrome. Effects of nasal continuous positive airway pressure

Introduction

Obstructive sleep apnoea syndrome (OSAS) is an important risk factor in cardiovascular disorders. Although the exact mechanism remains to be elucidated, the endothelial dysfunction process seems to be implicated.

Material and methods

In order to test this hypothesis, blood circulating levels of endothelial markers were measured at baseline and 1 year after treatment with continuous positive airway pressure (CPAP). We studied 37 males using polysomnography: 20 subjects with OSAS and a 17-subject control group. An OSAS-validated sleep questionnaire covering the most important cardiovascular risk factors was applied to all subjects. Furthermore, patients received a complete general physical examination and biochemistry test with lipid profile. The specific markers measured were intercellular cell adhesion molecule-1 (ICAM-1), E-selectin, endothelin-1, von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1).

Results

Obstructive sleep apnoea syndrome patients presented higher circulating levels of ICAM-1, endothelin-1 and PAI-1 than the control group. On the other hand, no differences were found in E-selectin and vWF. After 1 year of CPAP treatment, there was a significant decrease in circulating levels of ICAM-1 and PAI-1. On the other hand, no differences were found in endothelin-1, E-selectin and vWF.

Conclusions

Obstructive sleep apnoea syndrome is associated with elevated levels of ICAM-1 and PAI-1 and these levels normalize after treatment with CPAP.     

Interleukin 10 (IL10) and transforming growth factor β1 (TGFβ1) gene polymorphisms in persistent IgE-mediated cow's milk allergy

OBJECTIVES:

The aim of this cross-sectional study was to evaluate whether interleukin 10 (IL10) and transforming growth factor β1 (TGFβ1) gene polymorphisms were associated with persistent IgE-mediated cow''s milk allergy in 50 Brazilian children. The diagnostic criteria were anaphylaxis triggered by cow''s milk or a positive double-blind, placebo-controlled food challenge. Tolerance was defined as the absence of a clinical response to a double-blind, placebo-controlled food challenge or cow''s milk exposure.

METHOD:

The genomic DNA of the 50 patients and 224 healthy controls (HCs) was used to investigate five IL10 gene polymorphisms (-3575A/T, -2849A/G, -2763A/C, -1082G/A, -592C/A) and one TGFβ1 polymorphism (-509C/T).

RESULTS:

Among the five IL10 polymorphisms analyzed, homozygosis for the G allele at the -1082 position was significantly higher in the patients compared with the healthy controls (p = 0.027) and in the persistent cow''s milk allergy group compared with the healthy controls (p = 0.001).

CONCLUSIONS:

Homozygosis for the G allele at the IL10 -1082G/A polymorphism is associated with the persistent form of cow''s milk allergy.     

Increase of TRPV1-Immunoreactivity in Dorsal Root Ganglia Neurons Innervating the Femur in a Rat Model of Osteoporosis

Purpose

Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, which can be activated by capsaicin and other noxious stimuli. Recently, an association between bone pain and TRPV1 has been reported. However, the influence of osteoporosis on TRPV1 in the sensory system innervating the femur has not been reported.

Materials and Methods

TRPV1-immunoreactive (ir) in dorsal root ganglia (DRG) neurons labeled with neurotracer [Fluoro-Gold (FG)] innervating the femurs of Sprague Dawley rats were examined in control, sham, and ovariectomized (OVX) rats. We evaluated osteoporosis in the femurs and compared the proportion of TRPV1-ir DRG neurons innervating femur between the 3 groups of rats.

Results

OVX rats showed osteoporotic cancellous bone in the femur. FG labeled neurons were distributed from L1 to L6 DRG, but there was no significant difference in the proportion of labeled neurons between the 3 groups (p>0.05). The proportions of FG labeled TRPV1-ir DRG neurons were 1.7%, 1.7%, and 2.8% of DRG neurons innervating the femur, in control, sham-operated, and OVX rats, respectively. The proportion of TRPV1-ir neurons in DRG innervating the femur in OVX rats was significantly higher than that in control and sham-operated rats (p<0.05).

Conclusion

Under physiological conditions, DRG neurons innervating femurs in rats contain TRPV1. Osteoporosis increases the numbers of TRPV1-ir neurons in DRG innervating osteoporotic femurs in rats. These findings suggest that TRPV1 may have a role in sensory perception of osteoporotic femurs.     

Inhibitors caveolin-1 and protein kinase G show differential subcellular colocalization with Nitric oxide synthase

Background

Nitric oxide synthase (NOS) is negatively regulated by protein-protein interactions with caveolin-1 before extracellular activating signals release it for nitric oxide (NO) production. Smooth muscle protein kinase G (PKG) is a down-stream effector of NO signaling for relaxation of vascular smooth muscle cells (SMC). The PKG is also found in endothelial cells and it inhibits activated NOS within endothelial cells.

Methods

We used confocal fluorescence microscopy to colocalize the inhibitors caveolin-1 and PKG with NOS in freshly isolated neonatal lamb endothelial cells in order to corroborate the speculation of their differential effects on NOS. The roles of caveolin-1 and PKG as regulators of NOS were investigated by examining their respective subcellular sites of colocalization with NOS using qualitative fluorescence immunohistochemistry and confocal microscopy.

Results

Caveolin-1 was colocalized with NOS in the plasma membrane and Golgi. The PKG1-beta isoform was colocalized with serine116 phosphorylated NOS in the cytosol and in vesicular structures seen in the endoplasmic reticulum and in the nuclear region.

Conclusion

We conclude that unlike caveolin-1, a known pre-activation inhibitor of nascent NOS, PKG may be a post-activation inhibitor of NOS, possibly important for the recycling of the spent enzyme.     

Construction and identification of recombinant lentiviral vector containing HIV-1 Tat gene and its expression in 293T cells

Objective

To construct a lentiviral vector expressing HIV-1 Tat and identify its expression in 293T cells.

Methods

The gene fragment of HIV-1 Tat₁₀₁ was subcloned to lentiviral transfer vector pHAGE-CMV-MCS-IZsGreen, which was named pHAGE-Tat. Then the constructed pHAGE-Tat was used to co-transfect the packing 293T cells, together with the packaging plasmids pMD2.G and psPAX2. The packaged viral particles designated LV-Tat were used to infect the 293T cells and the viral titer was calculated. The expression of HIV-1 Tat in 293T cells was confirmed using RT-PCR and western blot.

Results

The recombinant lentiviral vector was successfully constructed and could express HIV-1 Tat in 293T cells. The virus titer was 5.73×10⁶ ifu/ml.

Conclusion

The successfully constructed recombinant lentiviral vector makes a strong foundation for further exploring the possible role of HIV-1 Tat in the development of prostate cancer.     

Multidrug resistance 1 gene polymorphisms may determine Crohn's disease behavior in patients from Rio de Janeiro

OBJECTIVES:

Conflicting data from studies on the potential role of multidrug resistance 1 gene polymorphisms in inflammatory bowel disease may result from the analysis of genetically and geographically distinct populations. Here, we investigated whether multidrug resistance 1 gene polymorphisms are associated with inflammatory bowel diseases in patients from Rio de Janeiro.

METHODS:

We analyzed 123 Crohn''s disease patients and 83 ulcerative colitis patients to determine the presence of the multidrug resistance 1 gene polymorphisms C1236T, G2677T and C3435T. In particular, the genotype frequencies of Crohn''s disease and ulcerative colitis patients were analyzed. Genotype-phenotype associations with major clinical characteristics were established, and estimated risks were calculated for the mutations.

RESULTS:

No significant difference was observed in the genotype frequencies of the multidrug resistance 1 G2677T/A and C3435T polymorphisms between Crohn''s disease and ulcerative colitis patients. In contrast, the C1236T polymorphism was significantly more common in Crohn''s disease than in ulcerative colitis (p = 0.047). A significant association was also found between the multidrug resistance 1 C3435T polymorphism and the stricturing form of Crohn''s disease (OR: 4.13; p = 0.009), whereas no association was found with penetrating behavior (OR: 0.33; p = 0.094). In Crohn''s disease, a positive association was also found between the C3435T polymorphism and corticosteroid resistance/refractoriness (OR: 4.14; p = 0.010). However, no significant association was found between multidrug resistance 1 gene polymorphisms and UC subphenotypic categories.

CONCLUSION:

The multidrug resistance 1 gene polymorphism C3435T is associated with the stricturing phenotype and an inappropriate response to therapy in Crohn''s disease. This association with Crohn''s disease may support additional pathogenic roles for the multidrug resistance 1 gene in regulating gut-microbiota interactions and in mediating fibrosis. Understanding the effects of several drugs associated with multidrug resistance 1 gene variants may aid in the selection of customized therapeutic regimens.     

Drug-drug interation prediction between ketoconazole and anti-liver cancer drug Gomisin G

Background

Gomisin G, isolated from herb Schisandra chinensis, exhibits anti-tumor activities. Therefore, Gomisin G is a drug candidate for anti-liver cancer therapy.

Aims

To predict the metabolic behavior and metabolism-based drug-drug interaction of gomisin G.

Methods

Molecular docking method was used. The crystal structure of CYP3A4 with the ligand ketoconazole was chosen from protein data bank (http://www.rcsb.org/pdb). Chemdraw software was used to draw the two-dimensional structure of gomisin G with standard bond lengths and angles.

Results

Gomisin G can be well docked into the activity site of CYP3A4, and distance between gomisin G the heme active site was 2.75 Å. To evaluate whether the inhibitors of CYP3A4 can affect the metabolism of gomisin G, co-docking of gomisin G and ketoconazole was further performed. The distance between ketoconazole and activity center (2.10 Å) is closer than the distance between gomisin G and activity center of CYP3A4, indicating the easy influence of CYP3A4''s strong inhibitor towards the metabolism of gomisin G.

Conclusion

Gomisin G is a good substrate of CYP3A4, and CYP3A4 inhibitors easily affect the metabolism of Gomisin G.     

Relationship between blood pressure levels and bone mineral density in postmenopausal Turkish women

Introduction

We investigated the association between bone mineral density (BMD) detected by dual-energy X-ray absorptiometric (DXA) method and blood pressure (BP) in a large sample of postmenopausal women.

Material and methods

The current study was based on a retrospective analysis of 586 postmenopausal women with a mean age of 60.8 ±8.8 years, who were screened for osteopenia or osteoporosis by DXA. Patients with hypertension (HT, n= 306) were compared with normotensive (NT, n = 290) individuals. Bone mineral density results for the femur neck and spine were classified into 3 groups according to World Health Organization criteria: normal (T score > –1.0 SD), osteopenia (T score –1.0 to –2.5 SD) and osteoporosis (T score < –2.5 SD). Patients with osteopenia or osteoporosis (T score < –1.0 SD) were grouped as having low bone mass (LBM).

Results

There were no significant differences in femur T score, femur BMD, femur Z score, spinal T score, spinal BMD and spinal Z score between hypertensive and normotensive groups. The group of patients with low bone mass calculated from femur T scores had higher age, systolic BP, duration of hypertension and duration of menopause, but lower BMI. Similarly, patients with low spine BMD had higher age and duration of menopause, but lower BMI. Linear regression analysis showed a significant correlation between systolic BP and femur BMD and T score values. Furthermore, logistic regression analysis revealed that hypertension is an independent predictor of spinal osteopenia and osteoporosis.

Conclusions

The presence of hypertension is an independent predictor of spinal low bone density in Turkish women after menopause.