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Objective: The purpose of this study was to investigate the effects of CYP2C19 gene mutations on clopidogrel antiplatelet activity in the patients with coronary heart disease treated by percutaneous coronary intervention. Methods: Patients with coronary heart disease, who hospitalized in the Second Affiliated Hospital of Nanchang University from March 2011 to June 2019, and healthy individuals with matching genetic background, gender, and age as controls were included in this study. Basic clinical data were analyzed and blood samples of all research subjects were obtained for extraction of DNA, and Sanger first-generation sequencing method was used to detect CYP2C19 gene mutation from full exon and exon and intron junction. CYP2C19 gene variations in patients with coronary heart disease were compared with the 1000 Genomes Browse database and the sequencing results of healthy controls to determine whether the gene variation was a genetic mutation or a genetic polymorphism. After that, PolyPhen-2 prediction software was used to analyze the harmfulness of gene mutations to predict the effect of mutations on protein function. The same dose of CYP2C19 wild-type plasmid and the CYP2C19 gene mutant plasmids were transfected into human normal liver cells HL-7702. After transfection of 24 h, the expression of CYP2C19 protease in each group was detected. The liver S9 protein was incubated with clopidogrel, acted on platelets to detect the platelet aggregation rate and the activity of human vasodilator-activated phosphoprotein (VASP). Results: A total of 1 493 patients with coronary heart disease (59.36%) were enrolled, the average age was (64.5±10.4) years old, of which 1 129 were male (75.62%). Meanwhile, 1 022 healthy physical examination volunteers (40.64%) were enrolled, and the average age was (64.1±11.0) years old, of which 778 were male (76.13%). A total of 5 gene mutations of CYP2C19 gene were identified in 12 patients (0.80%), namely, 4 known mutations T130K (1 case), M136K (6 cases), N277K (3 cases), V472I (1 case) and one new mutation G27V (1 case), no corresponding gene mutation was found in healthy controls. It was found that T130K and M136K were probably damaging, G27V was possibly damaging, and N277K and V472I were benign mutations. In vitro, we demonstrated that the platelet aggregation rate of the M136K gene mutation group was 24.83% lower than that of the wild type (59.58% vs. 34.75%; P<0.05), and the phosphorylated VASP level was 23.0% higher than that of the wild type (1.0 vs. 1.23; P<0.05). However, the platelet aggregation rate and phosphorylated VASP level were similar between of G27V, T130K, N277K, V472I gene mutation groups and wild type group (P>0.05). Conclusions: In this study, 5 gene mutations are defined in patients with coronary heart disease, namely G27V, T130K, M136K, N277K, V472I. In vitro functional studies show that CYP2C19 gene mutation M136K, as a gain-of-function gene mutation, can enhance the activation of CYP2C19 enzyme on clopidogrel, thereby inhibiting the platelet aggregation rate.
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OBJECTIVE@#Anabolic-androgenic steroids (AAS) represents a group of synthetic testosterone derivatives that play an important role in clinical treatment. These drugs are widely abused among the general public to increase lean weight and improve athletic performance. It has been reported that AAS use can produce many adverse effects, especially the occurrence of cardiovascular risk. Although there are many related studies, there has been no consensus on AAS use and cardiovascular risk. The present study was to review the effect of AAS on the cardiovascular system.@*DATA SOURCES@#The data in this review were obtained from articles included in PubMed and the National Center for Biotechnology Information database.@*STUDY SELECTION@#Original articles, case reports, and systematic reviews about AAS were selected for the article.@*RESULTS@#The use/abuse of AAS is correlated with higher cardiovascular risks, and many AAS users/abusers had cardiovascular diseases. However, there are many confounding factors in the studies that explored the causality between AAS intake and disease development, and additional studies are required to determine AAS toxicity.@*CONCLUSION@#AAS produces toxic effects on the cardiovascular system, and it is necessary to ensure that more people know this about AAS, including medical personnel.
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BACKGROUND@#The association between peripheral leukocyte count and bleeding events in nonvalvular atrial fibrillation (NVAF) patients treated with dabigatran remains unclear. This study aimed to explore the association between leukocyte count and bleeding events after excluding other confounders in NVAF patients taking dabigatran.@*METHODS@#A total of 851 NVAF patients treated with dabigatran (110 mg bid) were recruited from 12 centers in China from February 2015 to December 2017. Follow-up was completed by May 2018. The exposure and outcome variables were leukocyte count measured at baseline and the number of bleeding events within the subsequent 6 months. Multivariate Cox proportional hazards models were constructed to analyze independent associations, and a Cox proportional hazards regression with cubic spline functions and smooth curve fitting (penalized spline method) was used to address nonlinearity between leukocyte count and bleeding. The inflection point was calculated using a recursive algorithm, and then a two-piecewise Cox proportional hazards model for both sides of the inflection point was constructed.@*RESULTS@#During 6-month follow-up, 87 participants occurred bleeding events. For every 1 × 10/L increase in leukocyte count, the risk of bleeding increased by 11% (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 0.99-1.25). The smooth curve showed nonlinear relationship between leukocyte count and bleeding events. The inflection point of the leukocyte count was 6.75 × 10/L. For leukocyte counts < 6.75 × 10/L, the HR (95% CI) was 0.88 (0.69-1.13), and for leukocyte counts ≥ 6.75 × 10/L, the HR (95% CI) was 1.28 (1.09-1.51).@*CONCLUSION@#This study found a J-shaped association between baseline leukocyte count and risk of bleeding in NVAF patients treated with dabigatran.@*CLINICAL TRIAL REGISTRATION@#NCT02414035, https://clinicaltrials.gov.
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Objective@#Anabolic-androgenic steroids (AAS) represents a group of synthetic testosterone derivatives that play an important role in clinical treatment. These drugs are widely abused among the general public to increase lean weight and improve athletic performance. It has been reported that AAS use can produce many adverse effects, especially the occurrence of cardiovascular risk. Although there are many related studies, there has been no consensus on AAS use and cardiovascular risk. The present study was to review the effect of AAS on the cardiovascular system.@*Data sources@#The data in this review were obtained from articles included in PubMed and the National Center for Biotechnology Information database.@*Study selection@#Original articles, case reports, and systematic reviews about AAS were selected for the article.@*Results@#The use/abuse of AAS is correlated with higher cardiovascular risks, and many AAS users/abusers had cardiovascular diseases. However, there are many confounding factors in the studies that explored the causality between AAS intake and disease development, and additional studies are required to determine AAS toxicity.@*Conclusion@#AAS produces toxic effects on the cardiovascular system, and it is necessary to ensure that more people know this about AAS, including medical personnel.
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Background@#The association between peripheral leukocyte count and bleeding events in nonvalvular atrial fibrillation (NVAF) patients treated with dabigatran remains unclear. This study aimed to explore the association between leukocyte count and bleeding events after excluding other confounders in NVAF patients taking dabigatran.@*Methods@#A total of 851 NVAF patients treated with dabigatran (110 mg bid) were recruited from 12 centers in China from February 2015 to December 2017. Follow-up was completed by May 2018. The exposure and outcome variables were leukocyte count measured at baseline and the number of bleeding events within the subsequent 6 months. Multivariate Cox proportional hazards models were constructed to analyze independent associations, and a Cox proportional hazards regression with cubic spline functions and smooth curve fitting (penalized spline method) was used to address nonlinearity between leukocyte count and bleeding. The inflection point was calculated using a recursive algorithm, and then a two-piecewise Cox proportional hazards model for both sides of the inflection point was constructed.@*Results@#During 6-month follow-up, 87 participants occurred bleeding events. For every 1 × 109/L increase in leukocyte count, the risk of bleeding increased by 11% (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 0.99–1.25). The smooth curve showed nonlinear relationship between leukocyte count and bleeding events. The inflection point of the leukocyte count was 6.75 × 109/L. For leukocyte counts < 6.75 × 109/L, the HR (95% CI) was 0.88 (0.69–1.13), and for leukocyte counts ≥ 6.75 × 109/L, the HR (95% CI) was 1.28 (1.09–1.51).@*Conclusion@#This study found a J-shaped association between baseline leukocyte count and risk of bleeding in NVAF patients treated with dabigatran.@*Clinical trial registration@#NCT02414035, https://clinicaltrials.gov.
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AIM:To evaluate the role of heat shock protein 22(HSP22)in atherosclerosis(AS)induced by high-fat diet and in the intervention with atorvastatin(Ator).METHODS: Total 3 groups of 8 ~9-week-old ApoE-/-, HSP22-/-ApoE-/-and HSP22 +ApoE-/-male mice were used,with 18 mice in each group.After 1 week of adaptive feeding, the mice in each group were randomly divided into 2 subgroups: control group, and Ator group, HSP22 knockout group (KO group)and HSP22 knockout with Ator treatment group(KO+Ator group),and HSP22 overexpression group(Tg group)and HSP22 overexpression with Ator treatment group(Tg+Ator group).Atro at 10 mg· kg-1-d-1was administered to the mice in all Ator groups from the 5th week.The mice in the control groups were given saline.All these mice were fed for 13 weeks.Oil red O staining and HE staining of the aortic wall of the mice were used to measure the atherosclerotic le-sion burdens.The protein levels of HSP22,NF-κB, eNOS, ICAM-1 and IL-6 in the aorta and serum were examined by Western blot,immunohistochemistry and ELISA.RESULTS:Aortic Oil red O staining and HE staining showed that the relative area of aorta plaque in Tg group was less than that in KO group(P<0.05).The protein expression of HSP22 in Tg group was significantly higher than that in control group and KO group,and its expression in control group was signifi-cantly higher than that in KO group.The protein expression of eNOS in Tg group and control group was significantly higher than that in KO group.The protein expression of NF-κB and ICAM-1 in control group was significantly decreased as com-pared with KO group,and their expression was significantly higher than that in Tg group.No difference of serum IL-6 level was found among Tg group,KO group and control group.CONCLUSION:HSP22 gene deletion up-regulates the expres-sion of NF-κB and ICAM-1,and down-regulates the expression of eNOS,leading to accelerating AS.HSP22 overexpression decreases the expression of NF-κB and ICAM-1 and increases the expression of eNOS,thus attenuating AS development. HSP22 gene deletion partially limits the role of Ator in the expression of NF-κB,ICAM-1 and eNOS.HSP22 overexpression amplifies the reduced expression of ICAM-1 by the intervention with Ator,and further attenuates AS development.
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In mammals, ovarian follicle is made of an oocyte with its surrounding granulosa cells and theca cells. Follicular growth and development is a highly coordinated programmable process, which guarantees the normal oocyte maturation and makes it having the fertilizing capacity. The paracrine and autocrine between oocytes and granulosa cells are essential for the follicular development to provide a suitable microenvironment. Phosphatidylinositol-3 kinase /protein kinase B is one of these important regulatory signaling pathways during this developmental process, and bone morphogenetic protein-15 an oocyte-specific secreted signal molecule, which regulates the follicular development by paracrine in the mammalian ovary. The present article overviewed the role of phosphatidylinositol-3 kinase / protein kinase B signaling during the follicular development based on our previous investigation about protein kinase B /forkhead transcription factor forkhead family of transcription factors -3a, and then focused on the regulatory effects of bone morphogenetic protein-15, as a downstream signal molecule of phosphatidylinositol-3 kinase / forkhead family of transcription factors -3a pathway, on ovarian follicular development, which helped to further understand the molecular mechanism regulating the follicular development and to treat ovarian diseases like infertility.
Subject(s)
Animals , Female , Humans , Bone Morphogenetic Protein 15 , Physiology , Granulosa Cells , Physiology , Mammals , Ovarian Follicle , Ovary , Phosphatidylinositol 3-Kinase , Physiology , Proto-Oncogene Proteins c-akt , Physiology , Signal TransductionABSTRACT
<p><b>OBJECTIVE</b>To observe the protection of Heme oxygenase-1 (HO-1) from lipopolysaccharide (LPS)-induced cardiocyte injury and its mechanism.</p><p><b>METHODS</b>Cardiocyte was isolated from SD neonate rat and cultured in vitro, and was divided into control group (normal culture), LPS group (with stimulation of 30 micromoL/L LPS for 1 hour), LPS + Hemin group (with same treatment to LPS group after stimulation of 5 micromoL/L Hemin for 1 hour), and LPS + ZnPP group (with same treatment to LPS group after stimulation of 3 micromoL/L ZnPP for 1 hour). The level of lactic-dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) were measured by thio-barbituric acid and xanthine oxidase techniques. The cell heart rhythm, survival rate and apoptosis rate were examined. The expressions of nuclear factor kappaB (NF-kappaB), HO-1 and tumor necrosis factor-alpha (TNF-alpha) were measured with Western blotting. The HO-1 mRNA was examined by RT-PCR.</p><p><b>RESULTS</b>The level of LDH and MDA in LPS, LPS + Hemin, and LPS + ZnPP groups were (113 +/- 15), (79 +/- 13), (154 +/- 22) U/L, and (1.88 +/- 0.36), (1.16 +/- 0.32), (2.84 +/- 0.44) mmoL/L respectively, which were all obviously higher than those in control group [(69 +/- 10) U/L, (0.87 +/- 0.25) mmol/L, P < 0.05]. The level of SOD in LPS, PS + Hemin, and LPS + ZnPP groups (17.8 +/- 1.8, 22.5 +/- 2.4, 13.4 +/- 1.5 U/mL, respectively) was all obviously lower than that in control group (24.3 +/- 3.6 U/mL, P < 0.05). The apoptosis rate and heart rhythm were obviously higher and survival rate significantly lower in LPS, LPS + Hemin, and LPS + ZnPP groups than those in control group (P < 0.05). The level of HO-1mRNA in LPS, LPS + Hemin, and LPS + ZnPP groups was higher than that in control group (P < 0.01), among which LPS + Hemin group was the highest. The level of HO-1, TNF-alpha and NF-kappaB in LPS, LPS + Hemin, and LPS + ZnPP groups was higher than those in control group (P < 0.05), among which the level of HO-1 protein in LPS + Hemin group was the highest, the level of TNF-alpha and NF-kappaB in LPS + ZnPP group was highest.</p><p><b>CONCLUSION</b>LPS can induce cardiocyte injury, which can be inhibited through the anti-inflammatory, anti-oxidant, and anti-apoptosis functions by HO-1.</p>