Identification of disease-specific genes related to immune infiltration in nonalcoholic steatohepatitis using machine learning algorithms.

To identify disease signature genes associated with immune infiltration in nonalcoholic steatohepatitis (NASH), we downloaded 2 publicly available gene expression profiles, GSE164760 and GSE37031, from the gene expression omnibus database. These profiles represent human NASH and control samples and were used for differential genes (DEGs) expression screening. Two machine learning methods, the Least Absolute Shrinkage and Selection Operator regression model and Support Vector Machine Recursive Feature Elimination, were used to identify candidate disease signature genes. The CIBERSORT deconvolution algorithm was employed to analyze the infiltration of 22 immune cell types in NASH. Additionally, we constructed a NASH cell model using HepG2 cells treated with oleic acid and free fatty acids. The construction of the cell model was verified using oil red O staining, and Western blotting was used to detect the protein expression of the disease signature genes in both control and model groups. As a result, a total of 262 DEGs were identified. These DEGs were primarily associated with metal ion transmembrane transporter activity, sodium ion transmembrane transporter protein activity, calcium ion, and neuroactive ligand-receptor interactions. FOS, IGFBP2, dual-specificity phosphatase 1 (DUSP1), and IKZF3 were identified as disease signature genes of NASH by the least absolute shrinkage and selection operator and Support Vector Machine Recursive Feature Elimination algorithms for DEGs analysis. The receiver operating characteristic curves showed that FOS, IGFBP2, DUSP1, and IKZF3 had good diagnostic value (area under receiver operating characteristic curve > 0.8). These findings were validated in the GSE89632 dataset and through cellular assays. Immunocyte infiltration analysis revealed that NASH was associated with CD8 T cells, CD4 T cells, follicular helper T cells, resting NK cells, eosinophils, regulatory T cells, and γδ T cells. The FOS, IGFBP2, DUSP1, and IKZF3 genes were specifically associated with follicular helper T cells. Lipid droplet aggregation significantly increased in HepG2 cells treated with oleic acid and free fatty acids, indicating successful construction of the cell model. In this model, the expression of FOS, IGFBP2, and DUSP1 was significantly decreased, while that of IKZF3 was significantly elevated (P < .01, P < .001) compared with the control group. Therefore, FOS, IGFBP2, DUSP1, and IKZF3 can be considered as disease signature genes associated with immune infiltration in NASH.

Benzo(a)pyrene regulates chaperone-mediated autophagy via heat shock protein 90.

AIMS: Some studies have shown that the Benzo(a)pyrene (BaP) exposure induced oxidative damage, DNA damage and autophagy, but the molecular mechanism is not clear. Heat shock protein 90 (HSP90) is regarded as an important target in cancer therapy and a key factor in autophagy. Therefore, this study aims to clarify the new mechanism of BaP regulating CMA through HSP90. MAIN METHODS: C57BL mice were fed with BaP at a dose of 25.3 mg/kg. A549 cells were treated with different concerntrations of BaP, and MTT assay was used to observe the effect of BaP on the proliferation of A549 cells. DNA damage was detected by alkaline comet assay. Focus experiment for detection of γ-H2AX by immunofluorescence. The mRNA expression of HSP90, HSC70 and Lamp-2a was detected by qPCR. The protein expressions of HSP90, HSC70 and Lamp-2a were detected by Western blot. Next, we knocked down HSP90 expression by the HSP90 Inhibitor, NVP-AUY 922, exposed or HSP90α shRNA lentivirus transduction in A549 cells. KEY FINDINGS: In these studies, we first found that heat shock protein 90 (HSP90), heat shock cognate 70 (HSC70) and lysosomal-associated membrane protein type 2 receptor (Lamp-2a) expressions of C57BL mice lung tissue and A549 cells exposed to BaP were significant increase, as well as BaP induced DNA double-strand breaks (DSBs) and activated DNA damage responses, as evidenced by comet assay and γ-H2AX foci analysis in A549 cells. Our results demonstrated BaP induced CMA and caused DNA damage. Next, we knocked down HSP90 expression by the HSP90 Inhibitor, NVP-AUY 922, exposed or HSP90α shRNA lentivirus transduction in A549 cells. HSC70 and Lamp-2a expressions of these cells exposed to BaP were not significant increase, which showed that BaP inducted CMA was mediated by HSP90. Further, HSP90α shRNA prevented BaP induced of BaP which suggested BaP regulated CMA and caused DNA damage by HSP90. Our results elucidated a new mechanism of BaP regulated CMA through HSP90. SIGNIFICANCE: BaP regulated CMA through HSP90. HSP90 is involved in the regulation of gene instability induced by DNA damage by BaP, which promotes CMA. Our study also revealed that BaP regulates CMA through HSP90. This study fills the gap of the effect of BaP on autophagy and its mechanism, which will lead to a more comprehensive understanding of the action mechanism of BaP.

The Effect and Mechanism of Syringa pinnatifolia Hemsl. Ligans on Cerebral Ischemia-Reperfusion Injury and Oxidative Stress in Mice.

Lignans are the main components of Syringa pinnatifolia Hemsl. (SP). Previous studies have shown that SP lignans (SPL) can considerably improve CCl4-induced acute liver injury in mice by the anti-oxidative stress (OS) mechanism. In this study, we investigated the antioxidant effects of SPL on cerebral ischemia/reperfusion injury (CIRI) and its underlying molecular mechanism. We developed a middle cerebral artery occlusion/reperfusion (MCAO/R) model in mice to achieve CIRI and orally administered SPL daily for 1-3 days. We evaluated neurological function deficits and performed hematoxylin and eosin staining. We further calculated the infarct volume. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the brain were detected using corresponding kits. The transcription and protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) in brain tissues were analyzed by real-time reverse transcription polymerase chain reaction and western blotting, respectively. The results showed that SPL could remarkably ameliorate neurological functions and pathological damage in brain tissues, reducing the cerebral infarct volume. It also increased the SOD and GPx activities decreased the MDA levels as well as inhibited the expression of (NOX)2 and NOX4. We also found that the mRNA and protein levels of Nrf2, HO-1, and NQO1 in the CIRI mice increased transiently and peaked at 24 h of reperfusion, and then began to decline. SPL could reverse decreasing Nrf2 and HO-1 levels after 24 h. In conclusion, SPL can alleviate CIRI and OS by activating the Nrf2/HO-1 pathway.

Role and mechanism of benzo[a]pyrene in the transformation of chronic obstructive pulmonary disease into lung adenocarcinoma.

OBJECTIVE: This experiment is explores the genes that play a key role, their expression changes and the biological processes in the transformation of chronic obstructive pulmonary disease (COPD) into lung adenocarcinoma (LAC). Meanwhile, identify the effects of Benzo[a]pyrene (BaP) in the conversion of COPD into LAC. METHODS: 1. Differential expression genes of COPD and LAC were screened and analyzed by high-throughput microarray data between the two diseases and their respective control groups. 2. The screened genes were used for routine bioinformatics analysis such as functional analysis, expression verification, protein interaction analysis and functional enrichment. 3. Cigarette smoke extract (CSE) combined with lipopolysaccharide (LPS) was used to establish an in vitro COPD model. 4. MTT assay was used to detect the influence of B(a)P in effect on A549 cell proliferation. CCK-8, Transwell invasion test and scratch test were used to detect the cell proliferation, invasion and migration ability, while qPCR and Western Blot tests were used to observe the cell proliferation, apoptosis and changes in related indicators such as EMT. 5. Experimental method of separately adding agonists (tBHQ) and inhibitors (DIC) of NQO1 was used to confirm the effect of NQO1 on A549 cell proliferation, apoptosis, migration and invasion. 6. To further clarify whether BaP exerted effect on cell proliferation, apoptosis, migration and invasion through NQO1, we knocked down NQO1 gene and then infecting cells with BaP. RESULTS: 1. We screened genes of COPD and LAC using datasets from GSE151052, GSE118370, and GSE140797. After screening, the genes upregulated in COPD and downregulated in LAC were RTKN2, SLC6A4, and HBB, the gene downregulated in COPD and upregulated in LAC was NQO1, the genes downregulated in both COPD and LAC were FPR1, LYVE1 and PKHD1L1. 2. The main signaling pathways in which the target genes were enriched are cell cycle, EMT, PI3K/AKT, and apoptosis. In the data included GEPIA, PKHD1L1, FPR1, LYVE1, RTKN2, HBB, and SLC6A4 were significantly downregulated and NQO1 was upregulated in LAC relative to controls. In addition, there were 46 interaction proteins in the target genes, and the functions they enriched included hydrogen peroxide catabolism, etc. 3. When A549 cell was stimulated with 100 ng/mL LPS+ 10% CSE, the COX-2 expression indicated that COPD model in vitro was successfully established. 4. The optimal dose and action time were screened which were 1 µM and 24 h. Compared to the control group, COPD and BaP group increased cell proliferation and invasion capabilities. On the basis of COPD, adding BaP could further increase the proliferation and migration capabilities. Interestingly, the levels of NQO1 decreased in COPD models, while increased by BaP. 5. tBHQ can increase the proliferation and migration capacity of A549 cells, which is inhibited by the addition of DIC. 6. The enhanced proliferation, migration and invasion of A549 cells by BaP were attenuated after knockdown of NQO1. CONCLUSION: Our study reveals that PKHD1L1, FPR1, LYVE1, RTKN2, HBB, SLC6A4 and NQO1 may play an important role in the conversion of COPD to LAC. High NQO1 expression may increase the proliferation and migration ability of A549 cells, and BaP may promote the EMT state by increasing the expression of NQO1, thereby making the COPD model in vitro expose the tumor characteristics.

Study on molecular mechanism of benzo (ɑ) pyrene on CMA by HSP90ɑ and HIF-1ɑ.

OBJECTIVE: The effects of benzo (α) pyrene (BaP) on chaperone mediated autophagy (CMA) through heat shock protein 90 (HSP90) and hypoxia- inducible factor-1 (HIF-1) are studied by RNA interference and subcutaneous tumor formation technique in nude mice. METHODS: 40 nude mice that were inoculated with the silenced HSP90ɑ A549 cells line under the armpits of the forelimbs were divided into 4 groups, and were intragastrically administered with 1.80 mg/kg/d BaP-corn oil solutionfor for 60d (except the Control group), and the growth curves of nude mice and transplanted tumors were recorded. The size and morphological changes of tumors were observed by small animal imaging technique. qPCR, Western blot and Immunohistochemistry were used to detect the expression of HSP90ɑ, HSC70 and Lamp-2A. A549 cells were treated with 0.1 µmol/L, 1 µmol/L and 10 µmol/L BaP for 24 h, EPO and HIF-1ɑ concentration and HIF-1ɑ protein expression were detected by Elisa and Western blot; A549 cells were treated with 10 µmol/L BaP and HIF-1ɑ inhibitor for 24 h, qPCR, Western blot and Immunofluorescence methods were used to detect the expression of HSP90ɑ, HSC70 and Lamp-2A. RESULTS: The weight of nude mice and transplanted tumors silenced HSP90ɑ was reduced by BaP; the expression of HSP90ɑ, HSC70, Lamp-2A mRNA and proteins in transplanted tumor tissues silenced HSP90ɑ were reduced by BaP; the total number of bioluminescence photons of transplanted tumors silenced HSP90ɑ were reduced by BaP. The concentration of EPO and HIF-1ɑ and the expression of HIF-1ɑ protein in A549 cells was increased by 10 µmol/L BaP; with HIF-1ɑ inhibitors treated, HSP90ɑ, HSC70, Lamp-2A mRNA and proteins expression and the fluorescence intensity of HSP90ɑ were decreased of A549 cells. CONCLUSIONS: The growth of transplanted tumor in nude mice is promoted by BaP, and is inhibited when HSP90ɑ was silenced. BaP promotes the occurrence of CMA by promoting the expression of HSP90ɑ and HIF-1ɑ, which are vital regulatory genes of BaP activation of CMA.

Interaction between AhR and HIF-1 signaling pathways mediated by ARNT/HIF-1ß.

BACKGROUND: The main causes of lung cancer are smoking, environmental pollution and genetic susceptibility. It is an indisputable fact that PAHs are related to lung cancer, and benzo(a) pyrene is a representative of PAHs. The purpose of the current investigation was to investigate the interaction between AhR and HIF-1 signaling pathways in A549 cells, which provide some experimental basis for scientists to find drugs that block AhR and HIF-1 signaling pathway to prevent and treat cancer. METHODS: This project adopts the CYP1A1 signaling pathways and the expression of CYP1B1 is expressed as a measure of AhR strength index. The expression of VEGF and CAIX volume as a measure of the strength of the signal path HIF-1 indicators. Through the construction of plasmid vector, fluorescence resonance energy transfer, real-time quantitative PCR, western blotting and immunoprecipitation, the interaction between AhR signaling pathway and HIF-1 signaling pathway was observed. RESULTS: BaP can enhance the binding ability of HIF-1α protein to HIF-1ß/ARNT in a dose-dependent manner without CoCl2. However, the binding ability of AhR protein to HIF-1ß/ARNT is inhibited by HIF-1α signaling pathway in a dose-dependent manner with CoCl2. CONCLUSION: It is shown that activation of the AhR signaling pathway does not inhibit the HIF-1α signaling pathway, but activation of the HIF-1α signaling pathway inhibits the AhR signaling pathway.

Mechanism of Synsepalum dulcificum Daniell. Inhibiting Lung Adenocarcinoma.

Objective: Synsepalum dulcificum Daniell. (SD) is a natural plant fruit and is famous for containing miraculin. It has been reported that SD can be used as an adjuvant treatment to correct patients' loss of taste during the antitumor process, but the effect of SD itself as an antitumor is not clear. In this study, we investigated the mechanism of action of SD on lung adenocarcinoma using network pharmacology. Materials and Methods. The components of SD were identified by liquid chromatography-mass spectrometry, and then the compounds that affect tumor immunity of SD were screened and the related targets were predicted by TCMIO database. At the same time, the results were associated with lung adenocarcinoma targets included in the MalaCards and CTD databases, so as to construct a compound-target action network diagram and explore the mechanism of SD in the treatment of lung adenocarcinoma. In in vitro experiments, cell viability was determined and western blotting was used to detect the related expression of action targets to determine the therapeutic effect of SD. Results. In this experiment, 335 chemical components were identified in SD, and 107 components were related to tumor immunity. After screening by ADME, it was found that 11 compounds might be inhaled into the human body and affect the growth of lung adenocarcinoma. In vitro experiments showed that SD could inhibit the growth of lung adenocarcinoma A549 cells. SD could reduce the expression of PCNA (P < 0.05) and significantly increase the expression of Caspase-3 (P < 0.05). The results of further experiments showed that SD could significantly reduce the phosphorylation of EGFR (P < 0.05), and SD could also effectively inhibit the expression of JAK and STAT3 phosphorylation (P < 0.01) and inhibit the expression of PI3K and AKT phosphorylation (P < 0.01). Conclusion. SD can inhibit the growth of lung adenocarcinoma A549 cells and the potential mechanism was found to be the inhibition of EGFR/JAK/STAT3 and EGFR/PI3K/AKT signaling pathway, and the substance basis for SD to exert antitumor effect may be catechin, taxifolin, betaine, epigallocatechin gallate, erucamide, guanosine, kaempferol, lanosterol, morin, oleanolic acid, and quercetin.

Molecular mechanism of benzo [a] pyrene regulating lipid metabolism via aryl hydrocarbon receptor.

BACKGROUND: Benzo [a] pyrene (BaP), a potent carcinogen, has been proved that it has toxicological effects via activation the aryl hydrocarbon receptor (AhR) pathway. AhR can participate in regulating lipogenesis and lipolysis. This topic will verify whether BaP regulates lipid metabolism via AhR. METHODS: (1) C57BL/6 mice were gavaged with BaP for 12 weeks to detect serum lipids, glucose tolerance, and insulin resistance. Morphological changes in white adipose tissue (WAT) were detected by Hematoxylin and Eosin staining. The mRNA expression levels of adipogenesis-related factors included recombinant human CCAAT/enhancer binding protein alpha (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), and fatty acid binding protein 4 (FABP4) and inflammatory factors included nuclear factor kappa-B (NF-κB), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α) were detected using PCR. (2) Neutral lipid content changes in differentiated 3 T3-L1 adipocytes treated with BaP with and w/o AhR inhibitor were detected by Oil red staining. The protein expression levels of adipogenesis- and decomposition-related factors included PPARγ coactivator-1 alpha (PGC-1α), and peroxisome proliferation-activated receptor alpha (PPARα) were detected using western blotting. The mRNA expression levels of inflammatory factors were detected using PCR. RESULTS: (1) BaP inhibited body weight gain, decreased lipid content, increased lipid levels, and decreased glucose tolerance and insulin tolerance in mice; (2) BaP reduced the expressions of C/EBPα, PPARγ, FABP4, PGC-1α, and PPARα and increased the expressions of NF-κB, MCP-1, and TNF-α by activating AhR. CONCLUSION: BaP inhibit fat synthesis and oxidation while inducing inflammation by activating AhR, leading to WAT dysfunction and causing metabolic complications.

Lysophosphatidylcholine promotes intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression in human umbilical vein endothelial cells via an orphan G protein receptor 2-mediated signaling pathway.

The oxLDL-based bioactive lipid lysophosphatidylcholine (LPC) is a key regulator of physiological processes including endothelial cell adhesion marker expression. This study explored the relationship between LPC and the human umbilical vein endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) with a particular focus on the regulation of the LPC-G2A-ICAM-1/VCAM-1 pathway in this context. We explored the LPC-inducible role of orphan G protein receptor 2 (G2A) in associated regulatory processes by using human kidney epithelial (HEK293) cells that had been transfected with pET-G2A, human umbilical vein endothelial cells (HUVECs) in which an shRNA was used to knock down G2A, and western blotting and qPCR assays that were used to confirm changes in gene expression. For in vivo studies, a rabbit model of atherosclerosis was established, with serum biochemistry and histological staining approaches being used to assess pathological outcomes in these animals. The treatment of both HEK293 cells and HUVECs with LPC promoted ICAM-1 and VCAM-1 upregulation, while incubation at a pH of 6.8 suppressed such LPC-induced adhesion marker expression. Knocking down G2A by shRNA and inhibiting NF-κB activity yielded opposite outcomes. The application of a Gi protein inhibitor had no impact on LPC-induced ICAM-1/VCAM-1 expression. Atherosclerotic model exhibited high circulating LDL and LPC levels as well as high aortic wall ICAM-1/VCAM-1 expression. Overall, these results suggested that the LPC-G2A-ICAM-1/VCAM-1 pathway may contribute to the atherogenic activity of oxLDL, with NF-κB antagonists representing potentially viable therapeutic tools for the treatment of cardiovascular disease.

The Impact of the SARS-COV-2 Pandemic on the Mental Health and Employment Decisions of Medical Students in North China.

Background: The outbreak of severe respiratory syndrome coronavirus 2 (SARS-COV-2) has led to long periods of social isolation for individuals across the world. Although medical students generally have a high prevalence of mental health problems, they have received less attention than other groups concerning the impact of SARS-COV-2. Therefore, the present study investigated the mental health status, risk factors, and protective factors for mental health problems in medical students in North China during the SARS-COV-2 pandemic. Methods: A WeChat-based survey, which included the Depression Anxiety Stress Scale-21 and measures of social demographics, was performed twice. Risk and protective factors were identified by binary logistic regression analysis. Results: A total of 702 effective questionnaires were collected in two separate surveys. In total, 24.55% of medical students were suffering anxiety to different degrees of severity, 13.18% were suffering depression in the first survey, and 3.71% wanted to give up working in primary medical care during the SARS-COV-2 pandemic in the second survey. In contrast, during the SARS-COV-2 pandemic, a risk factor for anxiety and depression was gender which is male, while being knowledgeable about the SARS-COV-2 pandemic and having a lower academic burden were both protective factors. Conclusions: Measures are required to prevent increases in mental health problems in medical students. Our findings suggest that increasing knowledge about the SARS-COV-2 pandemic and reducing academic burden in medical students is extremely important during the SARS-COV-2 pandemic.

Mechanism of Anti-Inflammatory and Antibacterial Effects of QingXiaoWuWei Decoction Based on Network Pharmacology, Molecular Docking and In Vitro Experiments.

Background and Aim: QingXiaoWuWei Decoction (QXWWD) is a traditional Chinese medicine that is commonly used in clinical settings to treat inflammatory and bacterial diseases. However, there is still a lot to learn about its molecular mechanism. A network pharmacology approach was applied to investigate the pharmacological mechanisms of QXWWD in inflammation treatment. Methods: The basic mechanisms involved in the anti-inflammatory and antibacterial potentials of QXWWD were identified using network pharmacology and molecular docking. The principal components of QXWWD were identified by the HPLC-Q-Exactive-MS method. The antibacterial bioactivity of QXWWD was further investigated using the Kirby-Bauer disc diffusion method and the determination of the minimum inhibitory concentration. The anti-inflammatory activity of QXWWD was evaluated using mice ear swelling test, RAW264.7 cell culture, and pro-inflammatory cytokines measurement. Skin irritation and HE staining were employed to evaluate the safety of QXWWD topical use and to depict the drug's potential therapeutic function. The hub genes and signaling pathways associated with inflammatory and bacterial diseases were validated by western blot in addition to biochemical and pathological markers. Results: Our findings revealed that the ethanolic extract of QXWWD had a strong inhibitory effect against Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae. Meanwhile, QXWWD was potentially effective in suppressing ear swelling, elevated white blood cell counts, and the TNF-α, IL-1, and IL-6 levels. According to skin irritation, QXWWD was found to be safe when tested for topical application. The results of HE staining showed that the possible therapeutic role of QXWWD was related to the change in skin microstructure. Also, the network pharmacology, molecular docking as well as Q-Exactive-MS and HPLC analysis suggested that the synergistic effect of quercetin, luteolin and other ingredients could serve as main contributor of QXWWD for its anti-inflammatory and antibacterial activities. Moreover, the JUN, MAPK1, RELA, NFKBIA, MYC, and AKT1 were the potential identified key targets, and MAPK/PI3K/Akt was among the possibly involved signaling pathways in the anti-inflammatory and antibacterial activities of QXWWD. Conclusions: From a therapeutic standpoint, QXWWD may be a promising antibacterial and anti-inflammatory agent for the treatment of bacterial, acute, and chronic dermatitis.

Relationship between Methylation of FHIT and CDH13 Gene Promoter Region and Liver Cancer.

In order to demonstrate the relationship between methylation of fragile histidine triad (FHIT) and T-cadherin/H-cadherin (CDH13) genes and liver cancer, the methylation status of FHIT and CDH13 was detected in healthy individuals and in Mongolian and Han patients with liver cancer. The phenol-chloroform method was used to extract genomic DNA. The methylation specific polymerase chain reaction method was applied to detect the methylation status of FHIT and CDH13. The relationship between smoking and alcohol consumption and gene (FHIT and CDH13) methylation was analyzed. There was significant difference in methylation rate of FHIT (72.67%, 34.67%) and CDH13 (72.0%, 28.0%) between liver cancer patients and healthy individuals of Mongolian descent (P<0.05), as well as that of FHIT (68%, 30.67%) and CDH13 (64%, 26%) between liver cancer patients and healthy individuals of Han individuals (P<0.05). There was also a relationship between smoking and drinking and the methylation of FHIT and CDH13 (P<0.05). Thus, the methylation of FHIT and CDH13 had a relationship with liver cancer incidence. Smoking and alcohol ingestion may promote the methylation of FHIT and CDH13.

ALDH2 improved irbesartan treatment efficacy among rats with hypertension.

Hypertension is a common cardiovascular disease in clinical scenario. The level of leptin changes with the development of hypertension and is regulated by Aldehyde dehydrogenase2 (ALDH2). Our study explored the relationship between irbesartan treatment and ALDH2. Spontaneously hypertensive rats were treated with irbesartan solution and ALDH2 over expression adenovirus vector for experimental group, and the equivalent amount of spontaneously hypertensive rats was treated with irbesartan solution and null adenovirus vector for control group. Sham group included spontaneously hypertensive rats treated with saline solution and null adenovirus vector. Pathological change of cardiac muscle tissue was observed with microscope. N-terminal Pro-brain natriuretic peptide, blood pressure, left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS) and renal function were assessed to determine cardiovascular function. Expression of serum leptin and mRNA of leptin were examined, respectively. ALDH2 was confirmed by western blot examination. Statistical Analysis was performed to determine correlation. Compared with sham group, ALDH2 were decreased significantly in control group. Remarkable pathological changes of cardiovascular and renal injury were observed in control group rats, including increased NT-proBNP, renal interstitial fibrosis and aberrant hypertension. Compared with control group, experimental group had lower levels of blood pressure and NT-proBNP, but higher level of Glomerular Filtration Rate (GFR). Moreover, irbesartan -treated rats had significantly higher levels of leptin, suggesting irbesartan treatment ameliorated symptoms of hypertension. Expression of serum leptin had a negative correlation with mRNA of leptin (P<0.05). Moreover, compared with control group, ALDH2 over expression significantly improved irbesartan treatment, verified by hypertension related index. Decreased ALDH2 expression were correlated with progression of hypertension. Rats with Hypertension indeed benefited from irbesartan treatment. ALDH2 elevated the drug susceptibility of irbesartan treatment for hypertension via regulating serum leptin, and improved efficacy of irbesartan treatment on hypertension.

Low circulating ghrelin levels in women with polycystic ovary syndrome: a systematic review and meta-analysis.

Although numerous, human subject studies evaluating the relationship between circulating ghrelin levels and polycystic ovary syndrome (PCOS) risk have yielded inconsistent findings. We aimed to quantitatively assess the association by summarizing all available evidence from human subject studies. The PubMed and Web of Science databases were searched up to February 2015 for eligible studies. Studies were eligible if they reported circulating ghrelin levels in women with PCOS and healthy women controls. A fixed or random-effects model was used to pool risk estimations. Twenty studies including 894 PCOS patients and 574 controls were included in the meta-analysis. The studies had fair methodological quality. The pooling analysis of all available studies revealed that ghrelin levels were significantly lower in PCOS patients than in controls, with standardized mean difference of -0.40 (95% CI: -0.73, -0.08). The significant association persisted in many subgroup strata. However, the heterogeneity across studies was considerable and not eliminated in subgroup analyses. Meta-regression analysis further suggested that the heterogeneity might be relevant to variability in study location, PCOS relevant factors like HOMA-IR ratio, as well as other factors not assessed. In conclusion, our meta-analysis suggested that ghrelin levels were significantly lower in PCOS patients than in controls. Further studies with large sample sizes are warranted to replicate our findings.

Association of CYP2E1 and NAT2 polymorphisms with lung cancer susceptibility among Mongolian and Han populations in the Inner Mongolian region.

PURPOSE: To explore associations of CYP2E1 and NAT2 polymorphisms with lung cancer susceptibility among Mongolian and Han populations in the Inner Mongolian region. MATERIALS AND METHODS: CYP2E1 and NAT2 polymorphisms were detected by PCR-RFLP in 930 lung cancer patients and 1000 controls. RESULTS: (1) Disequilibrium of the distribution of NAT2 polymorphism was found in lung cancer patients among Han and Mongolian populations (p=0.031). (2) Lung cancer risk was higher in individuals with c1, D allele of CYP2E1 RsaI/PstI, DraI polymorphisms and slow acetylation of NAT2 (c1 compared with c2, OR=1.382, 95%CI: 1.178- 1.587, p=0.003; D compared with C, OR=1.241, 95%CI: 1.053-1.419, P<0.001; slow acetylation compared with rapid acetylation, OR=1.359, 95%CI:1.042-1.768, p=0.056) (3) Compared with c2/c2 and rapid acetylation, c1/c1 together with slow acetylation synergetically increased risk of lung cancer 2.83 fold. (4) Smokers with CYP2E1 c1/c1, DD, and NAT2 slow acetylation have 2.365, 1.916, 1.841 fold lung cancer risk than others with c2/c2, CC and NAT2 rapid acetylation, respectively. (5) Han smokers with NAT2 slow acetylation have 1.974 fold lung cancer risk than others with rapid acetylation. CONCLUSIONS: Disequilibrium distribution of NAT2 polymorphism was found in lung cancer patients among Han and Mongolian populations. Besides, Han smokers with NAT2 slow acetylation may have higher lung cancer risk compared with rapid acetylation couterparts. CYP2E1 c1/ c1, DD and NAT2 slow acetylation, especially combined with smoking, contributes to the development of lung cancer. CYP2E1 c1/c1 or DD genotype and NAT2 slow acetylation have strong synergistic action in increasing lung cancer risk.

Association between +936 C>T gene polymorphism of vascular endothelial growth factor and lung cancer: a meta-analysis.

BACKGROUND: +936C>T polymorphism of vascular endothelial growth factor (VEGF) is one of the most investigated polymorphisms, it has been suggested that it plays a vital role in tumorigenesis. Intensive studies centering on the association between VEGF +936C>T polymorphism and lung cancer risk or lung cancer patients' overall survival were conducted in recent years, but with inconclusive and ambiguous results. OBJECTIVE AND METHODS: We investigated whether VEGF +936C>T polymorphism influences lung cancer risk and lung cancer patients' overall survival (OS) using pooled odds ratios (ORs) and hazard ratios (HRs) with their corresponding 95% confidence intervals (CI) under different genetic models. RESULTS: A total of 12 eligible studies were included. In the overall analysis, we didn't find any statistical evidence that +936C>T polymorphism was related to the risk of lung cancer in any genetic model. However, increased lung cancer risk was detected in adenocarcinoma subgroup (OR=1.532, 95%CI: 1.016-2.312, P=0.042). For an aggregate result of survival analysis, +936C>T polymorphism was linked to an unfavorable OS (HR=2.248, 95%CI: 1.257-4.017, P=0.006) under homozygous model (TT/CC).

Susceptibility of lung cancer with polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 genotypes in the population of Inner Mongolia region.

BACKGROUND: To study the relationship of susceptibility to lung cancer with the gene polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1, GSTP1 and smoking status in Han and Mongolian populations of Inner Mongolia, an autonomous region of China. MATERIALS AND METHODS: PCR-RFLP, allele-specific and multiplex PCR were employed to identify the genotypes of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 in a case-control study of 322 lung cancer patients diagnosed by bronchoscopy and 456 controls free of malignancy. RESULTS: There is a significant difference in genotypic frequency of GSTT1 of healthy Mongolian and Han subjects. A statistically prominent association was found between CYP1A1 Msp1 (vt/vt) (OR=4.055, 95%CI:2.107-7.578, p=0.000), GSTM1 (-) (OR=2.290, 95%CI:1.467-3.573, p=0.000) and lung cancer in Mongolians. Similarly, in the Han population, CYP1A1 Msp1 (vt/vt) (OR=3.194, 95%CI:1.893-5.390, p=0.000) and GSTM1 (-) (OR=1.884, 95%CI:1.284-2.762, p=0.001) carriers also had an elevated risk of lung cancer. The smokers were more susceptible to lung cancer 2.144 fold and 1.631 fold than non-smokers in Mongolian and Han populations, respectively. The smokers who carried with CYP1A1 Msp1 (wt/vt+vt/vt), exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) respectively were found all to have a high risk of lung cancer. CONCLUSIONS: CYP1A1 Msp1 (vt/ vt) and GSTM1 (-) are risk factors of lung cancer in Han and Mongolian population in the Inner Mongolia region. The smokers with CYP1A1 Msp1 (wt/vt+vt/vt), CYP1A1 exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) genotypes, respectively, are at elevated risk of lung cancer.

[Polymorphism of CYP1A1 gene Msp I site in the Mongolian and Han nationality populations of Inner Mongolia of China].

OBJECTIVE: To study the polymorphism of CYP1A1 gene Msp I site in the Mongolian and Han nationality populations of Inner Mongolia. METHODS: The PCR-restriction fragment length polymorphism(PCR-RFLP) technique was used to analyze the genotypes of CYP1A1 gene Msp I site in 80 subjects of Mongolian nationality and 120 subjects of Han nationality among whom there is no blood relationship each other. RESULTS: The genotype frequency of CYP1A1 gene Msp I site showed that the wild-type, heterozygote, homozygous variants were 35.0%, 48.7%, 16.3% and 33.3%, 52.5%, 14.2% respectively distributions of Mongolian nationality and Han nationality population, and the Chi-square tests showed that there was no significant difference between the two groups. CONCLUSION: The genotype frequency distributions of CYP1A1 gene Msp I site did not exhibit the obvious difference between Mongolian nationality and Han nationality population of Inner Mongolia.

[Influence of smoke tar on mRNA expression of aromatic hydrocarbon receptor and cytochrome P4501A1 gene of mice lungs].

OBJECTIVE: To investigate the influence of the smoke tar on the expression of aromatic hydrocarbon receptor (AHR) and the cytochrome P4501Al (CYP1A1) gene of mice lungs. METHODS: The smoke tar of 5.29, 10.58 and 15.87 mg/kg was administered intraperitoneally in mice respectively. RNA of mice lungs was got with RNA kit. RT-PCR technique was used for determining AHR and CYP1A1 gene expression with beta-actin as control. RESULTS: The AHR gene expression level was (0.554 +/- 0.023) for the mice intraperitoneally administered with 5.29 mg/kg smoke tar for 72 hours with the significant difference in gene expression level compared with the Tween-80 group (0.484 +/- 0.045) (P < 0.05). The AHR gene expression levels were (0.555 +/- 0.014), (0.606 +/- 0.051), and (0.566 +/- 0.014), (0.684 +/- 0.069) for the mice intraperitoneally administered with 10.58 and 15.87 mg/kg smoke tar for 48 hours and 72 hours respectively with the significant difference in gene expression level compared with the Tween-80 group (0.486 +/- 0.060, 0.484 +/- 0.045) (P < 0.05, P < 0.01). The CYP1Al gene expression levels were (1.535 +/- 0.021), (1.643 +/- 0.046) and (1.624 +/- 0.056), (1.739 +/- 0.038) respectively with the significant difference compared with the Tween-80 group (l.436 +/- 0.016, 1.404 +/- 0.036) (P < 0.01). CONCLUSION: The smoke tar can regulate up the expression of AHR and CYP1A1 gene at a certain dosage and time. The regulation of the smoke tar for the expression of AHR was earlier than for that of CYP1A1.

[Relationship between CYP1A1 and GSTM1 genetic polymorphisms and lung cancer susceptibility in population of Inner Mongolia].

BACKGROUND: Lung cancer is one of malignant tumors to hurt human health. It has been known that the development of lung cancer may be associated with genetic polymorphism of some lung cancer related genes. The aim of this study is to explore the susceptibility to lung cancer in relation to CYP1A1 and GSTM1 genetic polymorphisms in population of Inner Mongolia. METHODS: CYP1A1 and GSTM1 genetic polymorphisms were determined by PCR-RFLP in 163 lung cancer cases and healthy controls respectively. RESULTS: The frequencies of CYP1A1 variation genotype (vt/vt) and GSTM1(-) were 36.8% and 65.0% in lung cancer cases and 19.0% and 48.9% in healthy controls respectively. Statistical tests showed significant difference in the frequencies between the two groups (Chi-Square =12.82, P=0.0001; Chi-Square = 9.78, P=0.002). The risk of lung cancer with CYP1A1 variation genotype was significantly higher than those of controls (OR= 2.48, 95% CI=1.51-4.08). The individuals who carried with GSTM1-null genotype had a high risk of lung cancer (OR=2.03, 95% CI=1.30-3.17). Combined analysis of the polymorphisms showed that percentage of CYP1A1(vt/vt)/GSTM1(-) in lung cancer and control groups was 28.8% and 8.0% respectively (Chi-Square = 23.883, P=0.0001). The people who carried with CYP1A1(vt/vt)/GSTM1(-) had a high risk of lung cancer (OR=4.90, 95% CI=2.50-9.83). Pearson Chi-Square of sex differential showed there was no significance between the homozygous variation genotype of CYP1A1/GSTM1(-) and the other genotypes of CYP1A1/GSTM1(-) neither in lung cancer group (Chi-Square=0.797, P=0.372) nor in control group (Chi-Square=0.670, P=0.761). Statistical tests showed that susceptibility to lung cancer was related to smoking (Chi-Square = 14.197, P=0.000), the risk of lung cancer in smoking individuals raised remarkably (OR=2.33, 95% CI=1.50-3.62). There may be a synergetic interaction between CYP1A1 variation genotype (vt/vt) and smoking on the elevated susceptibility to lung cancer (Chi-Square = 23.843, P=0.000), the smokers who carried with CYP1A1 (vt/vt) had a significantly higher risk of lung cancer (OR=4.44, 95% CI=2.40-8.32, Chi-Square = 23.843, P= 0.000). So did the GSTM1(-) and smoking on the elevated susceptibility to lung cancer, the significantly higher risk of lung cancer had also been found in those smokers who carried with GSTM1(-) (OR=7.32, 95% CI=3.39-15.50, Chi-Square = 36.708,P=0.000). CONCLUSIONS: The polymorphisms of CYP1A1 vt/vt and GSTM1(-) are the risk factors in lung cancer of Inner Mongolia. Smoking is also related to the susceptibility to lung cancer. There may be a synergetic interaction between CYP1A1 (vt/vt) and GSTM1(-) on the elevated susceptibility of lung cancer. So do the CYP1A1 (vt/vt), GSTM1(-) and smoking.