Prediction and validation of common targets in atherosclerosis and non-small cell lung cancer influenced by atorvastatin.

BACKGROUND: Cardiovascular disease and cancer are the main causes of morbidity and mortality worldwide. Studies have shown that these two diseases may have some common risk factors. Atorvastatin is mainly used for the treatment of atherosclerosis in clinic. A large number of studies show that atorvastatin may produce anti-tumor activities. This study aimed to predict the common targets of atorvastatin against atherosclerosis and non-small cell lung cancer (NSCLC) based on network pharmacology. METHODS: The target genes of atherosclerosis and NSCLC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The disease-target-component model map and the core network were obtained using Cytoscape 3.7.1. The MTS and wound healing assay were used to detect the effect of atorvastatin on cell viability and migration of A549 cells. The expression of potential common target genes of atorvastatin against atherosclerosis and NSCLC were confirmed in A549 cells and lung cancer tissues of patients. RESULTS: We identified 15 identical pathogenic genes, and four of which (MMP9, MMP12, CD36, and FABP4) were considered as the key target genes of atorvastatin in anti-atherosclerosis and NSCLC. The MTS and wound healing assays revealed that atorvastatin decreased A549 cells migration significantly. Atorvastatin markedly decreased the expression of MMP9, MMP12, CD36, and FABP4 in A549 cells and patients were treated with atorvastatin. CONCLUSIONS: This study demonstrated 15 common pathogenic genes in both atherosclerosis and NSCLC. And verified that MMP 9, MMP 12, CD 36 and FABP 4 might be the common target genes of atorvastatin in anti-atherosclerosis and NSCLC.

The novel small molecule BH3 mimetic nobiletin synergizes with vorinostat to induce apoptosis and autophagy in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer with few therapeutic options; therefore, the identification of new targets and drugs with potent combination therapy is desirable. We previously screened BH3 mimetics from a natural product library, and in this study, we validated nobiletin as a BH3 mimetic. Specifically, we observed its combination potential and mechanism with vorinostat in SCLC in vitro and in vivo. The results showed that combination treatment with nobiletin and vorinostat reduced the proliferation of SCLC H82 cells and increased the levels of apoptotic proteins such as cleaved caspase-9 and cleaved PARP. The combination treatment increased LC3-II expression and induced autophagic cell death. In addition, this treatment significantly inhibited H82 cell xenograft SCLC tumor growth in nude mice. The combination treatment with nobiletin and vorinostat efficiently increased autophagy by inhibiting the PI3K-AKT-mTOR pathway and promoting dissociation of the BCL-2 and Beclin 1 complex, increasing the level of isolated Beclin 1 to stimulate autophagy. Molecular docking and surface plasmon resonance analysis showed that nobiletin stably bound to the BCL-2, BCL-XL and MCL-1 proteins with high affinity in a concentration-dependent manner. These results suggest that nobiletin is a BH3-only protein mimetic. Furthermore, the combination of nobiletin with vorinostat increased histone H3K9 and H3K27 acetylation levels in SCLC mouse tumor tissue and enhanced the expression of the BH3-only proteins BIM and BID. We conclude that nobiletin is a novel natural BH3 mimetic that can cooperate with vorinostat to induce apoptosis and autophagy in SCLC.

Targeted nutritional intervention with enhanced recovery after surgery for carotid endarterectomy: A prospective clinical trial.

Ischemic stroke is the most common cerebrovascular disease, and vascular obstruction is an important cause of this disease. As the main method for the management of carotid artery stenosis, carotid endarterectomy (CEA) is an effective and preventive treatment measure in ischemic cerebrovascular disease. This study aims to propose the application of a new enhanced recovery after surgery (ERAS) nutritional support regimen in CEA, which can significantly improve the perioperative nutritional status of patients. A total of 74 patients who underwent CEA were included and randomly divided into two groups: 39 patients received nutritional therapy with the ERAS protocol (ERAS group) and 35 patients received routine perioperative nutritional support (control group). Our results showed that the levels of major clinical and biochemical parameters (albumin, hemoglobin, creatinine, calcium and magnesium levels, etc.) in the ERAS group were significantly higher than those in the control group after surgery (p < 0.05). Additionally, patients in the ERAS group had dramatically shorter postoperative length of stay and reflected higher mean satisfaction at discharge (p < 0.001). Moreover, no statistically significant differences were observed in postoperative complication rates and Mini-mental State Examination scores at discharge. The emergence of this neurosurgical ERAS nutritional support program can effectively intervene in perioperative nutritional status, and notably reduce postoperative hospital stays.

Pontibacter pamirensis sp. nov., isolated from saline-alkaline soil.

A novel bacterium, designated TRT317T, was isolated from saline-alkaline soil collected from the Pamir plateau in northwest China. Cells of this strain were Gram-stain-negative, aerobic rods and red-pink-coloured. Phylogenetic analysis using 16S rRNA gene sequences indicated that strain TRT317T showed the highest sequence similarity to the type strains of Pontibacter diazotrophicus (96.3 %) and Pontibacter yuliensis (96.2 %). Growth was observed at 4-40 °C, pH 6.0-10.0 and in the presence of up to 7 % (w/v) NaCl. The major fatty acids were iso-C15 : 0 and summed feature 4 (iso-C17 : 1 I/anteiso-C17 : 1 B). The polar lipids included phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified phospholipid, four unidentified glycolipids and five unidentified lipids. The whole-cell sugars of strain TRT317T were mannose, rhamnose, glucose, galactose, xylose, arabinose and four unidentified sugars. The sole respiratory quinone was MK-7. The genomic DNA G+C content of strain TRT317T was 47.7 mol%. The average nucleotide identity (ANI) value of strain TRT317T with P. diazotrophicus was 88.3 %, which is below the standard ANI threshold for species identification (95-96 %). Combined results of physiological, genotypic, phylogenetic and chemotaxonomic analyses demonstrated that strain TRT317T represents a novel species within the genus Pontibacter, for which the name Pontibacter pamirensis sp. nov. is proposed. The type strain is TRT317T (=CGMCC1.18690T=KCTC 82818T).

Sphingobacterium endophyticum sp. nov., a novel endophyte isolated from halophyte.

A bacterial strain designated NYYP31T was isolated from the leaves of an annual halophytes, Suaeda corniculata Bunge, collected from the southern edge of the Gurbantunggut desert, north-west China. Strain NYYP31T was Gram-staining negative, strictly aerobic, rod-shaped, non-motile, and non-spore-forming. Growth was observed at 4-42 °C, at pH 5.0-10.0, in the presence of up to 8% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences and coding sequences of 92 protein clusters showed that strain NYYP31T should be assigned to the genus Sphingobacterium. 16S rRNA gene sequence similarity analysis showed that strain NYYP31T was most closely related to the type strain of Sphingobacterium daejeonense (97.9%) and Sphingobacterium lactis (97.7%). The predominant isoprenoid quinone was MK-7. The major fatty acids were identified as iso-C15:0, iso-C17:0 3-OH and summed feature 3 (C16:1 ω7c and/or C16:1 ω6c). The polar lipids were phosphatidylethanolamine, two unidentified phospholipids, three unidentified lipids, three unidentified amino phospholipids, and two unidentified glycolipids. The genomic DNA G + C content was 36.4 mol%. The average nucleotide identity (ANI) values for strain NYYP31T to the type strains of S. daejeonense and S. lactis were 77.9 and 74.1%, respectively, which were below the cut-off level (95-96%) for species delineation. Based on the above results, strain NYYP31T represents a novel species of the genus Sphingobacterium, for which the name Sphingobacterium endophyticum sp. nov. is proposed. The type strain is NYYP31T (= CGMCC 1.16979T = NBRC 114258T).

Methylmalonic Acidemia Complicated by Homocystinuria Diseases: a Report of Three Cases.

This study aims to improve our understanding of methylmalonic acidemia (MMA) complicated by homocystinuria disease by analyzing the clinical characteristics, treatment response and prognosis of three patients. Hyperhomocysteinemia and developmental retardation were present in all patients, epilepsy was present in one patient, and hemolytic uremic syndrome was present in one patient. The conditions of two patients were complicated by pulmonary arterial hypertension, one patient by left pulmonary vein ectopic drainage to the coronary sinus and the other by noncompaction of the ventricular myocardium. The two MMA patients with the complication of severe pulmonary arterial hypertension died because of late diagnosis and irregular treatment of MMA. Echocardiography is necessary for patients with combined MMA and homocystinuria, and these patients are susceptible to cardiovascular disease. When a patient with combined MMA and homocystinuria has the complication of severe pulmonary arterial hypertension, the prognosis is poor.

Loss of Sfrp2 contributes to the neurological disorders related with morphine withdrawal via Wnt/ß-catenin signaling.

Morphine administration is a medical problem characterized by compulsive opioid use that causes terrible negative consequences. The exact mechanisms of morphine-induced dependence and morphine withdrawal symptoms remain unclear. Recent studies have revealed that the upregulation of Wnt/ß-catenin signaling plays important roles in morphine exposure and morphine withdrawal. Secreted frizzled-related protein 2 (Sfrp2) can prevent the activation of Wnt/ß-catenin signaling by competing with the Frizzled receptor for Wnt ligands. We conducted this study aimed to evaluate the effect of iatrogenic trauma induced by stereotactic surgery and the protective effect of stereotaxic Sfrp2 injection on morphine withdrawal symptoms in Male Sprague Dawley (SD) rats. Many techniques including western blot analysis and immunoprecipitation were used. Anxiety-related behaviors, morphine withdrawal syndrome, and dendritic spines were also examined in male SD rats after morphine treatment and stereotaxic injection of Sfrp2. Western blot results suggested that Wnt signaling was activated in the nucleus accumbens of SD rats suffering from morphine withdrawal and that Sfrp2 attenuated the overexpression of Wnt signaling. Similarly, the withdrawal-like symptoms of morphine dependent rats were abrogated by intracerebral Sfrp2 injection. The iatrogenic trauma induced by stereotactic surgery showed no influence on the Wnt signaling and withdrawal-like symptoms. Moreover, the results of Golgi-cox staining and DiI staining indicated that the damage on proximal spine density caused by morphine treatment was restored by intracerebral Sfrp2 injection. Together, the data presented here indicated that Sfrp2 abrogated the neurological disorders and loss of proximal spine related with morphine withdrawal via Wnt/ß-catenin signaling.

Microbacterium suaedae sp. nov., isolated from Suaeda aralocaspica.

Two bacterial strains, YZYP 306T and YZGP 509, were isolated from the halophyte Suaeda aralocaspica collected from the southern edge of the Gurbantunggut desert, north-west China. Cells were Gram-stain-positive, aerobic, non-motile, short rods. Strain YZYP 306T grew at 4-40 °C, while strain YZGP 509 grew at 4-42 °C, with optimum growth at 28 °C, and they both grew at pH 6.0-12.0 and 0-15 % (w/v) NaCl. Phylogenetic analyses of the 16S rRNA gene sequences placed the two strains within the genus Microbacterium with the highest similarities to Microbacterium indicum BBH6T (97.8 %) and Microbacterium sorbitolivorans SZDIS-1-1T (97.2 %). The average nucleotide identity value between YZYP 306T and M. indicum BBH6T was 78.3 %. The genomic DNA G+C contents of strains YZYP 306T and YZGP 509 were 68.49 and 68.53 mol%, respectively. The characteristic cell-wall amino acid was ornithine. Whole-cell sugars were galactose, mannose and ribose. The acyl type of the peptidoglycan was glycolyl. The major cellular fatty acids were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The major menaquinones were MK-10 and MK-11. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, an unidentified phospholipid and an unidentified glycolipid. These results are consistent with the classification of the two strains into the genus Microbacterium. On the basis of the evidence presented in this study, strains YZYP 306T and YZGP 509 are representatives of a novel species in the genus Microbacterium, for which the name Microbacterium suaedae sp. nov. is proposed. The type strain is YZYP 306T (=CGMCC 1.16261T=KCTC 49101T).

Microbacterium halophytorum sp. nov., a novel endophytic actinobacterium isolated from halophytes.

Two actinobacterial strains, YJYP 303T and YZYP 518, were isolated from two species of halophytes collected from the southern edge of the Gurbantunggut Desert. Cells were Gram-stain-positive, aerobic, short rods and without flagella. Growth of the two strains was found to occur at 4-44 °C, pH 6.0-12.0 and in the presence of up to 15 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the two strains are associated with members of the genus Microbacterium. In the phylogenetic tree, the two strains shared a clade with Microbacterium halotolerans YIM 70130T (97.58 % 16S rRNA gene sequence identity) and Microbacterium populi KCTC 29152T (96.54 %). The average nucleotide identity values of strain YJYP 303T and YZYP 518 to M. halotolerans YIM 70130T were determined to be 79.97 and 80.03 %, respectively. The genomic DNA G+C contents of strains YJYP 303T and YZYP 518 were 69.72 and 70.57 %, respectively. The major fatty acids were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The predominant respiratory quinones was MK-11, followed by MK-10 and MK-12. The muramic acid type of peptidoglycan was N-glycolyl. The whole-cell sugars were mannose, ribose, rhamnose, glucose, galactose and two unidentified sugars. The cell-wall amino acids were glutamic acid, ornithine, glycine and alanine. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, an unidentified phospholipid and an unidentified glycolipid. On the basis of the evidence presented in this study, strains YJYP 303T and YZYP 518 are characterized as members of a novel species in the genus Microbacterium, for which the name Microbacteriumhalophytorum sp. nov. is proposed. The type strain is YJYP 303T (=CGMCC 1.16264T=KCTC 49100T).

Streptomyces xinjiangensis sp. nov., an actinomycete isolated from Lop Nur region.

A novel actinobacterial strain, designated LPA192(T), was isolated from a soil sample collected from Lop Nur, Xinjiang Uygur Autonomous Region, Northwest China. A polyphasic approach was used to investigate the taxonomic position of strain LPA192(T). The isolate showed morphological and chemotaxonomic characteristics typical of members of the genus Streptomyces. Peptidoglycan was found to contain LL-diaminopimelic acid as the diagnostic diamino acid. The predominant menaquinones were MK-9(H6) and MK-10(H4). Polar lipids were phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylinositol. Major cellular fatty acids consist of C16:0, anteiso-C15:0 and C18:1 ω9c. The sugar in whole-cell hydrolysates was mannose. Phylogenetic analysis indicated that strain LPA192(T) is closely related to Streptomyces tanashiensis LMG 20274(T) (99.3 %), Streptomyces gulbargensis DAS131(T) (99.3 %), Streptomyces nashvillensis NBRC 13064(T) (99.3 %), Streptomyces roseolus NBRC 12816(T) (99.2 %) and Streptomyces filamentosus NBRC 12767(T) (99.1 %) while showing below 98.5 % sequencing similarities with other validly published Streptomyces species. However, DNA-DNA relatedness values between LPA192(T) and the closely related type strains were below 40 %, which are much lower than 70 % threshold value for species delineation. The genomic DNA G + C content of strain LPA192(T) was 69.3 mol %. Based on the differences in genotypic and phenotypic characteristics from the closely related strains, strain LPA192(T) is considered to represent a novel species of the genus Streptomyces for which the name Streptomyces xinjiangensis sp. nov. is proposed. The type strain is LPA192(T) (=KCTC 39601(T) = CGMCC 4.7288(T)).

Stackebrandtia cavernae sp. nov., a novel actinobacterium isolated from a karst cave sample.

A novel actinobacterial strain, YIM ART06T, was isolated from a rock sample of karst cave located at Guizhou province, south-west China, and was characterized by a polyphasic taxonomic approach. The morphological and chemotaxonomic properties of strain YIM ART06T were in accordance with those of the genus Stackebrandtia. The 16S rRNA gene sequence of strain YIM ART06T showed highest similarity to Stackebrandtia nassauensis JCM 14905T (98.0 %). The DNA-DNA hybridization value between strains YIM ART06T and S. nassauensis JCM 14905T was, however, moderately high (62.9 %) but below the 70 % limit for species identification. Strain YIM ART06T contained meso-diaminopimelic acid as the diagnostic diamino acid, and mannose, ribose and xylose in the whole-cell hydrolysates. The predominant menaquinones detected were MK-10(H4), MK-10(H6), MK-11(H4) and MK-11(H6), while the cell membrane polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylmethylethanolamine and three unidentified phospholipids. The genomic DNA G+C content of strain YIM ART06T was 71 mol%. The major fatty acids were anteiso-C17 : 0, iso-C17 : 0, iso-C16 : 0 and iso-C15 : 0. Based on the taxonomic characteristics from the genotypic and phenotypic results, strain YIM ART06T merits recognition as a representative of a novel species of the genus Stackebrandtia, for which the name Stackebrandtia cavernae sp. nov. is proposed. The type strain is YIM ART06T ( = KCTC 39599T = CCTCC AA 2015021T = DSM 100594T).

Saccharothrix lopnurensis sp. nov., a filamentous actinomycete isolated from sediment of Lop Nur.

A novel actinomycete strain, designated YIM LPA2h(T), was isolated from a sediment sample collected from Lop Nur, Xinjiang Uygur Autonomous Region, North-West China. The taxonomic position of strain YIM LPA2h(T) was investigated by a polyphasic approach. The morphological and chemotaxonomic properties of the isolate were in accordance with the members of the genus Saccharothrix. The 16S rRNA gene sequence of the strain showed highest similarities to Saccharothrix yanglingensis (98.6 %), Saccharothrix longispora (98.4 %) and Saccharothrix hoggarensis (98.3 %). However, the DNA-DNA hybridization values between the new isolate YIM LPA2h(T) and S. yanglingensis, S. longispora and S. hoggarensis were significantly below 70 %. Strain YIM LPA2h(T) was found to contain meso-diaminopimelic acid as diagnostic diamino acid. The major sugars in whole-cell hydrolysates were rhamnose, galactose, mannose, glucose and fructose. The major polar lipids were identified as phosphatidylethanolamine, phosphatidylhydroxylethanolamine, diphosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannoside. The predominant respiratory menaquinones were MK-9 (H4) and MK-10 (H4). The major fatty acids were C17:1 ω8c (15 %), iso-C15:0 (12 %), anteiso-C15:0 (12 %) and summed feature 3 (C16:1 ω6c/C16:1 ω7c, 10 %). The genomic DNA G+C content of strain YIM LPA2h(T) was determined to be 75 mol %. The genotypic and phenotypic results suggest that strain YIM LPA2h(T) represents a novel species of the genus Saccharothrix, for which the name Saccharothrix lopnurensis sp. nov. is proposed. The type strain is YIM LPA2h(T) (=CGMCC 4.7246(T)=KCTC 39545(T)).

Resting heart rate as a marker for identifying the risk of undiagnosed type 2 diabetes mellitus: a cross-sectional survey.

BACKGROUND: Fast resting heart rate might increase the risk of developing type 2 diabetes mellitus (T2DM). However, it is unclear whether resting heart rate could be used to predict the risk of undiagnosed T2DM. Therefore, the purposes of this study were to examine the association between resting heart rate and undiagnosed T2DM, and evaluate the feasibility of using resting heart rate as a marker for identifying the risk of undiagnosed T2DM. METHODS: A cross-sectional survey was conducted. Resting heart rate and relevant covariates were collected and measured. Fasting blood samples were obtained to measure blood glucose using the modified hexokinase enzymatic method. Predictive performance was analyzed by Receiver Operating Characteristic (ROC) curve. RESULTS: This study included 16, 636 subjects from rural communities aged 35-78 years. Resting heart rate was significantly associated with undiagnosed T2DM in both genders. For resting heart rate categories of <60, 60-69, 70-79, and ≥80 beats/min, adjusted odds ratios for undiagnosed T2DM were 1.04, 2.32, 3.66 and 1.05, 1.57, 2.98 in male and female subjects, respectively. For male subjects, resting heart rate ≥70 beats/min could predict undiagnosed T2DM with 76.56% sensitivity and 48.64% specificity. For female subjects, the optimum cut-off point was ≥79 beats/min with 49.72% sensitivity and 67.53% specificity. The area under the ROC curve for predicting undiagnosed T2DM was 0.65 (95% CI: 0.64-0.66) and 0.61(95% CI: 0.60-0.62) in male and female subjects, respectively. CONCLUSIONS: Fast resting heart rate is associated with an increased risk of undiagnosed T2DM in male and female subjects. However, resting heart rate as a marker has limited potential for screening those at high risk of undiagnosed T2DM in adults living in rural areas.

[Diagnostic investigation of the detection of granulocyte-macrophage colony stimulating factor antibody in serum for pulmonary alveolar proteinosis].

OBJECTIVE: To evaluate the diagnostic value of granulocyte-macrophage colony stimulating factor (GM-CSF) antibody in serum for pulmonary alveolar proteinosis (PAP). METHODS: Twelve PAP patients visiting Peking University People's Hospital or Fujian Provincial Hospital from January 1, 2002 to December 31, 2012, 25 patients with other pulmonary diseases (disease control), and 25 healthy volunteers (healthy control) were recruited in the study. The titer level of GM-CSF antibody in serum was determined with enzyme-linked immunosorbent assay (ELISA), and the clinical characteristics were collected in the PAP patients. RESULTS: The geometric mean titers of GM-CSF antibody in the PAP patients, the disease controls and the healthy controls were 1: 25 349, 1: 311 and 1: 256, respectively. The differences between the disease controls and the healthy controls were of no statistic significance (t = -1.14, P = 0.261) . With 3 times standard error (3s) above the mean value as the higher limit of X value(X = lgT, T standing for the reciprocal of the titer), the upper limit for T was 1698. With the T value ≥ 1698 as the diagnostic threshold for PAP, both the sensitivity and the specificity were 100%. The diagnostic value of GM-CSF antibody was similar to that of surgical lung biopsy and higher than that of transbronchial lung biopsy. CONCLUSION: The detection of serum GM-CSF is non-invasive, convenient and efficient for the diagnosis of PAP with high sensitivity and specificity.

Development and evaluation of a simple and effective prediction approach for identifying those at high risk of dyslipidemia in rural adult residents.

BACKGROUND: Dyslipidemia is an extremely prevalent but preventable risk factor for cardiovascular disease. However, many dyslipidemia patients remain undetected in resource limited settings. The study was performed to develop and evaluate a simple and effective prediction approach without biochemical parameters to identify those at high risk of dyslipidemia in rural adult population. METHODS: Demographic, dietary and lifestyle, and anthropometric data were collected by a cross-sectional survey from 8,914 participants living in rural areas aged 35-78 years. There were 6,686 participants randomly selected into a training group for constructing the artificial neural network (ANN) and logistic regression (LR) prediction models. The remaining 2,228 participants were assigned to a validation group for performance comparisons of ANN and LR models. The predictors of dyslipidemia risk were identified from the training group using multivariate logistic regression analysis. Predictive performance was evaluated by receiver operating characteristic (ROC) curve. RESULTS: Some risk factors were significantly associated with dyslipidemia, including age, gender, educational level, smoking, high-fat diet, vegetable and fruit intake, family history, physical activity, and central obesity. For the ANN model, the sensitivity, specificity, positive and negative likelihood ratio, positive and negative predictive values were 90.41%, 76.66%, 3.87, 0.13, 76.33%, and 90.58%, respectively, while LR model were only 57.37%, 70.91%, 1.97, 0.60, 62.09%, and 66.73%, respectively. The area under the ROC cure (AUC) value of the ANN model was 0.86±0.01, showing more accurate overall performance than traditional LR model (AUC = 0.68±0.01, P<0.001). CONCLUSION: The ANN model is a simple and effective prediction approach to identify those at high risk of dyslipidemia, and it can be used to screen undiagnosed dyslipidemia patients in rural adult population. Further work is planned to confirm these results by incorporating multi-center and longer follow-up data.