gutMGene: a comprehensive database for target genes of gut microbes and microbial metabolites.

gutMGene (http://bio-annotation.cn/gutmgene), a manually curated database, aims at providing a comprehensive resource of target genes of gut microbes and microbial metabolites in humans and mice. Metagenomic sequencing of fecal samples has identified 3.3 × 106 non-redundant microbial genes from up to 1500 different species. One of the contributions of gut microbiota to host biology is the circulating pool of bacterially derived small-molecule metabolites. It has been estimated that 10% of metabolites found in mammalian blood are derived from the gut microbiota, where they can produce systemic effects on the host through activating or inhibiting gene expression. The current version of gutMGene documents 1331 curated relationships between 332 gut microbes, 207 microbial metabolites and 223 genes in humans, and 2349 curated relationships between 209 gut microbes, 149 microbial metabolites and 544 genes in mice. Each entry in the gutMGene contains detailed information on a relationship between gut microbe, microbial metabolite and target gene, a brief description of the relationship, experiment technology and platform, literature reference and so on. gutMGene provides a user-friendly interface to browse and retrieve each entry using gut microbes, disorders and intervention measures. It also offers the option to download all the entries and submit new experimentally validated associations.

MiR-134-5p Regulates Myocardial Apoptosis and Angiogenesis by Directly Targeting KDM2A After Myocardial Infarction.

MiR-134-5p was found to have potential diagnostic value for myocardial infarction (MI), but its biological role in MI has not been reported. In this study, MI mouse model was established. Quantitative real-time PCR (qRT-PCR) and western blot were used to measure the expression of miR-134-5p, lysine demethylase 2A (KDM2A), and vascular endothelial growth factor (VEGF). Dual-Luciferase reporter (DLR) assay was used to explore the relationship between miR-134-5p and KDM2A. The influence of miR-134-5p on cardiomyocytes apoptosis was detected using methyl thiazolyl tetrazolium (MTT) assay. The results revealed that miR-134-5p was highly expressed in infarction tissues of MI mice. Knockdown of miR-134-5p inhibited hypoxia/reoxygenation (H/R) -induced cardiomyocyte apoptosis. In addition, KDM2A was the target gene of miR-134-5p and negatively regulated by miR-134-5p. The promotion effect on the protein level of KDM2A and VEGF induced by miR-134-5p inhibitor can be reversed by shKDM2A in cardiomyocytes. Further, silencing of miR-134-5p promoted myocardial angiogenesis and inhibited myocardial apoptosis via upregulating KDM2A in MI mice. Taken together, our research revealed that knockdown of miR-134-5p increased KDM2A expression, thereby suppressing myocardial apoptosis and promoting myocardial angiogenesis.

Updated incidence rates and risk factors of esophageal cancer in Nan'ao Island, a coastal high-risk area in southern China.

Esophageal cancer (EC) is one of the most common cancers in China. The purpose of this study was to investigate the updated incidence rates and risk factors of EC in Nan'ao Island, where the EC incidence rate was chronically the highest in southern China. To calculate the annual incidence rate, data on 338 EC cases from Nan'ao Cancer Registry system diagnosed during 2005-2011 were collected. A case-control study was conducted to explore the EC risk factors. One hundred twenty-five alive EC patients diagnosed during 2005-2011 and 250 controls were enrolled into the case-control study. A pre-test questionnaire on demography, dietary factors, drinking water treatment, and behavioral factors was applied to collect information of all participants. The average EC incidence rates during 2005-2011 were 66.09/105, 94.62/105, 36.83/105 for both genders, males and females, respectively, in Nan'ao Island. The EC incidence rate in males was 2.40- to 4.55-fold higher than that in females in the period from 2006 to 2011 (P < 0.05). Considering the onset age, males tend to be much younger than females and reached peak incidence rate at a younger age (P < 0.05). Drinking water treatment by filter (odds ratio [OR] = 0.28, 95% confidence interval [95% CI] = 0.13-0.58) and fruit consumption (OR = 0.55, 95% CI = 0.32-0.94) reduced the risk for EC. On the contrary, the pickled vegetables consumption (OR = 2.64, 95% CI = 1.46-4.76) and liquor drinking (OR = 2.32, 95% CI = 1.21-4.44) increased the risk for EC. These results may be of importance for future research on EC etiology and prevention strategies.

Poricoic acid A promotes angiogenesis and myocardial regeneration by inducing autophagy in myocardial infarction.

Myocardial infarction (MI) is a kind of cardiovascular diseases with high morbidity and mortality. Poricoic acid A (PAA) is the main active substance in Poria cocos, which has been discovered to exhibit an ameliorative role in the progression of many diseases. However, no report has been focused on the regulatory effects of PAA on MI progression. In this study, at first, oxygen glucose deprivation (OGD) treatment was performed in human cardiac microvascular endothelial cells (HCMECs) to mimic MI cell model. Our findings demonstrated that cell proliferation was reduced post OGD treatment, but which was reversed by PAA treatment. Moreover, PAA suppressed cell apoptosis in OGD-triggered HCMEC cells. Next, it revealed that PAA induced autophagy in OGD-treated HCMEC cells through enhancing LC3-II/LC3-I level and reducing P62 level. In addition, PAA strengthened the angiogenesis ability and migration ability in OGD-induced HCMEC cells. Lastly, it was uncovered that PAA modulated the AMPK/mTOR signaling pathway through affecting the p-mTOR/mTOR and p-AMPK/AMPK levels. In conclusion, PAA can promote angiogenesis and myocardial regeneration after MI by inducing autophagy through modulating the AMPK/mTOR pathway. This work suggested that PAA may be a potential and useful drug for MI treatment.

Association between glycemia and multi-vessel lesion in participants undergoing coronary angiography: a cross-sectional study.

Background: This study aims to elucidate the association between glycemia and the occurrence of multi-vessel lesions in participants undergoing coronary angiography. Methods: We analyzed 2,533 patients with coronary artery disease who underwent coronary angiography. Of these, 1,973 patients, identified by the endpoint of multi-vessel lesions, were examined using univariate and multivariate logistic regression analyses to determine the relationship between glycemia levels and multi-vessel lesion occurrence. Results: The analysis included 1,973 participants, among whom 474 patients were identified with coronary multi-vessel lesions. Univariate logistic regression analysis demonstrated a positive correlation between glycemia and the occurrence of coronary multi-vessel lesions (OR 1.04; 95% CI 1.01-1.08; p = 0.02). The adjusted model indicated that for each unit increase in glycemia, the risk of developing coronary multi-vessel lesions increased by 4%, showing a significant correlation (p < 0.05). Subgroup analyses revealed that the impact of glycemia on multi-vessel lesions in patients with PCI varied according to gender, age, and smoking status, with the effect being more pronounced in men, older patients, and smokers. Conclusion: Our findings establish a significant association between glycemia and the incidence of multi-vessel lesions, particularly pronounced in male patients, individuals over 45, and smokers.

Subtle mutations in the SMN1 gene in Chinese patients with SMA: p.Arg288Met mutation causing SMN1 transcript exclusion of exon7.

BACKGROUND: Proximal spinal muscular atrophy (SMA) is a common neuromuscular disorder resulting in death during childhood. Around 81~95% of SMA cases are a result of homozygous deletions of survival motor neuron gene 1 (SMN1) gene or gene conversions from SMN1 to SMN2. Less than 5% of cases showed rare subtle mutations in SMN1. Our aim was to identify subtle mutations in Chinese SMA patients carrying a single SMN1 copy. METHODS: We examined 14 patients from 13 unrelated families. Multiplex ligation-dependent probe amplification analysis was carried out to determine the copy numbers of SMN1 and SMN2. Reverse transcription polymerase chain reaction (RT-PCR) and clone sequencing were used to detect subtle mutations in SMN1. SMN transcript levels were determined using quantitative RT-PCR. RESULTS: Six subtle mutations (p.Ser8LysfsX23, p.Glu134Lys, p.Leu228X, p.Ser230Leu, p.Tyr277Cys, and p.Arg288Met) were identified in 12 patients. The p.Tyr277Cys mutation has not been reported previously. The p.Ser8LysfsX23, p.Leu228X, and p.Tyr277Cys mutations have only been reported in Chinese SMA patients and the first two mutations seem to be the common ones. Levels of full length SMN1 (fl-SMN1) transcripts were very low in patients carrying p.Ser8LysfsX23, p.Leu228X or p.Arg288Met compared with healthy carriers. In patients carrying p.Glu134Lys or p.Ser230Leu, levels of fl-SMN1 transcripts were reduced but not significant. The SMN1 transcript almost skipped exon 7 entirely in patients with the p.Arg288Met mutation. CONCLUSIONS: Our study reveals a distinct spectrum of subtle mutations in SMN1 of Chinese SMA patients from that of other ethnicities. The p.Arg288Met missense mutation possibly influences the correct splicing of exon 7 in SMN1. Mutation analysis of the SMN1 gene in Chinese patients may contribute to the identification of potential ethnic differences and enrich the SMN1 subtle mutation database.

Angiogenesis-Related Gene Signature-Derived Risk Score for Glioblastoma: Prospects for Predicting Prognosis and Immune Heterogeneity in Glioblastoma.

Background: Glioblastoma multiforme (GBM) is the most common malignant tumor in the central nervous system with poor prognosis and unsatisfactory therapeutic efficacy. Considering the high correlation between tumors and angiogenesis, we attempted to construct a more effective model with angiogenesis-related genes (ARGs) to better predict therapeutic response and prognosis. Methods: The ARG datasets were downloaded from the NCBI-Gene and Molecular Signatures Database. The gene expression data and clinical information were obtained from TCGA and CGGA databases. The differentially expressed angiogenesis-related genes (DE-ARGs) were screened with the R package "DESeq2". Univariate Cox proportional hazards regression analysis was used to screen for ARGs related to overall survival. The redundant ARGs were removed by least absolute shrinkage and selection operator (LASSO) regression analysis. Based on the gene signature of DE-ARGs, a risk score model was established, and its effectiveness was estimated through Kaplan-Meier analysis, ROC analysis, etc. Results: A total of 626 DE-ARGs were explored between GBM and normal samples; 31 genes were identified as key DE-ARGs. Then, the risk score of ARG signature was established. Patients with high-risk score had poor survival outcomes. It was proved that the risk score could predict some medical treatments' response, such as temozolomide chemotherapy, radiotherapy, and immunotherapy. Besides, the risk score could serve as a promising prognostic predictor. Three key prognostic genes (PLAUR, ITGA5, and FMOD) were selected and further discussed. Conclusion: The angiogenesis-related gene signature-derived risk score is a promising predictor of prognosis and treatment response in GBM and will help in making appropriate therapeutic strategies.

[Effect of electroacupuncture at "Shuigou" (GV26) and "Baihui" (GV20) on autophagy of hippo-campal neurons in rats with cerebral ischemia-reperfusion injury].

OBJECTIVE: To explore the effect of electroacupuncture (EA) at "Shuigou"(GV6) and "Baihui"(GV20) on autophagy of hippocampal neurons in cerebral ischemia-reperfusion (I/R) injury rats. METHODS: Forty-eight healthy male SD rats were randomly divided into sham operation, model and EA groups, with 16 rats in each group. The rat model of cerebral I/R injury was established by occlusion of the middle cerebral artery (MCAO). Rats of the EA group received EA at GV26 and GV20 for 20 min, once daily for 5 days. The neurological function of rats in each group was evaluated by Longa neurological function score. The cerebral infarction volume was measured by TTC staining. The levels of IL-6, IL-18 and TNF-α in cerebrospinal fluid were detected by ELISA. Real-time PCR and Western blot were respectively used to detect the expressions of autophagy-related proteins AMPK, Beclin-1, VPS34 and LC3B. RESULTS: Compared with the sham operation group, neurological function scores of rats in the model group were significantly increased (P<0.01); the volume of cerebral infarction was significantly increased (P<0.01); the contents of IL-6, IL-18 and TNF-α in cerebrospinal fluid were increased (P<0.01, P<0.05); the mRNA expression levels of AMPK, Beclin-1, VPS34 and LC3B were significantly increased (P<0.01); the protein expressions of AMPK, Beclin-1, VPS34 and the ratio of LC3B-Ⅱ/LC3B-Ⅰ were increased (P<0.01, P<0.05). After intervention and in comparison with the model group, the neurological function scores were decreased (P<0.05); the cerebral infarct volume were decreased (P<0.05); the contents of IL-6, IL-18 and TNF-α in cerebrospinal fluid were decreased (P<0.05); the mRNA expressions of AMPK, Beclin-1, VPS34 and LC3B were significantly decreased (P<0.01); the protein expressions of AMPK, Beclin-1, VPS34 and the ratio of LC3B-Ⅱ/LC3B-Ⅰ were decreased (P<0.05, P<0.01). CONCLUSION: EA can improve the neurological function and alleviate the degree of nerve injury in rats with cerebral I/R injury, which may be related to inhibiting the autophagy level of hippocampal neurons.

An independent poor-prognosis subtype of hepatocellular carcinoma based on the tumor microenvironment.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant tumor with a particularly poor prognosis. The tumor microenvironment (TME) is closely associated with tumorigenesis, progression, and treatment. However, the relationship between TME genes and HCC patient prognosis is poorly understood. METHODS: In this study, we identified two prognostic subtypes based on the TME using data from The Cancer Genome Atlas and Gene Expression Omnibus. The Microenvironment Cell Populations-counter method was used to evaluate immune cell infiltration in HCC. Differentially expressed genes between molecular subtypes were calculated with the Limma package, and clusterProfiler was used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses to identify genes related to the independent subtypes. We also integrated mRNA expression data into our bioinformatics analysis. RESULTS: We identified 4227 TME-associated genes and 640 genes related to the prognosis of HCC. We defined two major subtypes (Clusters 1 and 2) based on the analysis of TME-associated gene expression. Cluster 1 was characterized by increased expression of immune-associated genes and a worse prognosis than Cluster 2. CONCLUSIONS: The identification of these HCC subtypes based on the TME provides further insight into the molecular mechanisms and prediction of HCC prognosis.

Edaravone-Encapsulated Agonistic Micelles Rescue Ischemic Brain Tissue by Tuning Blood-Brain Barrier Permeability.

Thrombolysis has been a standard treatment for ischemic stroke. However, only 2-7% patients benefit from it because the thrombolytic agent has to be injected within 4.5 h after the onset of symptoms to avoid the increasing risk of intracerebral hemorrhage. As the only clinically approved neuroprotective drug, edaravone (EDV) rescues ischemic brain tissues by eradicating over-produced reactive oxygen species (ROS) without the limitation of therapeutic time-window. However, EDV's short circulation half-life and inadequate cerebral uptake attenuate its therapeutic efficacy. Here we developed an EDV-encapsulated agonistic micelle (EDV-AM) to specifically deliver EDV into brain ischemia by actively tuning blood-brain barrier (BBB) permeability. The EDV-AM actively up-regulated endothelial monolayer permeability in vitro. HPLC studies showed that EDV-AM delivered more EDV into brain ischemia than free EDV after intravenous injection. Magnetic resonance imaging also demonstrated that EDV-AM more rapidly salvaged ischemic tissue than free EDV. Diffusion tensor imaging indicated the highest efficiency of EDV-AM in accelerating axonal remodeling in the ipsilesional white matter and improving functional behaviors of ischemic stroke models. The agonistic micelle holds promise to improve the therapeutic efficiency of ischemic stroke patients who miss the thrombolytic treatment.

Predictors and outcomes of cardiac resynchronization therapy extended to the second generator.

BACKGROUND: A proportion of patients who receive cardiac resynchronization therapy with defibrillator (CRT-D) live to receive a second generator. Controversy exists on whether an implantable cardioverter-defibrillator (ICD) should be offered to patients who have normalized or near-normalized left ventricular ejection fraction (LVEF) at the time of generator replacement (GR). OBJECTIVE: The purpose of this study was to evaluate incidence of appropriate ICD therapy after CRT-D GR. METHODS: This series involved 1026 consecutive patients who underwent CRT-D implant between January 1, 2002 and December 31, 2012. Echocardiography was assessed before the initial device implant and before GR. ICDs were monitored at our device clinic in person or remotely, or both. RESULTS: Of the cohort, 227 patients (22.1%) underwent CRT-D GR at our institution. Approximately 48% of the patients who received new CRT-D generators were no longer meeting the guidelines indication for ICD use at the time of GR. These patients received subsequent appropriate ICD therapies at a significantly lower rate than those with LVEF <35% (12% vs 35%; P < .001). Of these patients, 47 (20.7%) had LVEF improvement to ≥50% at the time of GR. ICD therapy for ventricular arrhythmia in the ischemic group was 18.2%, while no patient in the nonischemic group received ICD therapy from the second generator after GR. CONCLUSION: Improvement in LVEF after CRT-D GR is associated with significantly reduced incidence of appropriate ICD therapy. Ventricular arrhythmia is less likely to develop with normalized LVEF in nonischemic cardiomyopathy.

Non-invasively differentiating extent of liver fibrosis by visualizing hepatic integrin αvß3 expression with an MRI modality in mice.

AIMS: To explore the potential of a dendrimer nanoprobe labeled with cyclic arginine-glycine-aspartic acid pentapeptide (cRGDyK) as a magnetic resonance imaging (MRI) tracer to non-invasively differentiate the extent of liver fibrosis. METHODS: Synthetic dendrimer nanoprobes were labeled with cRGDyK (Den-RGD) to form a formulation of hepatic stellate cell (HSC)-specific MRI tracer. An MRI modality was employed to visualize hepatic Den-RGD deposition in a mouse model of liver fibrosis caused by thioacetamide treatment. RESULTS: Den-RGD bound to activated HSCs via integrin αvß3 receptors. The labeling of nanoprobes with cRGDyK increased their affinity to and accelerated their uptake by activated HSCs. Most of intravenously administrated Den-RGD nanoprobes deposited in the fibrotic areas, and the deposited amount was paralleled with the severity of liver fibrosis. Majority of cells taking-up Den-RGD was found to be activated HSCs in fibrotic livers. An MRI modality using Den-RGD as a tracer demonstrated that the relative hepatic T1-weighed MR signal value was increased in parallel with the severity of liver fibrosis. CONCLUSION: The extent of Den-RGD deposition reflects integrin αvß3 expression in activated HSCs, and Den-RGD appears to be a useful formulation of MRI tracer and may non-invasively and quantitatively assess the extent of liver fibrosis.

Tunable Thermal-Sensitive Polymer-Graphene Oxide Composite for Efficient Capture and Release of Viable Circulating Tumor Cells.

A highly sensitive microfluidic system to capture circulating tumor cells from whole blood of cancer patients is presented. The device incorporates graphene oxide into a thermoresponsive polymer film to serve as the first step of an antibody functionalization chemistry. By decreasing the temperature, captured cells may be released for subsequent analysis.

Addition of chitosan to silicate cross-linked PEO for tuning osteoblast cell adhesion and mineralization.

The addition of chitosan to silicate (Laponite) cross-linked poly(ethylene oxide) (PEO) is used for tuning nanocomposite material properties and tailoring cellular adhesion and bioactivity. By combining the characteristics of chitosan (which promotes cell adhesion and growth, antimicrobial) with properties of PEO (prevents protein and cell adhesion) and those of Laponite (bioactive), the resulting material properties can be used to tune cellular adhesion and control biomineralization. Here, we present the hydration, dissolution, degradation, and mechanical properties of multiphase bio-nanocomposites and relate these to the cell growth of MC3T3-E1 mouse preosteoblast cells. We find that the structural integrity of these bio-nanocomposites is improved by the addition of chitosan, but the release of entrapped proteins is suppressed. Overall, this study shows how chitosan can be used to tune properties in Laponite cross-linked PEO for creating bioactive scaffolds to be considered for bone repair.

Silicate cross-linked bio-nanocomposite hydrogels from PEO and chitosan.

The compositions and the multi phase structures of bio-nanocomposite hydrogels made from silicate cross-linked PEO and chitosan are related to some of their physical and biological properties. The gels are injectable and self-healing because the cross-linking is physical and reversible under deformation. The presence of chitosan aggregates affects the viscoelastic properties and reinforces the hydrogel network. The chitosan adds advantageous properties to the hydrogel such as enhanced cell spreading and adhesion. In vitro biocompatibility data indicate that NIH 3T3 fibroblasts grow and proliferate on the bio-nanocomposite hydrogel as well as on hydrogel films.