Suppression of lncRNA MALAT1 reduces pro-inflammatory cytokines production by regulating miR-150-5p/ZBTB4 axis through JAK/STAT signal pathway in systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is a common chronic disease occurring in children. Increasing studies have demonstrated that long noncoding RNAs (lncRNAs) play important roles in the pathogenesis of diverse human diseases. This study aimed to explore the role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and its mechanism in sJIA. We found that the expression of MALAT1, the plasma level of pro-inflammatory cytokines (IL-6, IL-17, IL-1ß, and TNF-α) as well as MMP-8 and MMP-9 production were significantly elevated in sJIA patients. Moreover, we observed that the production of these cytokines in peripheral blood mononuclear cells (PBMCs) from sJIA patients were reduced after MALAT1 knockdown. Furthermore, bioinformatics analysis predicted that MALAT1 might bind to miR-150-5p and ZBTB4 was a downstream target gene of miR-150-5p. Besides, rescue assays revealed that MALAT1 knockdown-mediated suppressive effects on cytokine production could be reversed by ZBTB4 overexpression. In addition, MALAT1 activated the JAK/STAT signaling by upregulating ZBTB4 expression. In summary, our findings demonstrated that MALAT1 promoted pro-inflammatory cytokine and MMP production by targeting the miR-150-5p/ZBTB4 axis through JAK/STAT signaling pathway in sJIA, suggesting that MALAT1 may have a potential diagnostic biomarker for the pathogenesis and therapy of sJIA.

CNN-LRP: Understanding Convolutional Neural Networks Performance for Target Recognition in SAR Images.

Target recognition is one of the most challenging tasks in synthetic aperture radar (SAR) image processing since it is highly affected by a series of pre-processing techniques which usually require sophisticated manipulation for different data and consume huge calculation resources. To alleviate this limitation, numerous deep-learning based target recognition methods are proposed, particularly combined with convolutional neural network (CNN) due to its strong capability of data abstraction and end-to-end structure. In this case, although complex pre-processing can be avoided, the inner mechanism of CNN is still unclear. Such a "black box" only tells a result but not what CNN learned from the input data, thus it is difficult for researchers to further analyze the causes of errors. Layer-wise relevance propagation (LRP) is a prevalent pixel-level rearrangement algorithm to visualize neural networks' inner mechanism. LRP is usually applied in sparse auto-encoder with only fully-connected layers rather than CNN, but such network structure usually obtains much lower recognition accuracy than CNN. In this paper, we propose a novel LRP algorithm particularly designed for understanding CNN's performance on SAR image target recognition. We provide a concise form of the correlation between output of a layer and weights of the next layer in CNNs. The proposed method can provide positive and negative contributions in input SAR images for CNN's classification, viewed as a clear visual understanding of CNN's recognition mechanism. Numerous experimental results demonstrate the proposed method outperforms common LRP.

Reducing Defects Density and Enhancing Hole Extraction for Efficient Perovskite Solar Cells Enabled by π-Pb2+ Interactions.

Molecular doping is an of significance approach to reduce defects density of perovskite and to improve interfacial charge extraction in perovskite solar cells. Here, we show a new strategy for chemical doping of perovskite via an organic small molecule, which features a fused tricyclic core, showing strong intermolecular π-Pb2+ interactions with under-coordinated Pb2+ in perovskite. This π-Pb2+ interactions could reduce defects density of the perovskite and suppress the nonradiative recombination, which was also confirmed by the density functional theory calculations. In addition, this doping via π-Pb2+ interactions could deepen the surface potential and downshift the work function of the doped perovskite film, facilitating the hole extraction to hole transport layer. As a result, the doped device showed high efficiency of 21.41 % with ignorable hysteresis. This strategy of fused tricyclic core-based doping provides a new perspective for the design of new organic materials to improve the device performance.

Intramolecular dehydrogenative C-S bond coupling of thioamides to form 1,3-benzothiazines under metal-free conditions.

A novel HTIB-promoted direct intramolecular dehydrogenative C-S bond coupling reaction of thioamides has been developed to provide 1,3-benzothiazine derivatives in good yields. The reaction proceeds smoothly to reach completion at room temperature within 1 min under metal-free conditions. This protocol provides a mild and efficient strategy for the synthesis of six-membered N,S-containing heterocycles. Preliminary mechanistic studies indicate that a spirocyclic intermediate might be involved.

Qianggan extract improved nonalcoholic steatohepatitis by modulating lncRNA/circRNA immune ceRNA networks.

BACKGROUND: The traditional Chinese medicine prescription, Qianggan formula have been confirmed to be effective on non-alcoholic steatohepatitis (NASH), however, the underlying molecular mechanisms remain obscure. METHODS: Thirty-six male C57BL/6 mice were randomly divided into three groups: normal chow diet group; methionine-and-choline-deficient diet (MCD) group, and Qianggan extract (QG) intervention group (0.4 g/kg daily) that fed with MCD. The efficacy of QG was biochemically and histologically evaluated. The expression profiles of messenger ribonucleic acids (mRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) were examined using microarray and verified by RT-qPCR. RESULTS: QG significantly improved the phenotypic characteristics of NASH, as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) levels and liver inflammatory cytokines were significantly decreased. By the cutoff of a 1.5-fold change and P < 0.05, 6193 mRNAs, 5692 lncRNAs and 4843 circRNAs were identified as differentially expressed between the MCD and normal groups, and 514 mRNAs, 1182 lncRNAs and 443 circRNAs were identified as differentially expressed between the QG and MCD groups. The intersections (244 mRNAs, 259 lncRNAs and 98 circRNAs) among the three groups were chosen for analysis. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed that most overlapping mRNAs were related to immune functions such as natural-killer-cell-mediated cytotoxicity, intestinal immune network for IgA production, and T cell receptor signaling pathway. Pathway interactions, protein-protein interactions and molecular complex detection (MCODE) analysis identified numerous immune-related hub genes e.g. natural cytotoxicity triggering receptor 1(Ncr1), C-X-C motif chemokine ligand 9 (Cxcl9), Klra1, and Cd28. Finally, two lncRNAs (Sngh1 and Slc36a3os) and four circRNAs (circ_0009029, circ_0004572, circ_0009212 and circ_0009453) in competing endogenous RNA (ceRNA) networks were constructed by Cytoscape, and immune-related mRNAs (e.g., Cd28, Cd8a, Il15, and Klrk1) were involved in the ceRNA networks. CONCLUSIONS: LncRNA and circRNA-associated immune ceRNA networks might be the targets of QG in alleviating NASH, and our work may provide valuable clues for exploring the mechanisms underlying the effect of QG.

Micro-Doppler Feature Extraction of Inverse Synthetic Aperture Imaging Laser Radar Using Singular-Spectrum Analysis.

Different from microwave radar, laser radar could be more sensitive to the micro-Doppler (m-D) effect due to its wave length. This limits the application of conventional methods, such as time⁻frequency based approach, since the processing needs a receiver with much higher sampling frequency than microwave radar. In this paper, a micro-Doppler feature extraction algorithm is proposed for the inverse synthetic aperture imaging laser radar (ISAIL). Singular-spectrum analysis (SSA) is employed for separation and reconstruction of the micro-Doppler and rigid body signal. Clear ISAIL image is obtained by minimum entropy criteria after echo signal decomposition. After theoretical derivation, the computation efficiency and ability of the proposed method is proved by the results of simulation and real data of An-26.

Effect of atorvastatin on the apoptosis of human umbilical vein endothelial cells and its drug mechanism.

Recent studies have shown that statins can inhibit the apoptosis of vascular endothelial cells. Many pharmacological actions of statins have nothing to do with their cholesterol lowering effects. These effects are called non lipid lowering cardiovascular protective effects. In this study, by establishing a high glucose induced vascular endothelial cell apoptosis model, we explored the mechanism of the non lipid - related cardiovascular protective effect of atorvastatin. The results showed that atorvastatin could protect human umbilical vein endothelial cells from damage induced by new high glucose and inhibit apoptosis. High concentration atorvastatin can up regulate the expression of Bcl-2 and down regulate the expression of Bax protein (P<0.05). This suggests that statins may play a role in cardiovascular protection by inhibiting endothelial cell apoptosis. This result is confirmed by experiments, which can provide clues for clinical treatment, and combine drug therapy and lifestyle intervention to reduce blood sugar.

[Efficacy of short-term educational intervention for parents of preschool children with anxiety].

OBJECTIVE: To study the efficacy of short-term educational intervention for parents of preschool children with anxiety. METHODS: Forty-nine children with Spence Preschool Anxiety Scale (SPAS) scores of ≥ 48 were randomly divided into intervention and control groups. The children's parents in the intervention group received a collective curriculum on children's anxiety management six times, while the control group was only followed up. All children were evaluated for anxiety by the SPAS 3 and 6 months later, and then the results were compared between the two groups. RESULTS: The test was completed in 21 cases of the intervention group and 22 cases of the control group. At month 3, the intervention group had a significantly lower percentage of children with SPAS scores of ≥ 48 than the control group (62% vs 91%; P<0.05), and this percentage was also significantly lower in the intervention group than in the control group at month 6 (52% vs 82%; P<0.05). At month 3, the intervention group had a significantly reduced mean SPAS score, which was significantly lower than that of the control group (69 ± 12 vs 81 ± 12; P<0.01). At month 6, both groups showed significant decreases in SPAS score, but still the SPAS score was significantly lower in the intervention group than in the control group (65 ± 13 vs 78 ± 13; P<0.01). CONCLUSIONS: Early short-term education for parents can relieve their preschool children's anxiety effectively, but the long-term effect needs to be evaluated by follow-up.

Cluster-CAM: Cluster-weighted visual interpretation of CNNs' decision in image classification.

Despite the tremendous success of convolutional neural networks (CNNs) in computer vision, the mechanism of CNNs still lacks clear interpretation. Currently, class activation mapping (CAM), a famous visualization technique to interpret CNN's decision, has drawn increasing attention. Gradient-based CAMs are efficient, while the performance is heavily affected by gradient vanishing and exploding. In contrast, gradient-free CAMs can avoid computing gradients to produce more understandable results. However, they are quite time-consuming because hundreds of forward interference per image are required. In this paper, we proposed Cluster-CAM, an effective and efficient gradient-free CNN interpretation algorithm. Cluster-CAM can significantly reduce the times of forward propagation by splitting the feature maps into clusters. Furthermore, we propose an artful strategy to forge a cognition-base map and cognition-scissors from clustered feature maps. The final salience heatmap will be produced by merging the above cognition maps. Qualitative results conspicuously show that Cluster-CAM can produce heatmaps where the highlighted regions match the human's cognition more precisely than existing CAMs. The quantitative evaluation further demonstrates the superiority of Cluster-CAM in both effectiveness and efficiency.

Analytical interpretation of the gap of CNN's cognition between SAR and optical target recognition.

Synthetic aperture radar (SAR) automatic target recognition (ATR) is a crucial technique utilized in various scenarios of geoscience and remote sensing. Despite the remarkable success of convolutional neural networks (CNNs) in optical vision tasks, the application of CNNs in SAR ATR is still a challenging area due to the significant differences in the imaging mechanisms of SAR and optical images. This paper analytically addresses the cognitive gap of CNNs between optical and SAR images by leveraging multi-order interactions to measure their representation capacity. Furthermore, we propose a subjective evaluation strategy to compare human interactions with those of CNNs. Our findings reveal that CNNs operate differently for optical and SAR images. Specifically, for SAR images, CNNs' representation capacity is comparable to that of humans, as they can encode intermediate interactions better than simple and complex ones. In contrast, for optical images, CNNs excel at encoding simple and complex interactions, but not intermediate interactions.

Lingguizhugan decoction improves non-alcoholic steatohepatitis partially by modulating gut microbiota and correlated metabolites.

Background: Lingguizhugan decoction is a traditional Chinese medicine prescription that has been used to improve non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH). However, the anti-NASH effects and underlying mechanisms of Lingguizhugan decoction remain unclear. Methods: Male Sprague-Dawley rats were fed a methionine- and choline-deficient (MCD) diet to induce NASH, and then given Lingguizhugan decoction orally for four weeks. NASH indexes were evaluated by histopathological analysis and biochemical parameters including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver triglycerides (TG), etc. Fecal samples of rats were subjected to profile the changes of gut microbiota and metabolites using 16S rRNA sequencing and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS). Bioinformatics was used to identify Lingguizhugan decoction reversed candidates, and Spearman's correlation analysis was performed to uncover the relationship among gut microbiota, fecal metabolites, and NASH indexes. Results: Four-week Lingguizhugan decoction treatment ameliorated MCD diet-induced NASH features, as evidenced by improved hepatic steatosis and inflammation, as well as decreased serum AST and ALT levels. Besides, Lingguizhugan decoction partially restored the changes in gut microbial community composition in NASH rats. Meanwhile, the relative abundance of 26 genera was significantly changed in NASH rats, and 11 genera (such as odoribacter, Ruminococcus_1, Ruminococcaceae_UCG-004, etc.) were identified as significantly reversed by Lingguizhugan decoction. Additionally, a total of 99 metabolites were significantly altered in NASH rats, and 57 metabolites (such as TDCA, Glutamic acid, Isocaproic acid, etc.) enriched in different pathways were reversed by Lingguizhugan decoction. Furthermore, Spearman's correlation analyses revealed that most of the 57 metabolites were significantly correlated with 11 genera and NASH indexes. Conclusion: Lingguizhugan decoction may exert protective effects on NASH partially by modulating gut microbiota and correlated metabolites.

METTL3 promotes colorectal carcinoma progression by regulating the m6A-CRB3-Hippo axis.

BACKGROUND: Colorectal carcinoma (CRC) is the third most common cancer and second most common cause of cancer-related deaths worldwide. Ribonucleic acid (RNA) N6-methyladnosine (m6A) and methyltransferase-like 3 (METTL3) play key roles in cancer progression. However, the roles of m6A and METTL3 in CRC progression require further clarification. METHODS: Adenoma and CRC samples were examined to detect m6A and METTL3 levels, and tissue microarrays were performed to evaluate the association of m6A and METTL3 levels with the survival of patients with CRC. The biological functions of METTL3 were investigated through cell counting kit-8, wound healing, and transwell assays. M6A epitranscriptomic microarray, methylated RNA immunoprecipitation-qPCR, RNA stability, luciferase reporter, and RNA immunoprecipitation assays were performed to explore the mechanism of METTL3 in CRC progression. RESULTS: M6A and METTL3 levels were substantially elevated in CRC tissues, and patients with CRC with a high m6A or METTL3 levels exhibited shorter overall survival. METTL3 knockdown substantially inhibited the proliferation, migration, and invasion of CRC cells. An m6A epitranscriptomic microarray revealed that the cell polarity regulator Crumbs3 (CRB3) was the downstream target of METTL3. METTL3 knockdown substantially reduced the m6A level of CRB3, and inhibited the degradation of CRB3 mRNA to increase CRB3 expression. Luciferase reporter assays also showed that the transcriptional level of wild-type CRB3 significantly increased after METTL3 knockdown but not its level of variation. Knockdown of YT521-B homology domain-containing family protein 2 (YTHDF2) substantially increased CRB3 expression. RNA immunoprecipitation assays also verified the direct interaction between the YTHDF2 and CRB3 mRNA, and this direct interaction was impaired after METTL3 inhibition. In addition, CRB3 knockdown significantly promoted the proliferation, migration, and invasion of CRC cells. Mechanistically, METTL3 knockdown activated the Hippo pathway and reduced nuclear localization of Yes1-associated transcriptional regulator, and the effects were reversed by CRB3 knockdown. CONCLUSIONS: M6A and METTL3 levels were substantially elevated in CRC tissues relative to normal tissues. Patients with CRC with high m6A or METTL3 levels exhibited shorter overall survival, and METTL3 promoted CRC progression. Mechanistically, METTL3 regulated the progression of CRC by regulating the m6A-CRB3-Hippo pathway.

Jiangzhi Granule attenuates non-alcoholic steatohepatitis by suppressing TNF/NFκB signaling pathway-a study based on network pharmacology.

Jiangzhi Granule is a commonly used traditional Chinese medicine for treating non-alcoholic fatty liver disease. However, its key ingredients and underlying mechanisms for attenuating nonalcoholic steatohepatitis (NASH) remain unclear. To address this issue, UPLC-TOF-MS based chemical profiling, network pharmacology and animal experimental validation were employed. First, a total of 56 main ingredients of Jiangzhi Granule and 38 ingredients in the blood and liver (after oral administration) were identified. Then, 170 potential targets of the absorbed ingredients and 50 targets of NASH were identified, and 10 overlapped genes were identified as candidate targets of Jiangzhi Granule for NASH treatment. A Jiangzhi Granule-ingredients-targets-disease network was constructed using Cytoscape software, which included eight main ingredients (such as emodin, resveratrol and quercetin) and 10 candidate targets (such as TNF, IL6 and CCL2). Functional enrichment indicated that the candidate targets were enriched in multiple pathways (such as the TNF signaling pathway). Furthermore, a NASH mice model was constructed and intervened with Jiangzhi Granule. The results revealed that Jiangzhi Granule could ameliorate NASH characteristics, such as histopathological changes and liver cholesterol level. Meanwhile, Jiangzhi Granule significantly decreased the mRNA and protein expression of TNFα in NASH mice liver, suppressed NFκB activation, and inhibited the expression of macrophage activation marker F4/80 and M1-type polarization marker CD11b/CD11c. ELISA assay indicated that Jiangzhi Granule reduced pro-inflammatory cytokines (including TNFα, IL-1ß and IL-6) in the liver. Collectively, our results suggested that Jiangzhi Granule could attenuate NASH by suppressing TNF/NFκB signaling mediated macrophage M1-type polarization.

NEAT1 Knockdown Suppresses the Cisplatin Resistance in Ovarian Cancer by Regulating miR-770-5p/PARP1 Axis.

BACKGROUND: Long noncoding RNAs play essential roles in regulating drug resistance in cancers. However, how and whether lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) could mediate cisplatin resistance in ovarian cancer remain poorly understood. PATIENTS AND METHODS: Eighteen cisplatin-sensitive and 19 cisplatin-resistant patients with ovarian cancer were recruited. Cisplatin-resistant ovarian cancer cells were used for this study. The expression levels of NEAT1, microRNA (miR)-770-5p and poly adenosine diphosphate-ribose polymerase 1 (PARP1) were detected by quantitative real-time polymerase chain reaction or Western blot. Cisplatin resistance was assessed by the half-maximal inhibitory concentration (IC50) of cisplatin, cell viability and apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide, flow cytometry and Western blot, respectively. The target association between miR-770-5p and NEAT1 or PARP1 was investigated by dual-luciferase reporter assay. The xenograft model was used to investigate cisplatin resistance in vivo. RESULTS: NEAT1 expression is elevated in cisplatin-resistant ovarian cancer tissues and cells. Knockdown of NEAT1 repressed cisplatin resistance by decreasing the IC50 of cisplatin, cell viability and increasing apoptosis. MiR-770-5p was bound to NEAT1 and PARP1 was confirmed as a target of miR-770-5p. MiR-770-5p inhibition or PARP1 restoration could abate the effect of NEAT1 silencing on cisplatin resistance in cisplatin-resistant ovarian cancer cells. Moreover, NEAT1 knockdown reduced PARP1 expression by increasing miR-770-5p. Interference of NEAT1 decreased xenograft tumor growth by regulating miR-770-5p and PARP1. CONCLUSION: Knockdown of NEAT1 inhibited cisplatin resistance in ovarian cancer cells by up-regulating miR-770-5p and down-regulating PARP1, providing a new target for improving the efficacy of cisplatin-based therapy in ovarian cancer.

Association between tumor necrosis factor α and uterine fibroids: A protocol of systematic review.

BACKGROUND: This study will explore the association between tumor necrosis factor α (TNF-α) and uterine fibroids (UFs). METHODS: We will retrieve electronic databases in Cochrane Library, PUBMED, EMBASE, Web of Science, WANGFANG, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from inception to the present. All potential case-controlled studies investigating the association between TNF-α and UFs will be included in this study. Two researchers will independently select literature, appraise study quality, and extract outcome data. We will utilize a fixed-effects model or a random-effects model to synthesize outcome data. All data analysis will be performed by RevMan 5.3 software. RESULTS: The present study will supply high-quality synthesis and/or descriptive analysis of the recent evidence to explore the association between TNF-α and UFs. CONCLUSION: This study will exert evidence to determine whether or not TNF-α is associated with UFs. STUDY REGISTRATION NUMBER: INPLASY202070010.

Gan-Jiang-Ling-Zhu decoction alleviates hepatic steatosis in rats by the miR-138-5p/CPT1B axis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a commonly-encountered chronic liver disease which lacks verified pharmacological interventions. Gan-Jiang-Ling-Zhu decoction (GJLZ) is a classic formula utilized in clinical practice. In this study, we aimed to evaluate the therapeutic effect of GJLZ in NAFLD and explore the possible underlying mechanisms. METHODS: Twenty-four rats were randomly divided into three groups: normal group, fed with chow diet for 8 weeks; model group, fed with high fat diet for 8 weeks; and GJLZ group, initially fed HFD for 4 weeks, and then administered the GJLZ decoction for 4 weeks by oral gavage while continuously feeding HFD. Rats were sacrificed after the intervention, and liver tissues and blood samples were harvested. Liver steatosis was detected by HE and Oil Red O staining. Body weight and liver index were analyzed. Liver triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL), serum almandine aminotransferase (ALT), aspartate aminotransferase (AST), and nonesterified fatty acid (NEFA) were assayed using commercial kits. Differentially expressed genes were identified by RNA-sequencing and verified using real-time PCR (RT-PCR) and western blotting. Whole miRNAs were detected by RNA-sequence analysis, and mRNA-targeted miRNAs were verified by RT-PCR. The miRNA-mRNA regulation pattern was confirmed using the dual-luciferase reporter assay. RESULTS: Treatment with GJLZ significantly improved hepatic steatosis and inflammation, reduced liver index and liver TG content, and also significantly reduced serum ALT and AST levels. Based on the results of RNA-sequence analysis, five differentially expressed genes (DEGs) in the peroxisome proliferator-activated receptor (PPAR) signaling pathway were recognized. RT-PCR confirmed that carnitine palmitoyltransferase 1b (CPT1B) expression was significantly regulated by GJLZ treatment. GJLZ decoction intervention also increased significantly hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) expression. Next, miRNA profiling and screening were performed based on CPT1B alteration. Rno-miR-138-5p likely responded to GJLZ intervention, and rno-miR-138-5p inhibitor increased CPT1B expression while rno-miR-138-5p mimic reduced CPT1B expression. When CPT1B mutated, miR-138-5p mimic and inhibitor could not regulate the luciferase activity of CPT1B. CONCLUSIONS: GJLZ is an effective formula for NAFLD management, and its possible mechanism of action involves the regulation of CPT1B expression via rno-miR-138-5p.

Metabolomic Analysis Identifies Glycometabolism Pathways as Potential Targets of Qianggan Extract in Hyperglycemia Rats.

Qianggan formula, a designed prescription according to the Traditional Chinese Medicine (TCM) theory, is widely used in treating chronic liver diseases, and indicated to prevent blood glucose increase in patients via unknown mechanisms. To unravel the effects and underlying mechanisms of Qianggan formula on hyperglycemia, we administrated Qianggan extract to high fat and high sucrose (HFHS) diet rats. Results showed that four-week Qianggan extract intervention significantly decreased serum fasting blood glucose, hemoglobin A1c, and liver glycogen levels. Gas chromatography-mass spectrometry (GC-MS) approach was employed to explore metabolomic profiles in liver and fecal samples. By multivariate and univariate statistical analysis (variable importance of projection value > 1 and p value < 0.05), 44 metabolites (18 in liver and 30 in feces) were identified as significantly different. Hierarchical cluster analysis revealed that most differential metabolites had opposite patterns between pair-wise groups. Qianggan extract restored the diet induced metabolite perturbations. Metabolite sets enrichment and pathway enrichment analysis revealed that the affected metabolites were mainly enriched in glycometabolism pathways such as glycolysis/gluconeogenesis, pentose phosphate pathway, fructose, and mannose metabolism. By compound-reaction-enzyme-gene network analysis, batches of genes (e.g. Hk1, Gck, Rpia, etc) or enzymes (e.g. hexokinase and glucokinase) related to metabolites in enriched pathways were obtained. Our findings demonstrated that Qianggan extract alleviated hyperglycemia, and the effects might be partially due to the regulation of glycometabolism related pathways.

Gut Microbiota and Related Metabolites Were Disturbed in Ulcerative Colitis and Partly Restored After Mesalamine Treatment.

Mesalamine has been well used in the improvement of ulcerative colitis (UC) in clinics, however, the underlying mechanisms were not well illustrated. To explore its efficacy from the perspective of gut microbiota and related metabolites, we employed 16S rRNA sequencing and metabolomics approaches in stool samples across 14 normal healthy controls (NC group), 10 treatment-naïve UC patients (UC group) and 14 UC patients responded to mesalamine treatment (mesalamine group). We noted that the gut microbiota diversity and community composition were remarkably perturbed in UC group and partially restored by mesalamine treatment. The relative abundance of 192 taxa in genus level were significantly changed in UC group, and 168 genera were significantly altered after mesalamine intervention. Meanwhile, a total of 127 metabolites were significantly changed in UC group and 129 metabolites were significantly altered after mesalamine treatment. Importantly, we observed that many candidates including 49 genera (such as Escherichia-shigella, Enterococcus and Butyricicoccus) and 102 metatoblites (such as isoleucine, cholic acid and deoxycholic acid) were reversed by mesalamine. Spearman correlation analysis revealed that most of the candidates were significantly correlated with Mayo score of UC, and the relative abundance of specific genera were significant correlated with the perturbation of metabolites. Pathway analysis demonstrated that genera and metabolites candidates were enriched in many similar molecular pathways such as amino acid metabolism and secondary metabolites biosynthesis. Importantly, ROC curve analysis identified a gut microbiota signature composed of five genera including Escherichia-Shigella, Streptococcus, Megamonas, Prevotella_9 and [Eubacterium] _coprostanoligenes _group which might be used to distinguish UC group from both NC and mesalamine group. In all, our results suggested that mesalamine might exert a beneficial role in UC by modulating gut microbiota signature with correlated metabolites in different pathways, which may provide a basis for developing novel candidate biomarkers and therapeutic targets of UC.

Comprehensive RNA Sequencing in Adenoma-Cancer Transition Identified Predictive Biomarkers and Therapeutic Targets of Human CRC.

Specific molecular biomarkers for predicting the transition from colorectal adenoma to cancer have been identified, however, circular RNA (circRNA)-related signatures remain to be clarified. We carried out high-throughput RNA sequencing to determine the expression profiles of circRNAs, microRNAs (miRNAs), and mRNAs in human colorectal cancer (CRC), adenoma, and adjacent normal tissues. We identified 84 circRNAs, 41 miRNAs, and 398 mRNAs that were commonly differentially expressed in CRC and adenoma tissues compared with normal tissues. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analyses identified numerous cancer-related hub genes that might serve as potential therapeutic targets in CRC. Competing endogenous RNA (ceRNA) networks, including three circRNAs, three miRNAs, and 28 mRNAs were constructed, suggesting their potential role in cancer progression. Representative differentially expressed RNAs were validated by the Cancer Genome Atlas (TCGA) database and real-time PCR experiments. Receiver operating characteristic (ROC) curve analysis identified three circRNAs (hsa_circ_0049487, hsa_circ_0066875, and hsa_circ_0007444) as possible novel biomarkers predicting the transition from colonic adenoma to cancer. Overall, our findings may provide novel perspectives to clarify the mechanisms of the transition from premalignant adenoma to cancer and identify specific circRNA-related signatures with possible applications for the early diagnosis of and as potential therapeutic targets in CRC.