The mechanism of mitochondrial metabolic gene PMAIP1 involved in Alzheimer's disease process based on bioinformatics analysis and experimental validation.

OBJECTIVES: This study explored novel biomarkers that can affect the diagnosis and treatment in Alzheimer's Disease (AD) related to mitochondrial metabolism. METHODS: The authors obtained the brain tissue datasets for AD from the Gene Expression Omnibus (GEO) and downloaded the mitochondrial metabolism-related genes set from MitoCarta 3.0 for analysis. Differentially Expressed Genes (DEGs) were screened using the "limma" R package, and the biological functions and pathways were investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The LASSO algorithm was used to identify the candidate center genes and validated in the GSE97760 dataset. PMAIP1 with the highest diagnostic value was selected and its effect on the occurrence of AD by biological experiments. RESULTS: A sum of 364 DEGs and 50 hub genes were ascertained. GO and KEGG enrichment analysis demonstrated that DEGs were preponderantly associated with cell metabolism and apoptosis. Five genes most associated with AD as candidate central genes by LASSO algorithm analysis. Then, the expression level and specificity of candidate central genes were verified by GSE97760 dataset, which confirmed that PMAIP1 had a high diagnostic value. Finally, the regulatory effects of PMAIP1 on apoptosis and mitochondrial function were detected by siRNA, flow cytometry and Western blot. siRNA-PMAIP1 can alleviate mitochondrial dysfunction and inhibit cell apoptosis. CONCLUSION: This study identified biomarkers related to mitochondrial metabolism in AD and provided a theoretical basis for the diagnosis of AD. PMAIP1 was a potential candidate gene that may affect mitochondrial function in Hippocampal neuronal cells, and its mechanism deserves further study.

Integrated Bioinformatics and Experimental Analysis of Long Noncoding RNA Associated-ceRNA as Prognostic Biomarkers in Advanced Stomach Adenocarcinoma.

BACKGROUND: Advanced stomach adenocarcinoma (ASTAD) is a highly malignant and prognostically poor stage of gastric cancer. Recently, long noncoding RNA (lncRNA) was found to play a crucial role, including as competing endogenous RNA (ceRNA) in cancer. However, studies on large-scale sample in ASTAD are still lacking, thus we constructed the ceRNA network of ASTAD to explore its molecular mechanism. METHODS: We compared the expression of mRNAs, lncRNAs and miRNAs between ASTAD and normal tissues utilizing RNA-Seq and miRNA-seq Data from The Cancer Genome Atlas (TCGA). GO and KEGG enrichment analysis were executed for annotating the functions of differentially expressed mRNAs. Subsequently, we investigated the expression correlations between the differentially expressed lncRNAs and their respective mRNAs by constructing a ceRNA network. Kaplan-Meier survival analysis was used to assess the relationship between high/low risk scores based on this network with patient prognosis in TCGA training cohort and GSE15459 validation cohort. In vitro functional assays were employed to verify the cancer-promoting effects of key lncRNAs in the ceRNA network and their possible mechanisms. RESULTS: In ASTAD tissues, a total of 176 lncRNAs, 124 miRNAs, and 2205 mRNAs were identified as differentially expressed. Our constructed ceRNA network consisted 6 differentially expressed lncRNAs (PVT1, MAGI2-AS3, KCNQ1OT1, LINC02086, AC125807.2 and LINC02535), 25 miRNAs and 130 mRNAs, and the risk score derived from these lincRNAs could predict ASTAD patient outcomes. Key lncRNA LINC02086 was experimentally verified to enhance proliferation and migration of gastric cancer cells by competitively binding to miR-93a-5p with MMP3. CONCLUSION: Our comprehensive ceRNA network for ASTAD provides valuable insights into its molecular mechanisms, and LINC02086 may be used as an innovative target for clinical treatment.

Comprehensive bioinformatics and experimental analysis of SH3PXD2B reveals its carcinogenic effect in gastric carcinoma.

AIMS: We aim to explore the possibility and mechanism of SH3PXD2B as a reliable biomarker for gastric cancer (GC). MAIN METHODS: We used public databases to analyze the molecular characteristics and disease associations of SH3PXD2B, and KM database for prognostic analysis. The TCGA gastric cancer dataset was used for single gene correlation, differential expression, functional enrichment and immunoinfiltration analysis. SH3PXD2B protein interaction network was constructed by the STRING database. And the GSCALite database was used to explore sensitive drugs and perform SH3PXD2B molecular docking. The impact of SH3PXD2B silencing and over-expression by lentivirus transduction on the proliferation and invasion of human GC HGC-27 and NUGC-3 cells was determined. KEY FINDINGS: The high expression of SH3PXD2B in gastric cancer was related to the poor prognosis of patients. It may affect the progression of gastric cancer by forming a regulatory network with FBN1, ADAM15 and other molecules, and the mechanism may involve regulating the infiltration of Treg, TAM and other immunosuppressive cells. The cytofunctional experiments verified that it significantly promoted the proliferation and migration of gastric cancer cells. In addition, we found that some drugs were sensitive to the expression of SH3PXD2B such as sotrastaurin, BHG712 and sirolimus, and they had strong molecular combination of SH3PXD2B, which may provide guidance for the treatment of gastric cancer. SIGNIFICANCE: Our study strongly suggests that SH3PXD2B is a carcinogenic molecule that can be used as a biomarker for GC detection, prognosis, treatment design, and follow-up.

Design, Synthesis, and Biological Evaluation of [1,2,4]triazolo[4,3-a] Pyrazine Derivatives as Novel Dual c-Met/VEGFR-2 Inhibitors.

In this study, we designed and synthesized a series of novel [1,2,4]triazolo [4,3-a]pyrazine derivatives, and evaluated them for their inhibitory activities toward c-Met/VEGFR-2 kinases and antiproliferative activities against tested three cell lines in vitro. Most of the compounds showed satisfactory activity compared with lead compound foretinib. Among them, the most promising compound 17l exhibited excellent antiproliferative activities against A549, MCF-7, and Hela cancer cell lines with IC50 values of 0.98 ± 0.08, 1.05 ± 0.17, and 1.28 ± 0.25 µM, respectively, as well as excellent kinase inhibitory activities (c-Met IC50 = 26.00 nM and VEGFR-2 IC50 = 2.6 µM). Moreover, compound 17l inhibited the growth of A549 cells in G0/G1 phase in a dose-dependent manner, and induced the late apoptosis of A549 cells. Its intervention on intracellular c-Met signaling of A549 was verified by the result of Western blot. Fluorescence quantitative PCR showed that compound 17l inhibited the growth of A549 cells by inhibiting the expression of c-Met and VEGFR-2, and its hemolytic toxicity was low. Molecular docking and molecular dynamics simulation indicated that compound 17l could bind to c-Met and VEGFR-2 protein, which was similar to that of foretinib.

Multimode participation of traditional Chinese medicine in the treatment of COVID-19.

BACKGROUND: The outbreak of COVID-19 has swiftly spread across China and all over the world, resulting in severe contagious pneumonia. However, no specific anti-COVID-19 drugs or methods are available for the treatment of this acute and fatal disease. In recent years, as the efficacy and safety of traditional Chinese medicine (TCM) have been universally acknowledged, it has been brought to a crucial status domestically and overseas for the treatment of COVID-19. METHODS: We searched relevant literature, electronic databases, and official statements, diagnoses and protocols to retrieve studies and applications related to traditional Chinese medicine for COVID-19 in terms of regulations and policies, clinical evidence, preclinical rationale and big data analysis and then summarized the discovery and development of potential drugs and their targets. RESULTS: Clinicians, researchers, governments, the public, colleges, institutes and companies collected and classified associated policies, regulations and actual contributions, searched clinical trials and preclinical experimental outcomes from databases, studied potential TCM drugs with possible mechanisms, retrieved numerous big data analysis method and gathered pooled results of compounds along with their effective targets to make traditional Chinese medicine vital to cover all stages of patients in the treatment and control of COVID-19. CONCLUSION: Traditional Chinese medicine provides new evidence to support the clinical value of TCM for COVID-19.

Efficacy and Safety of PARP Inhibitor Combination Therapy in Recurrent Ovarian Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVES: Though it is known to all that PARP inhibitors (PARPis) are effective when used as maintenance alone for women with recurrent ovarian cancer (ROC), little is known about whether using them in combination with other drugs would contribute to a better efficacy. We performed a systematic review and meta-analysis to explore the efficacy and safety of PARPi combination therapy compared with monotherapy. MATERIALS AND METHODS: We searched for randomized controlled trials (RCTs) that offered the date we needed in PubMed, Embase, Cochrane, and major conference. Data extraction and processing were completed by three investigators to compare OS, PFS, and ORR both in intervention and in control subset. Then, we calculated the pooled RR and 95% CI of all-grade and high-grade adverse effects to study its safety. And we evaluated the within-study heterogeneity by using subgroup and sensitivity analysis. RESULTS AND CONCLUSION: A total of three eligible RCTs covering 343 women were included. In PFS analysis, PARP inhibitor (PARPi) combination therapy can significantly improve PFS for women with ROC when compared with the controls (HR: 0.46, 95% CI: 0.35 to 0.59), especially for those with mutated BRCA (HR: 0.29, 95% CI: 0.19 to 0.45). And in OS analysis, combination therapy is not inferior to monotherapy (HR: 0.90, 95% CI: 0.50 to 1.61). As for ORR, the effectiveness of combination therapy and monotherapy was almost the same (RR: 1.04, 95% CI: 0.82 to 1.31). Additionally, combination therapy seldom causes more adverse events, both in all-grade and in high grade. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, International Prospective Register of Systematic Reviews (PROSPERO) (identifier, CRD42018109933).

Transcription factor POU4F2 promotes colorectal cancer cell migration and invasion through hedgehog-mediated epithelial-mesenchymal transition.

As a POU homeodomain transcription factor, POU4F2 has been implicated in regulating tumorigenic processes in various cancers. However, the role of POU4F2 in colorectal cancer (CRC) remains unclear. Here, we revealed that POU4F2 functions as a tumor promotor in CRC. Bioinformatics analysis in specimens from CRC patients and expression analysis in CRC cell lines showed that POU4F2 was upregulated at the mRNA and protein levels in CRC. Depletion of POU4F2 suppressed the metastatic phenotypes of CRC cells, including cell migration, invasion, and the expression of epithelial-mesenchymal transition (EMT) markers. Moreover, depletion of POU4F2 decreased the number of lung metastatic nodes in nude mice. Mechanistically, POU4F2 positively regulated the Hedgehog signaling pathway, as inferred from the downregulation of the expression of sonic Hedgehog homolog, patched 1, Smoothened, and GLI family zinc finger 1 in vitro and vivo following silencing of POU4F2. Furthermore, the SMO agonist SAG reversed the effects of POU4F2 knockdown in CRC. Functionally, POU4F2 contributed to the Hedgehog signaling-regulated activation of the EMT process and promotion of CRC cell migration and invasion. Collectively, these findings elucidated the role of POU4F2 as a tumor promotor in CRC through the regulation of Hedgehog signaling-mediated EMT and suggested that POU4F2 suppression might be a promising therapeutic target in inhibiting CRC metastasis.