Tofacitinib prevents depressive-like behaviors through decreased hippocampal microgliosis and increased BDNF levels in both LPS-induced and CSDS-induced mice.

Depressive disorders are a global mental health challenge that is closely linked to inflammation, especially in the post-COVID-19 era. The JAK-STAT pathway, which is primarily associated with inflammatory responses, is not fully characterized in the context of depressive disorders. Recently, a phase 3 retrospective cohort analysis heightened that the marketed JAK inhibitor tofacitinib is beyond immune diseases and has potential for preventing mood disorders. Inspired by these clinical facts, we investigated the role of the JAK-STAT signaling pathway in depression and comprehensively assessed the antidepressant effect of tofacitinib. We found that aberrant activation of the JAK-STAT pathway is highly conserved in the hippocampus of classical depressive mouse models: LPS-induced and chronic social defeat stress (CSDS)-induced depressive mice. Mechanistically, the JAK-STAT pathway mediates proinflammatory cytokine production and microgliosis, leading to synaptic defects in the hippocampus of both depressive models. Remarkably, the JAK inhibitor tofacitinib effectively reverses these phenomena, contributing to its antidepressant effect. These findings indicate that the JAK/STAT pathway could be implicated in depressive disorders, and suggest that the JAK inhibitor tofacitinib has a potential translational implication for preventing mood disorders far beyond its current indications.

Placental growth factor alleviates hyperglycemia-induced trophoblast pyroptosis by regulating mitophagy.

INTRODUCTION: Hyperglycemia is closely related to trophoblast dysfunction during pregnancy and results in suppressed invasion, migration, and pro-inflammatory cell death of trophoblasts. Hyperglycemia is a dependent risk factor for gestational hypertension accompanied by decreased placental growth factor (PLGF), which is important for maternal and fetal development. However, there is currently a lack of evidence to support whether PLGF can alleviate trophoblast cell dysfunction caused by high blood sugar. Here, we aim to clarify the effect of hyperglycemia on trophoblast dysfunction and determine how PLGF affects this process. METHODS: The changes in placental tissue histomorphology from gestational diabetes mellitus (GDM) patients were compared with those of normal placentas. HTR8/SVneo cells were cultured in different amounts of glucose to examine cellular pyroptosis, migration, and invasion as well as PLGF levels. Furthermore, the levels of pyroptosis-related proteins (NLRP3, pro-caspase1, caspase1, IL-1ß, and Gasdermin D [GSDMD]) as well as autophagy-related proteins (LC3-II, Beclin1, and p62) were examined by Western blotting. The GFP-mRFP-LC3-II system and transmission electron microscopy were used to detect mitophagy levels, and small interfering RNAs targeting BCL2 Interacting Protein 3 (siBNIP3) and PTEN-induced kinase 1 (siPINK1) were used to determine the role of mitophagy in pyroptotic death of HTR-8/SVneo cells. RESULTS: Our results show that hyperglycemia upregulates NLRP3, pro-caspase1, caspase1, IL-1ß at the protein level in GDM patients. High glucose (HG, 25 mM) inhibits viability, invasion, and migration of trophoblast cells while suppressing superoxide dismutase levels and promoting malondialdehyde production, thus leading to a senescence associated beta-gal-positive cell burst. PLGF levels in nucleus and the cytosol are also inhibited by HG, whereas PLGF treatment inhibited pyroptosis-related protein levels of NLRP3, pro-caspase1, caspase1, IL-1ß, and GSDMD, Gasdermin D N-terminal domain (GSDMD-N). HG-induced mitochondrial dysfunction and BNIP3 and PINK1/Parkin expression. Knocking down BINP3 and PINK1 abolished the protective role of PLGF by preventing mitophagy. CONCLUSION: PLGF inhibited hyperglycemia, while PLGF reversed hyperglycemic injury by promoting mitophagy via the BNIP3/PINK1/Parkin pathway. Altogether, these results suggest that PLGF may protect against trophoblast dysfunction in diabetes.

MicroRNAs: key regulators of the trophoblast function in pregnancy disorders.

The placenta is essential for a successful pregnancy and healthy intrauterine development in mammals. During human pregnancy, the growth and development of the placenta are inseparable from the rapid proliferation, invasion, and migration of trophoblast cells. Previous reports have shown that the occurrence of many pregnancy disorders may be closely related to the dysfunction of trophoblasts. However, the function regulation of human trophoblast cells in the placenta is poorly understood. Therefore, studying the factors that regulate the function of trophoblast cells is necessary. MicroRNAs (miRNAs) are small, non-coding, single-stranded RNA molecules. Increasing evidence suggests that miRNAs play a crucial role in regulating trophoblast functions. This review outlines the role of miRNAs in regulating the function of trophoblast cells and several common signaling pathways related to miRNA regulation in pregnancy disorders.

Synthesis, Fluorescence, and Bioactivity of Novel Isatin Derivatives.

The isatin group is widespread in nature and is considered to be a privileged building block for drug discovery. In order to develop novel SHP1 inhibitors with fluorescent properties as tools for SHP1 biology research, this work designed and synthesized a series of isatin derivatives. The presentive compound 5a showed good inhibitory activity against SHP1PTP with IC50 of 11 ± 3 µM, displayed about 92% inhibitory rate against MV-4-11 cell proliferation at the concentration of 20 µM, exhibited suitable fluorescent properties with a long emission wavelength and a large Stokes shift, and presented blue fluorescent imaging in HeLa cells with low cytotoxicity. This study could offer chemical tool to further understand SHP1 biology and develop novel SHP1 inhibitors in therapy.

Histone Deacetylase 1 Expression and Regulatory Network in Lung Adenocarcinoma Based on Data Mining and Implications for Targeted Treatment.

Background and Aims: Histone deacetylase 1 (HDAC1) codes a protein that is a component of the histone deacetylase complex. The abnormal expression of HDAC1 is strongly correlated with cell proliferation, differentiation, transcription, and translation. Through continuous screening of genes associated with changes in lung adenocarcinoma (LUAD), gene networks are formed to explore tumor pathogenesis and new therapeutic targets. Methods: We evaluated HDAC1 gene survival analysis and its expression of LUAD using relevant websites and databases (TCGA and GEO databases). Through data mining, we determined the frequency and type of HDAC1 mutation, obtained the relevant heat map of the gene interaction network, completed the analysis of gene ontology and function enrichment, and understood the pharmaceutic of HDAC1. Results: We found that HDAC1 expression was associated with the prognosis of patients with LUAD. In gene expression analysis, HDAC1 was highly expressed in LUAD, and the HDAC1 interaction gene network (MARCKSL, eIF3I) was closely related to cellular gene expression. Functional network analysis shows that the expression of HDAC1 is related to the monitoring point of the G1-S phase of the cell cycle and the activation of the Notch signaling pathway (CSL transcription factor), which is involved in the process of cell proliferation and differentiation and gene expression associated with new therapeutic targets. Conclusion: Our data revealed the expression and potential regulatory factors of HDAC1 in LUAD of data mining, which laid a foundation for the study of the occurrence, development, and treatment of HDAC1 in LUAD.

Risk score = LncRNAs associated with doxorubicin metabolism can be used as molecular markers for immune microenvironment and immunotherapy in non-small cell lung cancer.

Doxorubicin is the most effective anthracycline chemotherapy drug in the treatment of cancer, and it is an effective single agent in the treatment of non-small cell lung cancer (NSCLC). There is a lack of studies on the differentially expressed doxorubicin metabolism-related lncRNAs in NSCLC. In this study, we extracted related genes from the TCGA database and matched them with lncRNAs. Doxorubicin metabolism-related lncRNA-based gene signatures (DMLncSig) were gradually screened from univariate regression, LASSO regression, and multivariate regression analysis, and the risk score model was constructed. These DMLncSig were subjected to a GO/KEGG analysis. We then used the risk model to construct the TME model and analyze drug sensitivity. The IMvigor 210 immunotherapy model was cited for validation. Eventually, we performed tumor stemness index differences, survival, and clinical correlation analyses.

Epigenetic Control of Vascular Smooth Muscle Cell Function in Atherosclerosis: A Role for DNA Methylation.

Atherosclerosis is a complex vascular inflammatory disease in which multiple cell types are involved, including vascular smooth muscle cells (VSMCs). In response to vascular injury and inflammatory stimuli, VSMCs undergo a "phenotypic switching" characterized by extracellular matrix secretion, loss of contractility, and abnormal proliferation and migration, which play a key role in the progression of atherosclerosis. DNA methylation modification is an important epigenetic mechanism that plays an important role in atherosclerosis. Studies investigating abnormal DNA methylation in patients with atherosclerosis have determined a specific DNA methylation profile, and proposed multiple pathways and genes involved in the etiopathogenesis of atherosclerosis. Recent studies have also revealed that DNA methylation modification controls VSMC function by regulating gene expression involved in atherosclerosis. In this review, we summarize the recent advances regarding the epigenetic control of VSMC function by DNA methylation in atherosclerosis and provide insights into the development of VSMC-centered therapeutic strategies.

Comprehensive transcriptomic and co-expression analysis of ABL1 gene and molecularly targeted drugs in hepatocellular carcinoma based on multi-database mining.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Consequently, it is essential to identify biomarkers for treatment response and the prognosis prediction. We investigated whether ABL1 can function as a biomarker or a drug target for HCC. We assessed the ABL1 expression, genetic alterations and patients' survival from LinkedOmics, GEO, TCGA and Human Protein Atlas. We analyzed PPI, GO and KEGG pathways. GSEA was analyzed for functional comparison. The current drugs targeting ABL1 were statistically analyzed using DRUGSURV and DGIdb database. We found ABL1 is overexpressed in HCC and its higher expression reduces survival probability. Genetic changes of ABL1 are not frequent. We screened out 25 differentially expressed genes correlated with ABL1. The top functions of ABL1 are biological regulation, metabolic process, protein-containing, and protein binding. KEGG pathways showed that ABL1 and correlated with ABL1 significantly genes markedly enriched in the ErbB signaling pathway, and pathways in cancer. We counted the existing drugs targeting ABL1, which indicates that inhibiting ABL1 expression may improve the survival probability of HCC. In conclusion, ABL1 plays a crucial role in the development and progression of this cancerization and is a potential drug target.

SARS-CoV-2: The Monster Causes COVID-19.

Coronaviruses are viruses whose particles look like crowns. SARS-CoV-2 is the seventh member of the human coronavirus family to cause COVID-19 which is regarded as a once-in-a-century pandemic worldwide. It holds has the characteristics of a pandemic, which has broy -55ught many serious negative impacts to human beings. It may take time for humans to fight the pandemic. In addition to humans, SARS-CoV-2 also infects animals such as cats. This review introduces the origins, structures, pathogenic mechanisms, characteristics of transmission, detection and diagnosis, evolution and variation of SARS-CoV-2. We summarized the clinical characteristics, the strategies for treatment and prevention of COVID-19, and analyzed the problems and challenges we face.