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To study the effects of ubenimex (UBE) combined with pemetrexed (PEM) on lung adenocarcinoma cell behavior and its molecular mechanism, the tissue samples from lung adenocarcinoma patients who received PEM chemotherapy, those with PEM combined with UBE chemotherapy, and healthy volunteers were retrieved and analyzed. The expression levels of the suppressor of cytokine signaling 1 (SOCS1) in the human lung adenocarcinoma cancer cell lines A549 and PC-9 and tissues were detected by qRT-PCR. MTT assay was performed for cell proliferation. Cell apoptosis was detected by flow cytometry. Cell invasion ability was assessed using the Transwell assay. The expression levels of the JAK2/STAT3 signaling pathway proteins and apoptosis-related proteins were detected by Western blot. The antitumor effect of PEM combined with UBE was tested in nude mice using the tumor formation assay. Our results showed that UBE treatment, alone or combined with PEM, inhibited lung adenocarcinoma cell migration, invasion, and proliferation; promoted apoptosis; significantly increased the G0/G1-phase cell ratio; reduced the S-phase cell ratio; and inhibited the in vivo growth of tumor cells. UBE alone or in combination with PEM also inhibited the JAK2/STAT3 signaling pathway in lung adenocarcinoma cells. In addition, UBE combined with PEM therapy was associated with increased SOCS1 expression in patients' serum and knocking down SOCS1 reversed the antitumor effects of UBE and PEM. Overall, combination therapy with UBE and PEM could inhibit the JAK2-STAT3 signaling pathway by upregulating SOCS1 expression to hinder the progression of lung adenocarcinoma cells. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a prevalent risk factor for cognitive impairment. Aerobic exercise can improve T2DM-related cognitive impairment; however, the possible mechanisms remain elusive. Thus, we assessed db/m mice and leptin receptor-deficient (db/db) mice that did or did not perform aerobic exercise (8 m/min, 60 min/day, and 5 days/week for 12 weeks). In this study, cognitive function was significantly impaired in the T2DM mice; aerobic exercise improved cognitive impairment through activating the AMPK/SIRT1 signalling pathway and inhibiting the JAK2/STAT3 signalling pathway in T2DM mice. However, after the application of RO8191 (JAK2 activator) or Compound C (AMPK inhibitor), the positive improvement of the exercise was evidently suppressed. Taken together, our data indicated that long-term aerobic exercise improves type 2 diabetes mellitus-related cognitive impairment by inhibiting JAK2/STAT3 and enhancing AMPK/SIRT1 pathways in mice. [ABSTRACT FROM AUTHOR]

Background. As a chronic disease, osteoarthritis has caused great trouble to the health of middle-aged and elderly people. Studies have shown that glucosamine (GlcN) can be used to abate the progression and improve this disease. Based on this point of view, we try to verify the connection between GlcN and osteoarthritis and find more effective biomarkers. Methods. We downloaded the GSE72575 data set from the GEO database, and used the R language to perform DEG analysis on the gene expression profile of the samples. Next, the GO function and the KEGG signaling pathways were analyzed through the DAVID database, and then, the KEGG pathways enriched in the gene set were analyzed based on GSEA. Then, the PPI network of DEGs was constructed based on the STRING online database, and finally, the hub genes were selected by Cytoscape. Results. Three GlcN-treated MH7A cell treatment groups and 3 control groups in the GSE72575 data set were studied. Through analysis, there were 52 DEGs in these samples. Then, through GO, KEGG, and GSEA, regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway, FoxO signaling pathway, JAK-STAT signaling pathway, PI3K-Akt signaling pathway, TGF-beta signaling pathway, and ECM receptor interaction were involved in the regulatory mechanisms of the osteoarthritis pathogenesis. After that, the hub genes IL6 and DDIT3 were identified through PPI network construction and analysis. And it was found that IL6 was lowly expressed in the group with GlcN-treated MH7A cells, while DDIT3 was highly expressed. Conclusion. The above results provide a basis for GlcN to participate in the treatment of osteoarthritis and a possibility for finding effective therapeutic targets. [ABSTRACT FROM AUTHOR]

Background. Tuberculosis (TB) is a serious chronic bacterial infection caused by Mycobacterium tuberculosis (MTB). It is one of the deadliest diseases in the world and a heavy burden for people all over the world. However, the hub genes involved in the host response remain largely unclear. Methods. The data set GSE11199 was studied to clarify the potential gene network and signal transduction pathway in TB. The subjects were divided into latent tuberculosis and pulmonary tuberculosis, and the distribution of differentially expressed genes (DEGs) was analyzed between them using GEO2R. We verified the enriched process and pathway of DEGs by making use of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The construction of protein-protein interaction (PPI) network of DEGs was achieved through making use of the Search Tool for the Retrieval of Interacting Genes (STRING), aiming at identifying hub genes. Then, the hub gene expression level in latent and pulmonary tuberculosis was verified by a boxplot. Finally, through making use of Gene Set Enrichment Analysis (GSEA), we further analyzed the pathways related to DEGs in the data set GSE11199 to show the changing pattern between latent and pulmonary tuberculosis. Results. We identified 98 DEGs in total in the data set GSE11199, 91 genes upregulated and 7 genes downregulated included. The enrichment of GO and KEGG pathways demonstrated that upregulated DEGs were mainly abundant in cytokine-mediated signaling pathway, response to interferon-gamma, endoplasmic reticulum lumen, beta-galactosidase activity, measles, JAK-STAT signaling pathway, cytokine-cytokine receptor interaction, etc. Based on the PPI network, we obtained 4 hub genes with a higher degree, namely, CTLA4, GZMB, GZMA, and PRF1. The box plot showed that these 4 hub gene expression levels in the pulmonary tuberculosis group were higher than those in the latent group. Finally, through Gene Set Enrichment Analysis (GSEA), it was concluded that DEGs were largely associated with proteasome and primary immunodeficiency. Conclusions. This study reveals the coordination of pathogenic genes during TB infection and offers the diagnosis of TB a promising genome. These hub genes also provide new directions for the development of latent molecular targets for TB treatment. [ABSTRACT FROM AUTHOR]

This article has been retracted by Hindawi following an investigation undertaken by the publisher [[1]]. Wiley and Hindawi regrets that the usual quality checks did not identify these issues before publication and have since put additional measures in place to safeguard research integrity. [Extracted from the article]

The infection of human macrophages by pathogenic bacteria induces different signaling pathways depending on the type of cellular receptors involved in the microorganism entry and on their mechanism(s) of survival and replication in the host cell. It was reported that Stat proteins play an important role in this process. In the present study, we investigate the changes in Stat-1 activation (phosphorylation in p-tyr701) after uptake of two Gram-positive (Listeria monocytogenes and Staphylococcus aureus) and two Gram-negative bacteria (Salmonella typhimurium and Legionella pneumophila) characterized by their varying abilities to enter, survive, and replicate in human macrophages. Comparing the results obtained with Gram-negative and Gram-positive bacteria, Stat-1 activation in macrophages does not seem to be related to LPS content. The p-tyr701Stat-1 expression levels were found to be independent of the internalized bacterial number and IFN-γ release. On the contrary, Jak/Stat-1 pathway activation only occurs when an active infection has been established in the host macrophage, and it is plausible that the differences in the expression levels of p-tyr701Stat-1 could be due to different survival mechanisms or to differences in bacteria life cycles within macrophages. [ABSTRACT FROM AUTHOR]

Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition. [ABSTRACT FROM AUTHOR]