Objective: We aimed to investigate the relationship between titin (TTN) gene mutations and thyroid cancer (THCA) and to explore the feasibility of the TTN gene as a potential prognostic indicator of THCA. Methods: From TCGA-THCA cohort, we performed a series of analyses to evaluate the prognostic value and potential mechanism of TTN in THCA. These patients were divided into the mutant-type (MUT) group and the wild-type (WT) group. Differentially expressed genes (DEGs) in the two groups were screened using the ‘DESeq2’ R package. Functional enrichment analysis was performed, and the protein–protein interaction (PPI) network, transcription factor (TF)-target interaction networks, and competitive endogenous RNA (ceRNA) regulatory networks were established for the DEGs. The TIMER database was applied for immune cell infiltration. Survival analysis and Cox regression analysis were used to analyze the potential prognostic value of the TTN gene. Results: Differential expression analysis showed that 409 genes were significantly up-regulated and 36 genes were down-regulated. Functional enrichment analysis revealed that TTN gene mutations played a potential role in the development of THCA. Analysis of the immune microenvironment indicated that TTN gene mutations were significantly associated with enrichment of M0 macrophages. Survival analysis showed that the MUT group predicted poorer prognosis than the WT group. Cox regression analysis demonstrated that TTN gene mutations were an independent risk factor for THCA. Nomograms also confirmed the prognostic values of the TTN gene in THCA. Conclusions In summary, our results demonstrated that TTN gene mutations predict poor prognosis in patients with THCA. This is the first study to research TTN gene mutations in THCA and to investigate their prognostic value in THCA.

Insulin secretion from pancreatic β-cells regulates glucose metabolism and is related to various diseases including diabetes. The late endosomal/lysosomal adaptor MAPK and mTOR activator 1 (LAMTOR1) is one of the subunits of the 'Ragulator' complex and plays an important role in energy metabolism including glucose metabolism. The present study was designed to explore the role of LAMTOR1 in murine pancreatic β-cell function. A murine model with β cell-specific deficiency (βLamtor1-KO) was generated to assess β-cell function (insulin sensitivity paired with β-cell responses) by hyperglycemic clamp in vivo. Islet perfusion and mitochondrial functional analyses were performed to investigate the individual steps in the insulin secretion pathway. Results showed that glucose tolerance in vivo as well as glucose-stimulated insulin secretion in the hyperglycemic clamp and islet perfusion were higher in βLamtor1-KO mice compared to the control models. Although mitochondrial dysfunction was present, the deletion of Lamtor1 increased glutamate content in the mouse insulin granules as well as acetyl-CoA carboxylase 1 (ACC1) activity thus enhancing insulin secretion. Together, our data indicate that LAMTOR1 is important for maintaining mitochondrial function in mouse pancreatic β-cells, however deletion of Lamtor1 increases the amplification pathway induced by glutamate and ACC1, ultimately leading to increased insulin secretion. These findings suggest that knockout of Lamtor1 is a potential technique for improving pancreatic β-cell function and treating diabetes.

The use of mesenchymal stem cells (MSCs) has become a new strategy for treating diabetic kidney disease (DKD). However, the role of placenta derived mesenchymal stem cells (P-MSCs) in DKD remains unclear. This study aims to investigate the therapeutic application and molecular mechanism of P-MSCs on DKD from the perspective of podocyte injury and PINK1/Parkin-mediated mitophagy at the animal, cellular, and molecular levels. Western blotting, reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to detect the expression of podocyte injury-related markers and mitophagy-related markers, SIRT1, PGC-1α, and TFAM. Knockdown, overexpression, and rescue experiments were performed to verify the underlying mechanism of P-MSCs in DKD. Mitochondrial function was detected by flow cytometry. The structure of autophagosomes and mitochondria were observed by electron microscopy. Furthermore, we constructed a streptozotocin-induced DKD rat model and injected P-MSCs into DKD rats. Results showed that as compared with the control group, exposing podocytes to high-glucose conditions aggravated podocyte injury, represented by a decreased expression of Podocin along with increased expression of Desmin, and inhibited PINK1/Parkin-mediated mitophagy, manifested as a decreased expression of Beclin1, the LC3II/LC3I ratio, Parkin, and PINK1 associated with an increased expression of P62. Importantly, these indicators were reversed by P-MSCs. In addition, P-MSCs protected the structure and function of autophagosomes and mitochondria. P-MSCs increased mitochondrial membrane potential and ATP content and decreased the accumulation of reactive oxygen species. Mechanistically, P-MSCs alleviated podocyte injury and mitophagy inhibition by enhancing the expression of the SIRT1-PGC-1α-TFAM pathway. Finally, we injected P-MSCs into streptozotocin-induced DKD rats. The results revealed that the application of P-MSCs largely reversed the markers related to podocyte injury and mitophagy and significantly increased the expression of SIRT1, PGC-1α, and TFAM compared with the DKD group. In conclusion, P-MSCs ameliorated podocyte injury and PINK1/Parkin-mediated mitophagy inhibition in DKD by activating the SIRT1-PGC-1α-TFAM pathway.

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BackgroundIn recent years, the role of BAI1-associated protein 2-like 2 (BAIAP2L2) in the prognosis and immune microenvironment of various cancers has attracted increasing attention. However, its clinical value and immune infiltration in liver hepatocellular carcinoma (LIHC) remain unclear.ObjectiveTo investigate the prognostic value of BAIAP2L2 and its correlation with immune infiltration in LIHC, we conducted corresponding data mining.MethodsIn this study, The Cancer Genome Atlas, GTEx, StarBase, UALCAN, TIMER, GEPIA, Human Protein Atlas, Kaplan–Meier Plotter, cBioPortal, LinkedOmics, STRING and BioGPS databases were used to analyze BAIAP2L2 in cancers. Logistic regression and Cox regression were performed to analyze the correlation between clinical features and BAIAP2L2 expression in LIHC. In addition, the diagnostic and prognostic values of BAIAP2L2 in LIHC were determined by receiver operating characteristic (ROC) curves and nomograms. Single-sample gene set enrichment analysis (ssGSEA), BioGPS and TIMER were used to analyze the correlation between BAIAP2L2 and immune infiltration. More importantly, quantitative real-time polymerase chain reaction was used to verify BAIAP2L2 expression in a liver cancer cell line and a normal cell line. Visualization of data was mostly achieved using R language, version 3.6.3.ResultsHigh BAIAP2L2 levels indicated poor overall survival (OS) and disease-free survival (DFS) of patients with LIHC. Abnormally increased expression of BAIAP2L2 in LIHC may be the result of both genetic alterations and lower DNA methylation levels. Furthermore, Cox regression analysis showed that high BAIAP2L2 expression was an independent risk factor for OS and DFS in patients with liver cancer. ROC curves and nomograms also confirmed the diagnostic and prognostic values of BAIAP2L2 in LIHC. Additionally, a PPI network of BAIAP2L2 was established and results implyed that BAIAP2L2 interacts with MTSS1, AMPH, FCHO1, SYT9, PDK2, MTSS1L, PM20D1, CHST4 and PALM3. ssGSEA showed that BAIAP2L2 was associated with T cells and natural killer cells. Simultaneously, the TIMER database showed that the expression of BAIAP2L2 in LIHC was positively correlated with tumor infiltrating cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells.ConclusionsThrough pan-cancer analysis, prognostic and immunological value of BAIAP2L2 in LIHC was identified. This is the first report on the potential of BAIAP2L2 as a prognostic biomarker and its correlation with immune infiltration in LIHC.