Malignant glioma exerts a metabolic shift from oxidative phosphorylation (OXPHOs) to aerobic glycolysis, with suppressed mitochondrial functions. This phenomenon offers a proliferation advantage to ...tumor cells and decrease mitochondria-dependent cell death. However, the underlying mechanism for mitochondrial dysfunction in glioma is not well elucidated. MTCH2 is a mitochondrial outer membrane protein that regulates mitochondrial metabolism and related cell death. This study aims to clarify the role of MTCH2 in glioma.
Bioinformatic analysis from TCGA and CGGA databases were used to investigate the association of MTCH2 with glioma malignancy and clinical significance. The expression of MTCH2 was verified from clinical specimens using real-time PCR and western blots in our cohorts. siRNA-mediated MTCH2 knockdown were used to assess the biological functions of MTCH2 in glioma progression, including cell invasion and temozolomide-induced cell death. Biochemical investigations of mitochondrial and cellular signaling alternations were performed to detect the mechanism by which MTCH2 regulates glioma malignancy.
Bioinformatic data from public database and our cohort showed that MTCH2 expression was closely associated with glioma malignancy and poor patient survival. Silencing of MTCH2 expression impaired cell migration/invasion and enhanced temozolomide sensitivity of human glioma cells. Mechanistically, MTCH2 knockdown may increase mitochondrial OXPHOs and thus oxidative damage, decreased migration/invasion pathways, and repressed pro-survival AKT signaling.
Our work establishes the relationship between MTCH2 expression and glioma malignancy, and provides a potential target for future interventions.
Glioma is one of the most malignant brain tumors and accounts for the majority of brain cancer related death. Despite progress on mechanistic studies, current understandings of the initiation and ...progression of glioma are still incomplete. Previous studies demonstrate that
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(EN2), a homeobox-containing transcription factor, is associated with tumorigenesis in a range of cancers heterogeneously, however, the profiles of EN2 expression and its potential functions in gliomas remain unclear.
Real-time PCR was used to identify the expression of EN2 in glioma tissues. To study the biological function of EN2 in glioma, we compared the cell viability and proliferation profiles between EN2 overexpressed and control cells using cell counting kit-8 (CCK8) assay, EdU incorporation assay and colony formation assay. Flow cytometry and Hoechst staining assays were performed to investigate the role of EN2 on glioma cell death. Finally, wound healing and transwell assays were carried out to investigate the role of EN2 on glioma cell invasion.
We identified that EN2 was downregulated in human gliomas compared with paired adjacent normal tissues and negatively associated with glioma malignancy. Elevated EN2 expression inhibits cell proliferation, enhances glioma sensitivity to temozolomide and inhibits migration/invasion of glioma cells.
Our data identify a novel function of EN2 in glioma suppression and provide potential therapeutic targets for glioma therapy.
Liver fibrosis, a rising cause of chronic liver diseases, could eventually develop into cirrhosis and liver failure. Current diagnosis of liver fibrosis relies on pathological examination of hepatic ...tissues acquired from percutaneous biopsy, which may produce invasive injuries. Here, for non-invasive assessment of liver fibrosis, we applied comparative multi-omics in non-human primates (rhesus macaques) and subsequent serum biopsy in human patients. Global transcriptomics showed significant gene enrichment of metabolism process, in parallel with oxidative stress and immune responses in fibrotic primates. Targeted metabolomics were concordant with transcriptomic patterns, identifying elevated lipids and porphyrin metabolites during hepatic fibrosis. Importantly, liquid biopsy results validated that specific metabolites in the serum (e.g., biliverdin) were highly diagnostic to distinguish human patients from healthy controls. Findings describe the interconnected transcriptional and metabolic network in primate liver fibrosis and provide potential indices for non-invasive detection of liver fibrosis in humans.
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•Establishment of a robust liver fibrosis model in rhesus macaques•Comprehensive exploration of transcriptomic/metabolomic signatures of liver fibrosis•Non-invasive serum biopsy providing a potential approach for evaluating liver fibrosis•Preliminary evidence for biliverdin as a potential liver fibrosis biomarker
Diagnostic technique in health technology; Nonclinical topic
Hepatosteatosis, characterized by excessive accumulation of lipids in the liver, is a major health issue in modern society. Understanding how altered hepatic lipid metabolism/homeostasis causes ...hepatosteatosis helps to develop therapeutic interventions. Previous studies identify mitochondrial dysfunction as a contributor to hepatosteatosis. But, the molecular mechanisms of mitochondrial dysfunction leading to altered lipid metabolism remain incompletely understood. Our previous work shows that Rheb, a Ras-like small GTPase, not only activates mTORC1 but also promotes mitochondrial ATP production through pyruvate dehydrogenase (PDH). In this study, we further demonstrate that Rheb controls hepatic triglyceride secretion and reduces diet-induced lipid accumulation in a mouse liver. Genetic deletion of
causes rapid and spontaneous steatosis in the liver, which is unexpected from the role of mTORC1 that enhances lipid synthesis, whereas Rheb transgene remarkably reduces diet-induced hepatosteatosis. Results suggest that the hepatosteatosis in
KO is an outcome of impaired lipid secretion, which is linked to mitochondrial ATP production of hepatocytes. Our findings highlight an under-appreciated role of Rheb in the regulation of hepatic lipid secretion through mitochondrial energy production, with therapeutic implication.
•Pemphigus vulgaris (PV) and bullous pemphigoid (BP) shared dysregulated immune response.•T and B lymphocytes served as executors of PV and BP.•Macrophages emerged as elusive participants in PV and ...BP.•Immune cells targeting strategy was promising in disease management.
Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are two major subtypes of autoimmune bullous diseases (AIBD), characterized by blisters and erosions of skin and/or mucous membranes with dysregulated immune activity. Current literature established that T and B cells are the main executors of PV and BP. Emerging evidence revealed that macrophages and related cytokines also contribute to these diseases. While the role of lymphocytes on PV and BP is well established, the definitive functions of macrophages in disease progression are not fully understood. Furthermore, current status of clinical trials targeting immune cells is poorly recapitulated in PV and BP. In this review, we summarized current knowledge in this rapidly advancing field, with emphasis on the individual functions of immune cells and their interactions, as well as ongoing clinical trials targeting immune cells, to provide novel insights in mechanistic understanding and clinical management of PV and BP.
Background
Head and neck squamous cell carcinoma (HNSCC) represents one of the most malignant cancers worldwide, with poor survival. Experimental evidence implies that glycolysis/hypoxia is ...associated with HNSCC. In this study, we aimed to construct a novel glycolysis‐/hypoxia‐related gene (GHRG) signature for survival prediction of HNSCC.
Methods
A multistage screening strategy was used to establish the GHRG prognostic model by univariate/least absolute shrinkage and selection operator (LASSO)/step multivariate Cox regressions from The Cancer Genome Atlas cohort. A nomogram was constructed to quantify the survival probability. Correlations between risk score and immune infiltration and chemotherapy sensitivity were explored.
Results
We established a 12‐GHRG mRNA signature to predict the prognosis in HNSCC patients. Patients in the high‐risk score group had a much worse prognosis. The predictive power of the model was validated by external HNSCC cohorts, and the model was identified as an independent factor for survival prediction. Immune infiltration analysis showed that the high‐risk score group had an immunosuppressive microenvironment. Finally, the model was effective in predicting chemotherapeutic sensitivity.
Conclusions
Our study demonstrated that the GHRG model is a robust prognostic tool for survival prediction of HNSCC. Findings of this work provide novel insights for immune infiltration and chemotherapy of HNSCC, and may be applied clinically to guide therapeutic strategies.
Yuan et al. established and validated a 12‐GHRG signature for the prognostic prediction of HNSCC, which has potential for use in clinical settings for convenient prognostic monitoring. Moreover, the GHRG model could predict the immune infiltrate features and chemotherapy drug sensitivities of HNSCC.
The morphological structure and metabolic activity of mitochondria are coordinately regulated by circadian mechanisms. However, the mechanistic interplay between circadian mechanisms and ...mitochondrial architecture remains poorly understood. Here, we demonstrate circadian rhythmicity of Rheb protein in liver, in line with that of Per2. Using genetic mouse models, we show that Rheb, a small GTPase that binds mTOR, is critical for circadian oscillation of mTORC1 activity in liver. Disruption of Rheb oscillation in hepatocytes by persistent expression of Rheb transgene interrupted mTORC1 oscillation. We further show that Rheb‐regulated mTORC1 altered mitochondrial fission factor DRP1 in liver, leading to altered mitochondrial dynamics. Our results suggest that Rheb/mTORC1 regulated DRP1 oscillation involves ubiquitin‐mediated proteolysis. This study identifies Rheb as a nodal point that couples circadian clock and mitochondrial architecture for optimal mitochondrial metabolism.
Twin proximal support vector regression is a new regression machine designed by using twin support vector machine and proximal support vector regression. In this paper, we use the above models ...framework to build a new regression model, called the twin proximal least squares support vector regression model based on heteroscedastic Gaussian noise (TPLSSVR-HGN). The least square method is introduced and the regularization terms b 1 2 and b 2 2 are added respectively. It transforms an inequality constraint problem into two simpler equality constraint problems, which not only improves the training speed and generalization ability, but also effectively improves the forecasting accuracy. In order to solve the parameter selection problem of model TPLSSVR-HGN, the particle swarm optimization algorithm with fast convergence speed and good robustness is selected to optimize its parameters. In order to verify the forecasting performance of TPLSSVR-HGN, it is compared with the classical regression models on the artificial data set, UCI data set and wind-speed data set. The experimental results show that TPLSSVR-HGN has better forecasting effect than the classical regression models.
We investigated the role of miR-99a in regulating depressant activity by administering crocin in an animal model of chronic unpredictable mild stress (CUMS). A CUMS rat model was built and crocin was ...intraperitoneally injected to examine its role in depression-like behaviors. Depression-like behaviors were analyzed using an open-field test (OFT), sucrose preference test (SPT), forced swimming test (FST), and elevated maze test (EPM). Representative depressant activity occurred in CUMS rats. The SPT/OFT/EPM/FST results also indicated that the administration of crocin could reduce depression-like activity in CUMS rats. Postsynaptic density protein 95 (PSD-95), SYN, P-TrkB, BDNF protein expression was remarkably downregulated in the hippocampal formation of CUMS rats but was recovered after treatment with crocin. In addition, crocin injection increased norepinephrine (NE)/ dopamine (DA)/ serotonin (5-HT) levels in the hippocampus of CUMS rats. miR-99a expression in the hippocampal formation of CUMS rats was remarkably lower than that in the control group; crocin administration increased hippocampal miR-99a levels. In addition, the upregulation of miR-99a in the hippocampus of CUMS rats resulted in a phenotype similar to that of the crocin injection group, whereas miR-99a downregulation in crocin-injected CUMS rats counteracted the effect of crocin on depression-like behaviors. Moreover, FKBP51 was identified as a direct target of miR-99a, which inhibits downstream FKBP51 in primary hippocampal neurons. Crocin exerts anti-depressant effects in hippocampal dysfunction by promoting miR-99a and activating the TrkB/BDNF signaling pathway in the hippocampal formation of CUMS rats.
Purpose
Glioma is a highly malignant and unfavorable cancer in the brain. Recent evidence highlights the vital role of cilia-related pathways as novel regulators of glioma development. However, the ...prognostic potential of ciliary pathways in glioma is still ambiguous. In this study, we aim to construct a gene signature using cilia-related genes to facilitate the prognostication of glioma.
Methods
A multi-stage approach was employed to build the ciliary gene signature for prognostication of glioma. The strategy involved the implementation of univariate, LASSO, and stepwise multivariate Cox regression analyses based on TCGA cohort, followed by independent validation in CGGA and REMBRANDT cohort. The study further revealed molecular differences at the genomic, transcriptomic, and proteomic levels between distinct groups.
Results
A prognostic tool utilizing a 9-gene signature based on ciliary pathways was developed to assess the clinical outcomes of glioma patients. The risk scores generated by the signature demonstrated a negative correlation with patient survival rates. The validation of the signature in an independent cohort reinforced its prognostic capabilities. In-depth analysis uncovered distinctive molecular characteristics at the genomic, transcriptomic, and protein-interactive levels in the high- and low-risk groups. Furthermore, the gene signature was able to predict the sensitivity of glioma patients to conventional chemotherapeutic drugs.
Conclusion
This study has established the utility of a ciliary gene signature as a reliable prognostic predictor of glioma patient survival. Findings not only enhance our comprehension of the intricate molecular mechanisms of cilia pathways in glioma, but also hold significant clinical implications in directing chemotherapeutic strategies.
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