Identification and validation of roles of lysyl oxidases in the predictions of prognosis, chemotherapy and immunotherapy in glioma.

Background: Previous investigations have illustrated that lysyl oxidase family enzymes (LOXs) are contributing factors for tumor progression and remodeling immunomicroenvironment. However, it is scarce regarding comprehensive analysis of LOXs in the predictions of prognosis, chemotherapy and immunotherapy in glioma, the highly invasive brain tumor. Our present work aimed to explore the prognostic value, chemotherapeutic drug sensitivity and immunotherapy according to distinct LOXs expressions in glioma through bioinformatics analysis and experimental verification. Methods: We collected gene expression data and clinical characteristics from the public databases including Chinese Glioma Genome Atlas (CGGA)-325, CGGA-693, the Cancer Genome Atlas (TCGA), IMvigor210 and Van Allen 2015 cohorts. The correlations between the clinicopathological factors and differential LOXs expressions were analyzed. The ROC curve and Kaplan-Meier analysis were conducted to evaluate the prediction ability of prognosis. Chemotherapeutic drug sensitivity via distinct LOXs expression levels was predicted using the pRRophetic package. Immune score, immune cell infiltration and immune checkpoint expression levels were also analyzed through diverse algorithms in R software. Finally, mRNA and protein expressions of LOXs were validated in glioma cells (T98G and A172) by real-time quantitative PCR and Western blot, respectively. Results: Our results demonstrated that high levels of LOXs expressions were positively associated with glioma grades, older age and MGMT unmethylated status while elevations of LOXs were negatively correlated with IDH mutation or 1p/19q co-deletion. Furthermore, the glioma patients with low levels of LOXs also exhibited better prognosis. Also, differential LOXs expressions were associated with at least 12 chemotherapeutic drug sensitivity. Besides, it was also found that glioma patients with high LOXs expressions showed higher enrichment scores for immune cell infiltration and increased levels of immune checkpoints, suggesting the critical role of distinct LOXs expression levels for glioma immunotherapy. The predictive roles of LOXs expression in tumor immunotherapy were also validated in two immunotherapy cohorts including IMvigor 210 and Van Allen 2015. Experimental results revealed that expressions of LOX, LOXL1, LOXL2, and LOXL3 were higher in glioma cell lines at mRNA and protein levels. Conclusion: Our findings altogether indicate that LOXs have potent predictive value for prognosis, chemotherapy and immunotherapy in glioma patients.

Ferroptosis-related gene signature predicts prognosis and immunotherapy in glioma.

AIMS: Glioma is a highly invasive brain tumor, which makes prognosis challenging and renders patients resistant to various treatments. Induction of cell death is promising in cancer therapy. Ferroptosis, a recently discovered regulated cell death, can be induced for killing glioma cells. However, the prognostic prediction of ferroptosis-related genes (FRGs) in glioma remains elusive. METHODS: The mRNA expression profiles and gene variation and corresponding clinical data of glioma patients and NON-TUMOR control were downloaded from public databases. Risk score based on a FRGs signature was constructed in REMBRANDT cohort and validated in other datasets including CGGA-693, CGGA-325, and TCGA. RESULTS: Our results demonstrated that the majority of FRGs was differentially expressed among GBM, LGG, and NON-TUMOR groups (96.6%). Furthermore, the glioma patients with low-risk score exhibited a more satisfactory clinical outcome. The better prognosis was also validated in the glioma patients with low-risk score no matter to which grade they were affiliated. Functional analysis revealed that the high-risk score group was positively correlated with the enrichment scores for immune checkpoint blockade-related positive signatures, indicating the critical role of glioma immunotherapy via risk score. CONCLUSION: A novel FRGs-related risk score can predict prognosis and immunotherapy in glioma patients.

The mutual interplay of redox signaling and connexins.

Connexins (Cxs) are ubiquitous transmembrane proteins that possess both channel function (e.g., formations of gap junction and hemichannel) and non-channel properties (e.g., gene transcription and protein-protein interaction). Several factors have been identified to play a role in the regulation of Cxs, which include those acting intracellularly, as redox potential, pH, intramolecular interactions, and post-translational modifications (e.g., phosphorylation, S-nitrosylation) as well as those acting extracellularly, such as Ca2+ and Mg2+. The relationship between redox signaling and Cxs attracts considerable attention in recent years. There is ample evidence showing that redox signaling molecules (e.g., hydrogen peroxide (H2O2), nitric oxide (NO)) affect Cxs-based channel function while the opening of Cx channels also triggers the transfer of various redox-related metabolites (e.g., reactive oxygen species, glutathione, nicotinamide adenine dinucleotide, and NO). On the basis of these evidences, we propose the existence of redox-Cxs crosstalk. In this review, we briefly discuss the interaction between redox signaling and Cxs and the implications of the intersection in disease pathology and future therapeutic interventions.

Dietary nutrition for neurological disease therapy: Current status and future directions.

Adequate food intake and relative abundance of dietary nutrients have undisputed effects on the brain function. There is now substantial evidence that dietary nutrition aids in the prevention and remediation of neurologic symptoms in diverse pathological conditions. The newly described influences of dietary factors on the alterations of mitochondrial dysfunction, epigenetic modification and neuroinflammation are important mechanisms that are responsible for the action of nutrients on the brain health. In this review, we discuss the state of evidence supporting that distinct dietary interventions including dietary supplement and dietary restriction have the ability to tackle neurological disorders using Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, Huntington's disease and multiple sclerosis as examples. Additionally, it is also highlighting that diverse potential mechanisms such as metabolic control, epigenetic modification, neuroinflammation and gut-brain axis are of utmost importance for nutrient supply to the risk of neurologic condition and therapeutic response. Finally, we also highlight the novel concept that dietary nutrient intervention reshapes metabolism-epigenetics-immunity cycle to remediate brain dysfunction. Targeting metabolism-epigenetics-immunity network will delineate a new blueprint for combating neurological weaknesses.

Antioxidants Targeting Mitochondrial Oxidative Stress: Promising Neuroprotectants for Epilepsy.

Mitochondria are major sources of reactive oxygen species (ROS) within the cell and are especially vulnerable to oxidative stress. Oxidative damage to mitochondria results in disrupted mitochondrial function and cell death signaling, finally triggering diverse pathologies such as epilepsy, a common neurological disease characterized with aberrant electrical brain activity. Antioxidants are considered as promising neuroprotective strategies for epileptic condition via combating the deleterious effects of excessive ROS production in mitochondria. In this review, we provide a brief discussion of the role of mitochondrial oxidative stress in the pathophysiology of epilepsy and evidences that support neuroprotective roles of antioxidants targeting mitochondrial oxidative stress including mitochondria-targeted antioxidants, polyphenols, vitamins, thiols, and nuclear factor E2-related factor 2 (Nrf2) activators in epilepsy. We point out these antioxidative compounds as effectively protective approaches for improving prognosis. In addition, we specially propose that these antioxidants exert neuroprotection against epileptic impairment possibly by modulating cell death interactions, notably autophagy-apoptosis, and autophagy-ferroptosis crosstalk.