Common Signaling Pathways Research Articles

MKK7 deficiency in mature neurons impairs parental behavior in mice.

c‐Jun N‐terminal kinases (JNKs) are constitutively activated in mammalian brains and are indispensable for their development and neural functions. MKK7 is an upstream activator of all JNKs. However, whether the common JNK signaling pathway regulates the brain's control of social behavior remains unclear. Here, we show that female mice in which Mkk7 is deleted specifically in mature neurons (Mkk7flox/floxSyn‐Cre mice) give birth to a normal number of pups but fail to raise them due to a defect in pup retrieval. To explore the mechanism underlying this abnormality, we performed comprehensive behavioral tests. Mkk7flox/floxSyn‐Cre mice showed normal locomotor functions and cognitive ability but exhibited depression‐like behavior. cDNA microarray analysis of mutant brain revealed an altered gene expression pattern. Quantitative RT‐PCR analysis demonstrated that mRNA expression levels of genes related to neural signaling pathways and a calcium channel were significantly different from controls. In addition, loss of neural MKK7 had unexpected regulatory effects on gene expression patterns in oligodendrocytes. These findings indicate that MKK7 has an important role in regulating the gene expression patterns responsible for promoting normal social behavior and staving off depression.

Abstract 15092: The Yin-yang of Bmpr2 and Ces1 in the Pulmonary Endothelium Aad Its Role in Pulmonary Arterial Hypertension

Background/Hypothesis: Pulmonary Arterial Hypertension (PAH) is a life-threatening disease characterized by loss of pulmonary microvessels and vascular remodeling. Loss of function BMPR2 mutations contribute to pulmonary endothelial cell (EC) apoptosis and oxidative stress, but their reduced penetrance suggests need for additional modifiers. Carboxylesterase1 (CES1) is endoplasmic reticulum (ER) enzyme responsible for detoxification, proteostasis, and redox balance. Similar to BMPR2 mutations, we found that loss of CES1 is associated with oxidative stress and apoptosis. In this study, we explore a plausible link between BMPR2 pathway and CES1 regulation in promoting EC survival and angiogenesis. Methods: PECs & lung tissue from healthy donors and PAH patients were obtained from PHBI. To induce oxidative stress, we used H 2 O 2 (100 μM) & methamphetamine HCl (METH, 0.5-2mM). Both siRNA and pharmacological approaches were used to inhibit BMPR2, Nrf2, and CES1 expression. Caspase and Matrigel assays were used to assess PEC survival and tube formation, respectively. Results: RNAseq of BMPR2-mutant PECs showed significantly less CES1 expression, which correlated with reduced protein expression in PEC lysates and within lung vascular lesions. In healthy PECs, BMP9 stimulation led to increase in CES1 expression that was absent post BMPR2 knockdown. CES1 gene transcription was by BMPR2-dependent activation of Nrf2, a transcription factor responsible for antioxidant gene expression and mitochondrial biogenesis. Inhibition of Nrf2 activation by ML385 (5μM) abrogates BMP9 induced CES1 mRNA levels similar to BMPR2 knockdown. The connection between BMPR2 and CES1 was further strengthened by CES1 knockdown studies in PECs that demonstrated reduction in BMPR2 protein synthesis associated with ER stress and reduced autophagy. Finally, lung examination in CRISPR generated CES1 +/- mice demonstrated increased microvascular muscularization at normoxia compared to wild type mice. Conclusion: BMPR2 and CES1 are part of common signaling pathway that protects PECs against oxidative stress and mitochondrial damage through a positive feedback loop. Interventions that restore CES1 activity could rescue BMPR2 signaling and serve as novel PAH therapeutics.

TAMI-32. TEMPOROSPATIAL INVASION AND GENETIC EVOLUTION FROM INFRATENTORIAL TO SUPRATENTORIAL COMPARTMENT IN DIFFUSE MIDLINE GLIOMA

Abstract Diffuse midline gliomas (DMGs) are very aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 tumor foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3 K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of K27 tri-methylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-Myc, SOX2, p65/p50 NF-kB and STAT3 transcription factors, EGFR, FGFR2, PDGFRa/b and MET receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-Src in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis allowed spatiotemporal modeling of tumor progression and identified two general pathways of supratentorial invasion, and a multitude of migratory subpopulations within the infratentorial compartment. It also delineated common signaling pathways and potential therapeutic targets, revealing an unsuspected activation of a multitude of oncogenic pathways that may explain the resistance of DMG to current therapies.

Targeting fibroblast growth factor 23-responsive pathways uncovers controlling genes in kidney mineral metabolism

Fibroblast Growth Factor 23 (FGF23) is a bone-derived hormone that reduces kidney phosphate reabsorption and 1,25(OH)2 vitamin D synthesis via its required co-receptor alpha-Klotho. To identify novel genes that could serve as targets to control FGF23-mediated mineral metabolism, gene array and single-cell RNA sequencing were performed in wild type mouse kidneys. Gene array demonstrated that heparin-binding EGF-like growth factor (HBEGF) was significantly up-regulated following one-hour FGF23 treatment of wild type mice. Mice injected with HBEGF had phenotypes consistent with partial FGF23-mimetic activity including robust induction of Egr1, and increased Cyp24a1 mRNAs. Single cell RNA sequencing showed overlapping HBEGF and EGF-receptor expression mostly in the proximal tubule, and alpha-Klotho expression in proximal and distal tubule segments. In alpha-Klotho-null mice devoid of canonical FGF23 signaling, HBEGF injections significantly increased Egr1 and Cyp24a1 with correction of basally elevated Cyp27b1. Additionally, mice placed on a phosphate deficient diet to suppress FGF23 had endogenously increased Cyp27b1 mRNA, which was rescued in mice receiving HBEGF. In HEK293 cells with stable alpha-Klotho expression, FGF23 and HBEGF increased CYP24A1 mRNA expression. HBEGF, but not FGF23 bioactivity was blocked with EGF-receptor inhibition. Thus, our findings support that the paracrine/autocrine factor HBEGF could play novel roles in controlling genes downstream of FGF23 via targeting common signaling pathways.

MicroRNA-145 targets in cancer and the cardiovascular system: evidence for common signaling pathways.

miRNAs are small regulatory RNAs which govern gene expression post-transcriptionally by primarily binding to the 3'-UTR of mRNA target genes. miR-145 is a well-studied miRNA that has been implicated in controlling a range of biological processes. miR-145 is expressed in a variety of tissues and cell types and acts as a tumor-suppressor by regulating target gene signaling pathways involved in different aspects of tumor growth and progression. There is also strong evidence that highlights the important functions of miR-145 in the cardiovascular system. Here, we review the mechanisms of miR-145 in tumorigenesis and cancer progression and compare and contrast with the roles of miR-145 in cardiovascular development and disease. We discuss the important targets of miR-145 in cancer and their possible link to the cardiovascular system.

RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD.

The receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients. We measured airway inflammation and AHR in wild-type, RAGE-/- , TLR4-/- and TLR4-/- RAGE-/- mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients. RAGE-/- mice were protected against CS-induced neutrophilia and AHR. In contrast, TLR4-/- mice were not protected against CS-induced neutrophilia and had more severe CS-induced AHR. TLR4-/- RAGE-/- mice were not protected against CS-induced neutrophilia but were partially protected against CS-induced mediator release and AHR. Current smoking was associated with significantly lower AGER and TLR4 expression irrespective of COPD status, possibly reflecting negative feedback regulation. However, consistent with preclinical findings, AGER expression correlated with higher sputum neutrophil counts and more severe AHR in COPD patients. TLR4 expression did not correlate with neutrophilic inflammation or AHR. Inhibition of RAGE but not TLR4 signalling may protect against airway neutrophilia and AHR in COPD.

Advances in intervention methods and brain protection mechanisms of in situ and remote ischemic postconditioning.

Ischemic postconditioning (PostC) conventionally refers to a series of brief blood vessel occlusions and reperfusions, which can induce an endogenous neuroprotective effect and reduce cerebral ischemia/reperfusion (I/R) injury. Depending on the site of adaptive ischemic intervention, PostC can be classified as in situ ischemic postconditioning (ISPostC) and remote ischemic postconditioning (RIPostC). Many studies have shown that ISPostC and RIPostC can reduce cerebral IS injury through protective mechanisms that increase cerebral blood flow after reperfusion, decrease antioxidant stress and anti-neuronal apoptosis, reduce brain edema, and regulate autophagy as well as Akt, MAPK, PKC, and KATP channel cell signaling pathways. However, few studies have compared the intervention methods, protective mechanisms, and cell signaling pathways of ISPostC and RIPostC interventions. Thus, in this article, we compare the history, common intervention methods, neuroprotective mechanisms, and cell signaling pathways of ISPostC and RIPostC.

Identification of common signatures in idiopathic pulmonary fibrosis and lung cancer using gene expression modeling

BackgroundIdiopathic pulmonary fibrosis (IPF) is associated with an increased risk for lung cancer, but the underlying mechanisms driving malignant transformation remain largely unknown. This study aimed to identify differentially expressed genes (DEGs) distinguishing IPF and lung cancer from healthy individuals and common genes driving the transformation from healthy to IPF and lung cancer.MethodsThe gene expression data for IPF and non-small cell lung cancer (NSCLC) were retrieved from the Gene Expression Omnibus (GEO) database. The DEG signatures were identified via unsupervised two-way clustering (TWC) analysis, supervised support vector machine analysis, dimensional reduction, and mutual exclusivity analysis. Gene enrichment and pathway analyses were performed to identify common signaling pathways. The most significant signature genes in common among IPF and lung cancer were further verified by immunohistochemistry.ResultsThe gene expression data from GSE24206 and GSE18842 were merged into a super array dataset comprising 86 patients with lung disorders (17 IPF and 46 NSCLC) and 51 healthy controls and measuring 23,494 unique genes. Seventy-nine signature DEGs were found among IPF and NSCLC. The peroxisome proliferator-activated receptor (PPAR) signaling pathway was the most enriched pathway associated with lung disorders, and matrix metalloproteinase-1 (MMP-1) in this pathway was mutually exclusive with several genes in IPF and NSCLC. Subsequent immunohistochemical analysis verified enhanced MMP1 expression in NSCLC associated with IPF.ConclusionsFor the first time, we defined common signature genes for IPF and NSCLC. The mutually exclusive sets of genes were potential drivers for IPF and NSCLC.

Chemokine CXCL14 acts as a potential genetic target for liver fibrosis

There are multiple causes of liver fibrosis, common ones include ethanol, toxins, and cholestasis. However, whether these different etiologies lead to the same pathological outcomes contain common genetic targets or signaling pathways, the current research has not attracted widespread attention. GSE40041 and GSE55747 were downloaded from the Gene Expression Omnibus (GEO) database. GSE40041 and GSE55747 represent the differential expression profiles in the liver of mice with bile duct ligation (BDL) and carbon tetrachloride (CCl4) induced liver fibrosis models, respectively. By using GEO2R, 701 differential expression genes (DEGs) in GSE40041 and 6540 DEGs in GSE55747 were identified. 260 co-DEGs were shared and extracted for gene ontology (GO) analysis. Through GO analysis, it was found that the regulation of cell migration in biological processes (BPs) was closely related to the pathogenesis of liver fibrosis, and the genes involved in this process include a key gene, chemokine (C-X-C motif) ligand 14 (CXCL14). Subsequently, further bioinformatic analysis showed that CXCL14 may be regulated by miR-122 to participate in the progression of liver fibrosis. Then real-time PCR and western blotting were performed to validate the expression of CXCL14 in liver tissue after liver fibrosis caused by different etiologies (ethanol, CCl4). The expression of CXCL4 in liver fibrosis induced by BDL was verified in another GEO dataset. Basically consistent with our bioinformatics results, our experimental results showed that the expression of CXCL14 was most significantly increased in alcoholic liver fibrosis model, followed by CCl4-induced liver fibrosis, which was also significantly increased in the BDL-induced model. Thus, CXCL14 can act as a common potential genetic target for different liver fibrosis diseases.

Correlation between the coexpression of zinc finger and SCAN domain-containing protein 31 and transcriptional activator with PDZ-binding motif and prognosis in hepatocellular carcinoma.

BackgroundTranscriptional coactivator with PDZ binding motif (TAZ) regulates multiple biological processes and has been found to be related to hepatocellular carcinoma (HCC). However, common signaling pathways downstream after TAZ knockdown may also be important.MethodsTAZ was knocked down in an HCC cell line, and its potential target genes were analyzed. A decrease in the expression of zinc finger and SCAN domain-containing protein 31 (ZSCAN31) was observed. The difference in ZSCAN31 expression was evaluated, and its effect on survival in HCC patients who received surgical resection was determined.ResultsZSCAN31 was over-expressed in HCC tissues and was associated with low overall survival (OS) in HCC patients after surgical resection. Analysis of tissue samples from 83 HCC patients who underwent surgical resection in our hospital produced similar results. High ZSCAN31 expression was significantly associated with tumor size. High expression levels of both TAZ and ZSCAN31 were related to poor OS. A positive correlation was identified between ZSCAN31 expression and TAZ expression, and the protein binding of ZSCAN31 and TAZ was confirmed by co-immunoprecipitation (Co-IP) assay using an HCC cell line.ConclusionsZSCAN31 is associated with TAZ expression in HCC cells, and the targeting of ZSCAN31 and TAZ may represent a novel therapeutic approach in HCC.

FMO1 Is Involved in Excess Light Stress-Induced Signal Transduction and Cell Death Signaling.

Because of their sessile nature, plants evolved integrated defense and acclimation mechanisms to simultaneously cope with adverse biotic and abiotic conditions. Among these are systemic acquired resistance (SAR) and systemic acquired acclimation (SAA). Growing evidence suggests that SAR and SAA activate similar cellular mechanisms and employ common signaling pathways for the induction of acclimatory and defense responses. It is therefore possible to consider these processes together, rather than separately, as a common systemic acquired acclimation and resistance (SAAR) mechanism. Arabidopsis thaliana flavin-dependent monooxygenase 1 (FMO1) was previously described as a regulator of plant resistance in response to pathogens as an important component of SAR. In the current study, we investigated its role in SAA, induced by a partial exposure of Arabidopsis rosette to local excess light stress. We demonstrate here that FMO1 expression is induced in leaves directly exposed to excess light stress as well as in systemic leaves remaining in low light. We also show that FMO1 is required for the systemic induction of ASCORBATE PEROXIDASE 2 (APX2) and ZINC-FINGER OF ARABIDOPSIS 10 (ZAT10) expression and spread of the reactive oxygen species (ROS) systemic signal in response to a local application of excess light treatment. Additionally, our results demonstrate that FMO1 is involved in the regulation of excess light-triggered systemic cell death, which is under control of LESION SIMULATING DISEASE 1 (LSD1). Our study indicates therefore that FMO1 plays an important role in triggering SAA response, supporting the hypothesis that SAA and SAR are tightly connected and use the same signaling pathways.

Mechanistic targets for BPH and prostate cancer-a review.

All men, almost, suffer from prostatic disorders in average life expectancy. In the year of 1950s, the first autopsy of prostate gland discovered the link between Benign prostatic hyperplasia (BPH) and Prostate Cancer (PCa). After that, many histology, biochemistry, epidemiology studies explained the association and associated risk factor for the same. From the various scientific evidence, it is proved that both diseases share some common transcription factors and signalling pathways. Still, BPH cannot be considered as the first step of PCa progression. To define, the relationship between both of the diseases, a well-defined large epidemiological study is needed. Along with androgen signalling, imbalanced apoptosis, oxidative stress, and microbial infection also crucial factors that significantly affect the pathogenesis of BPH. Various signalling pathways are involved in the progression of BPH. Androgen signalling is the driving force for the progress of PCa. In PCa androgen signalling is upregulated as compared to a healthy prostate. Some dominant Androgen-regulated genes and their functions have been discussed in this work.

Differential expression of microRNAs and their target genes in cervical intraepithelial neoplasias of varying severity

Background.Currently, little is known about the specific microRNAs involved in the development of cervical intraepithelial neoplasia(CIN1, 2, 3) and the transition to cancer in situ (CIS). Our meta-analysis allowed us to isolate 8 microRNAs (hsa-miR-1246, hsa-miR-145-5p, hsa-miR-196b-5p, hsa-miR-34a-5p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-375-5p, hsa-miR-96-5p) with potential significance in the progression of precancerous diseases to cervical cancer.Objective:to analyze the expression features of hsa-miR-1246, hsa-miR-145-5p, hsa-miR-196b-5p, hsa-miR-34a-5p, hsa-miR-20a-5p,hsa-miR-21-5p, hsa-miR-375-5p, hsa-miR-96-5p and their target genes, as well as genes associated with them in common signaling pathways in the tissues of the cervix in patients with CIN1–3 and CIS.Materials and methods.To assess the expression level of microRNA and matrixRNA, the quantitative polymerase chain reaction in real time method was used. Data analysis was carried out in the Python programming language using the SciPy library. Search for target genes was performed using the TarPmiR algorithm and the overrepresentation of microRNAs in signaling pathways (Over-Representation Analysis) was analyzed. To identify genes associated with target genes in common signaling pathways, GIANT (Genome-scale Integrated Analysis of gene Networks in Tissues) and network integration with several associations algorithms were used.Results.For microRNAs miR-145, miR-196b, miR-34a, miR-20a, miR-21, miR-375 and miR-96 a decrease in expression was found in the subgroup of patients with CIS, while for 4 microRNAs (miR-145, miR-34a, miR-20a and miR-375), an increase in the expression level was found for CIN1, 2. The detected features of microRNA expression in subgroups of patients with CIN1–3 and CIS also affected the expression of their target genes (CDKN2A, MKI67, TOP2A and CD82), as well as the genes associated with them in common signaling pathways (PGK1, THBS4 (TSP4) and ECM1).Conclusion.Thus, the study revealed that each degree of CIN is characterized by its own specific molecular profile – the differential expression of microRNAs, their target genes and the genes associated with them in the general signaling pathways.

Morphological landscape of endothelial cell networks reveals a functional role of glutamate receptors in angiogenesis

Angiogenesis plays a key role in several diseases including cancer, ischemic vascular disease, and Alzheimer’s disease. Chemical genetic screening of endothelial tube formation provides a robust approach for identifying signalling components that impact microvascular network morphology as well as endothelial cell biology. However, the analysis of the resulting imaging datasets has been limited to a few phenotypic features such as the total tube length or the number of branching points. Here we developed a high content analysis framework for detailed quantification of various aspects of network morphology including network complexity, symmetry and topology. By applying our approach to a high content screen of 1,280 characterised drugs, we found that drugs that result in a similar phenotype share the same mechanism of action or common downstream signalling pathways. Our multiparametric analysis revealed that a group of glutamate receptor antagonists enhances branching and network connectivity. Using an integrative meta-analysis approach, we validated the link between these receptors and angiogenesis. We further found that the expression of these genes is associated with the prognosis of Alzheimer’s patients. In conclusion, our work shows that detailed image analysis of complex endothelial phenotypes can reveal new insights into biological mechanisms modulating the morphogenesis of endothelial networks and identify potential therapeutics for angiogenesis-related diseases.

Interleukin-6 Blocking vs. JAK-STAT Inhibition for Prevention of Lung Injury in Patients with COVID-19.

The severe respiratory insufficiency observed during COVID-19 infection may not be directly related to a cytopathogenic effect induced by the virus itself, but to an exaggerated and inappropriate immune response. In an effort to reduce the severity of organ dysfunction, including respiratory insufficiency, monoclonal antibodies (Mabs) that block the interleukin-6 receptor, such as tocilizumab, sarilumab, and siltuximab, are under investigation for the treatment of COVID-19. However, blocking of just one of the many cytokines involved in the inflammatory reaction may not slow down the magnitude of the process. Since timing is important, the immune deficiency induced by IL6 blockade at the late immunodeficiency phase of sepsis that follows the initial inflammatory response may be detrimental. Finally, monitoring the degree and duration of IL6 blockade may be challenging because of the long half-life of Mabs (2–3 weeks). Pro- and anti-inflammatory cytokines act through a common JAK-STAT signaling pathway, which can be inhibited by JAK-STAT inhibitors. Ruxolitinib, a tyrosine kinase inhibitor selective for JAK1, 2, blocks many pro- and anti-inflammatory cytokines including IL6. Ruxolitinib has favorable pharmacodynamics and an acceptable safety profile. The short half-life (4–6 h) of the drug offers the opportunity for ideal monitoring of the degree and duration of cytokine blocking, simply by the adjusting dose and duration of therapy. From a theoretical point of view, the balanced control of cytokine blockade throughout the course of the septic process should be the cornerstone of modern management. According to this hypothesis, maximization of blocking should be attempted at the phase of hyper-inflammation for preventing severe organ damage, while pro-inflammatory blockade should be minimized at the late phase of immunoparalysis for prevention of secondary infections. Based on the above considerations, we consider that the efficacy and safety of this drug deserves testing in the context of a controlled randomized trial.

Comparison of transcriptomic changes between zebrafish and mice upon high fat diet reveals evolutionary convergence in lipid metabolism

Hyperlipidemia is an abnormal elevation of lipid level in blood, which affects more than 100 million people in US. Zebrafish has recently emerged as a model to study pathophysiology associated with hyperlipidemia. As a poikilotherm, the innate response toward a high fat diet regimen in zebrafish is likely to be distinct from humans, and therefore, additional caution is warranted to appropriately interpret results obtained from zebrafish model. However, to date, detailed comparative analyses on similarities and dissimilarities between zebrafish and mammals, in particular, at molecular level, have not been reported yet. Here, we identified changes in hepatic specific transcriptomic profiles of zebrafish fed with a high fat diet regimen and comparatively analyzed transcriptomic changes in zebrafish and mice. While a number of previously identified risk factors for human hyperlipidemia has been upregulated in zebrafish fed with a high fat diet regimen, zebrafish hepatic transcriptome does not share high similarity with mice. Despite these differences, KEGG pathway analyses revealed that similar signaling pathways upregulated in zebrafish and mice as a response to a high fat diet. Our data show that these two species may utilize species-specific set of genes to upregulate common signaling pathways, indicating evolutionary convergence between poikilotherm and homeotherm in regulating lipid metabolism and validating the use of zebrafish as a model for human hyperlipidemia and associated diseases.

Parkinson's: A Disease of Aberrant Vesicle Trafficking.

Parkinson's disease (PD) is a leading cause of neurodegeneration that is defined by the selective loss of dopaminergic neurons and the accumulation of protein aggregates called Lewy bodies (LBs). The unequivocal identification of Mendelian inherited mutations in 13 genes in PD has provided transforming insights into the pathogenesis of this disease. The mechanistic analysis of several PD genes, including α-synuclein (α-syn), leucine-rich repeat kinase 2 (LRRK2), PTEN-induced kinase 1 (PINK1), and Parkin, has revealed central roles for protein aggregation, mitochondrial damage, and defects in endolysosomal trafficking in PD neurodegeneration. In this review, we outline recent advances in our understanding of these gene pathways with a focus on the emergent role of Rab (Ras analog in brain) GTPases and vesicular trafficking as a common mechanism that underpins how mutations in PD genes lead to neuronal loss. These advances have led to previously distinct genes such as vacuolar protein-sorting-associated protein 35 (VPS35) and LRRK2 being implicated in a common signaling pathway. A greater understanding of these common nodes of vesicular trafficking will be crucial for linking other PD genes and improving patient stratification in clinical trials underway against α-syn and LRRK2 targets.

Global activation of oncogenic pathways underlies therapy resistance in diffuse midline glioma

Diffuse midline gliomas (DMGs) are aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3-K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of H3-K27 trimethylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-MYC, SOX2, p65/p50 NF-κB and STAT3 transcription factors, EGFR, FGFR2, PDGFRα/β receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-SRC in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis revealed a complex spatiotemporal evolution in diffuse intrisic pontine glioma, recommending pontine and cerebellar biopsies for accurate populational genetic characterization, and delineated common signaling pathways and potential therapeutic targets. It also revealed an unsuspected activation of a multitude of oncogenic pathways, including cancer cell reprogramming, explaining the resistance of DMG to current therapies.

Microglia mediated neuroinflammation - signaling regulation and therapeutic considerations with special reference to some natural compounds.

Neuroinflammation plays a central role in multiple neurodegenerative diseases and neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemic injury etc. In this connection, microglia, the key players in the central nervous system, mediate the inflammatory response process. In brain injuries, activated microglia can clear the cellular debris and invading pathogens and release neurotrophic factors; however, prolonged microglia activation may cause neuronal death through excessive release of inflammatory mediators. Therefore, it is of paramount importance to understand the underlying molecular mechanisms of microglia activation to design an effective therapeutic strategy to alleviate neuronal injury. Recent studies have shown that some natural compounds and herbal extracts possess anti-inflammatory properties that may suppress microglial activation and ameliorate neuroinflammation and hence are neuroprotective. In this review, we will update some of the common signaling pathways that regulate microglia activation. Among the various signaling pathways, the Notch-1, mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) have been reported to exacerbate microglia mediated neuroinflammation that is implicated in different neuropathological diseases. The search for natural compounds or agents, specifically those derived from natural herbal extracts such as Gastrodin, scutellarin, RG1 etc. has been the focus of many of our recent studies because they have been found to regulate microglia activation. The pharmacological effects of these agents and their potential mechanisms for regulating microglia activation are systematically reviewed here for a fuller understanding of their biochemical action and therapeutic potential for treatment of microglia mediated neuropathological diseases.

Radio-Susceptibility of Nasopharyngeal Carcinoma: Focus on Epstein- Barr Virus, MicroRNAs, Long Non-Coding RNAs and Circular RNAs.

Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer. As a neoplastic disorder, NPC is a highly malignant squamous cell carcinoma that is derived from the nasopharyngeal epithelium. NPC is radiosensitive; radiotherapy or radiotherapy combining with chemotherapy are the main treatment strategies. However, both modalities are usually accompanied by complications and acquired resistance to radiotherapy is a significant impediment to effective NPC therapy. Therefore, there is an urgent need to discover effective radio-sensitization and radio-resistance biomarkers for NPC. Recent studies have shown that Epstein-Barr virus (EBV)-encoded products, microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), which share several common signaling pathways, can function in radio-related NPC cells or tissues. Understanding these interconnected regulatory networks will reveal the details of NPC radiation sensitivity and resistance. In this review, we discuss and summarize the specific molecular mechanisms of NPC radio-sensitization and radio-resistance, focusing on EBV-encoded products, miRNAs, lncRNAs and circRNAs. This will provide a foundation for the discovery of more accurate, effective and specific markers related to NPC radiotherapy. EBVencoded products, miRNAs, lncRNAs and circRNAs have emerged as crucial molecules mediating the radio-susceptibility of NPC. This understanding will improve the clinical application of markers and inform the development of novel therapeutics for NPC.