Neuregulin-1 Fosters Supportive Interactions between Microglia and Neural Stem/Progenitor Cells

Microglia play diverse roles in homeostasis and pathology of the central nervous system (CNS). Their response to injury or insult is critical for initiating neuroinflammation and tissue damage as well as resolution of inflammation and wound healing. Changes to the microenvironment of microglia appear to be a key determinant of their phenotype and their role in the endogenous repair process in the injured or diseased CNS. Our recent findings have identified a positive role for neuregulin-1 (Nrg-1) in regulating immune response in spinal cord injury and focal demyelinating lesions. We show that increasing the tissue availability of Nrg-1 after injury can promote endogenous repair by modulating neuroinflammation. In the present study, we sought to elucidate the specific role of Nrg-1 in regulating microglial activity and more importantly their influence on the behavior of neural stem/progenitor cells (NPCs). Using injury-relevant in vitro systems, we demonstrate that Nrg-1 attenuates the expression of proinflammatory mediators in activated microglia. Moreover, we provide novel evidence that availability of Nrg-1 can restore the otherwise suppressed phagocytic ability of proinflammatory microglia. Interestingly, the presence of Nrg-1 in the microenvironment of proinflammatory microglia mitigates their inhibitory effects on NPC proliferation. Nrg-1 treated proinflammatory microglia also augment mobilization of NPCs, while they had no influence on their suppressive effects on NPC differentiation. Mechanistically, we show that Nrg-1 enhances the interactions of proinflammatory microglia and NPCs, at least in part, through reduction of TNF-α expression in microglia. These findings provide new insights into the endogenous regulation of microglia-NPC interactions and identify new potential targets for optimizing this important crosstalk during the regenerative process after CNS injury and neuroinflammatory conditions

Screening of a clinically and biochemically diagnosed SOD patient using exome sequencing: A case report with a mutations/variations analysis approach

Background: Sulfite oxidase deficiency (SOD) is a rare neurometabolic inherited disorder causing severe delay in developmental stages and premature death. The disease follows an autosomal recessive pattern of inheritance and causes deficiency in the activity of sulfite oxidase, an enzyme that normally catalyzes conversion of sulfite to sulfate. Aim of the study: SOD is an underdiagnosed disorder and its diagnosis can be difficult in young infants as early clinical features and neuroimaging changes may imitate some common diseases. Since the prognosis of the disease is poor, using exome sequencing as a powerful and efficient strategy for identifying the genes underlying rare mendelian disorders can provide important knowledge about early diagnosis, disease mechanisms, biological pathways, and potential therapeutic targets. Patients and methods: In this study, a case who was a newborn infant boy with suspected SOD and his healthy parents were recruited for exome sequencing. The first laboratory reports of the patient were positive urine sulfite, elevated urinary thiosulfate, and high levels of plasma lactate and pyruvate. The patient also presented some symptoms such as intractable seizures, abnormal tone, feeding difficulties, profound mental retardation, abnormal respiratory drive, aspiration pneumonia, microcephaly, and dislocated ocular lenses. The genomic DNA of the patient and his parents was extracted from peripheral blood lymphocytes as targets for exome sequencing, performed by Axeq Technologies (Amsterdam, the Netherlands). Results: The results showed no single predominate mutation in the SUOX gene as one of the candidate genes involved in the catabolism of sulfur-containing amino acids. The same results obtained in the molybdenum cofactor biosynthetic genes (MOCS1, MOCS2, and GEPH genes). Instead, the results revealed that causal variations are present in genes underlying in different biochemical pathways among which the sulfur metabolism, signaling and signal transduction, and transcription pathways are of higher importance. Conclusion: In this study, several classes of genes were introduced as candidate genes involved in SOD. However, further studies are necessary to examine the reported genes in more details on how these genes may relate to each other and contribute to the pathology of SOD disease

Association of CYP3A4 and CYP3A5 polymorphisms with Iranian breast cancer patients

Background: Polymorphisms of different gene have been reported to be associated with cancer including breast cancer. Hospitalization rate for breast cancer has increased over the years in Iran. Aim: The aim of this study was to examine whether polymorphisms in the CYP3A4 and CYP3A5 genes affect the risk of developing breast cancer. Subjects and methods: The genotype distribution and allele frequencies of four CYP3A4*1A, CYP3A4*1B, CYP3A5*1 and CYP3A5*3 single-nucleotide polymorphisms were determined in 250 subjects from the general population in Ahvaz city (southwest of Iran) including 200 healthy subjects and 50 individuals affected with breast cancer. Results and conclusion: The genotype frequency of CYP3A4*1A/*1A (A/A) in both case and control groups was 100%; however, there was no subject with either CYP3A4 * 1A/ * 1B (A/G) or CYP3A4*1B/*1B (G/G) genotype. For CYP3A5 gene, CYP3A5*3/*3mutant homozygote genotype frequency was found to be 99% (n = 198) and 98% (n = 49) in control and patient groups respectively. CYP3A5*1/*1 wild-type genotype was calculated to be 1% (n = 2) in the control group and 2% (n = 1) in the case group. No. CYP3A5*1/*3 heterozygote genotype was detected in the both groups. The results showed that there was no association between breast cancer, CYP3A5 (P-value = 0.561) and CYP3A4 allele distribution

Genotype and allelic frequencies of CYP2E1*5B polymorphism in the southwest population of Iran

Background: Cytochrome P450 2E1 (CYP2E1) is a main enzyme which plays a major role in activating and detoxifying many xenobiotics, carcinogens and drugs. Available studies suggest that CYP2E1 single nucleotide polymorphisms (SNPs) are involved in the risk of developing certain cancers after exposure to carcinogens. The purpose of the present study was to assess genotype and allele frequencies of polymorphic CYP2E1*5B in the Iranian population. Material and Methods: This study was performed on 200 healthy individuals (female: 100, male: 100) in medical laboratories of Ahvaz during 2011. The CYP2E1 *5B (rs3813867 G-1293C) assessment was carried out using PCR-RFLP method. The data were analyzed with ĸ2 and hardy-Weinberg Equation statistically methods. Results: The frequency of *1A/*1A (c1/c1), *1A/*5B (c1/c2) and *5B/*5B (c2/c2) genotypes was computed 97, 3 and 0 percent, respectively. The frequency of *1A (c1) and *5B (c2) alleles was computed 98.5 and 1.5 percent, respectively. No statistically significant difference was between two genders (p>0.05). Conclusion: The genotype distribution and allele frequencies of CYP2E1*5B polymorphism were similar to Turkish and some of the European populations. However, there are significant interethnic differences when the Iranian population is compared with the Eastern Asian, American and some of the European populations. The allelic distribution of this polymorphism did not vary with gender

An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate

International audienceOTX2 is a potent oncogene that promotes tumor growth in Group 3 medulloblastoma. However, the mechanisms by which OTX2 represses neural differentiation are not well characterized. Here, we perform extensive multiomic analyses to identify an OTX2 regulatory network that controls Group 3 medulloblastoma cell fate. OTX2 silencing modulates the repressive chromatin landscape, decreases levels of PRC2 complex genes and increases the expression of neurodevelopmental transcription factors including PAX3 and PAX6. Expression of PAX3 and PAX6 is significantly lower in Group 3 medulloblastoma patients and is correlated with reduced survival, yet only PAX3 inhibits self-renewal in vitro and increases survival in vivo. Single cell RNA sequencing of Group 3 medulloblastoma tumorspheres demonstrates expression of an undifferentiated progenitor program observed in primary tumors and characterized by translation/elongation factor genes. Identification of mTORC1 signaling as a downstream effector of OTX2-PAX3 reveals roles for protein synthesis pathways in regulating Group 3 medulloblastoma pathogenesis

Combined MEK and JAK/STAT3 pathway inhibition effectively decreases SHH medulloblastoma tumor progression

RNA sequencing of MEK inhibitor (selumetinib)-treated tumors reveals an upregulation of the JAK/STAT3 pathway, with combinatorial therapeutic strategies of JAK/STAT3 inhibitors and selumetinib investigated for the SHH subgroup of medulloblastoma