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Abstract: The mitogen-activated protein kinase organizer 1 (Morg1) has been recently identified as modular scaffold regulating ERK signaling. Morg1 also attenuates expression of the hypoxia-inducible factor-1α (HIF-1α) by activating or stabilizing of prolyl-hydroxylase 3 (PHD3). Here we demonstrate for the first time that Morg1 is expressed in the human brain in neurons, glial cells, and blood vessel walls. Immunohistochemistry, RT real-time PCR and western blotting indicated that Morg1 expression is reduced in human brain tissue with ischemic damage. Moreover, reactive astrocytes in the surrounding brain tissue showed strong Morg1 expression. Since hypoxic adaptation with enhancing HIF-1α expression can engage a genetic program leading to profound sparing of brain tissue and enhanced recovery of function, down-regulation of Morg1 expression in the ischemic brain may be viewed as an intrinsic mechanism to stimulate this response. On the other hand, upregulation of Morg1 in astrocytes surrounding the penumbra may counteract this hypoxic adaptation. [Copyright &y& Elsevier]

Abstract: The multitargeted tyrosine-kinase inhibitor sunitinib is a highly effective anti-angiogenic and cytostatic agent in the therapy of various tumours. While malignant gliomas have been shown to be responsive to sunitinib, detailed studies analysing human meningiomas are missing. We therefore analysed the effects of sunitinib in two benign (BenMen-1, HBL52) and two malignant (IOMM-Lee, KT21MG) human meningioma cell lines and found that DNA synthesis was significantly (p ⩽0.001) inhibited following 1, 2 or 5μM sunitinib, with IC50 values between 2 and 5μM in all cell lines. This effect was associated with a G2M-arrest at 10μM for BenMen-1, HBL52 and IOMM-Lee, and 20μM in KT21MG cells. Nuclear bisbenzimide staining revealed chromatin condensation following treatment with sunitinib concentrations of 10μM or higher. Corresponding, cell viability assays showed a significant (p ⩽0.001) short term decrease of viable cells (24h) only for high sunitinib concentrations with IC50-values between 10 and 20μM. However, pre-irradiated meningioma cells (5Gy) showed a sensitivity shift towards IC50-values around 5μM sunitinib. We also found that 5μM strongly reduced meningioma cell migration in vitro. Western blot analyses showed abolished platelet derived growth factor receptor (PDGFR)-autophosphorylation after sunitinib. Interestingly, the drug also inhibited the autophosphorylation of the receptor tyrosine kinase fms-like tyrosine kinase 3 (Flt3) in a dose-dependent manner. Taken together, the present data show that micromolar sunitinib has strong cytostatic and anti-migratory effects on human meningioma cells. [Copyright &y& Elsevier]

microRNAs (miRNAs) are small non-coding RNA-molecules that influence translation by binding to the target gene mRNA. Many miRNAs are found in nested arrangements within larger protein-coding host genes. miRNAs and host genes in a nested arrangement are often transcribed simultaneously, which may indicate that both have similar functions. miRNAs have been implicated in regulating defense responses against pathogen infection in C. elegans and in mammals. Here, we asked if miRNAs in nested arrangements and their host genes are involved in the C. elegans response against infection with Bacillus thuringiensis (Bt). We performed miRNA sequencing and subsequently focused on four nested miRNA-host gene arrangements for a functional genetic analysis. We identified mir-58.1 and mir-2 as negative regulators of C. elegans resistance to Bt infection. However, we did not find any miRNA/host gene pair in which both contribute to defense against Bt. [Display omitted] • 12% of C. elegans miRNA genes are significantly differentially expressed after B. thuringiensis (Bt) infection. • 50% of downregulated miRNAs are nested within a similarly downregulated host gene. • Loss of mir-58.1 and mir-2 leads to enhanced resistance to Bt. • Loss of the miRNA host genes ppfr-1 and pmp-5 leads to susceptibility to Bt. • miRNAs and their host genes likely act independently in nematode defense against Bt. [ABSTRACT FROM AUTHOR]