LHPP impedes energy metabolism by inducing ubiquitin-mediated degradation of PKM2 in glioblastoma.

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a new-found tumor suppressor in a variety of tumors. While, it is still unknown about its role in glioma. In this study, we found that LHPP is abnormally decreasing or absent in glioblastoma, and the low expression of LHPP is associated with poor median survival in glioma patients. Functional assay revealed that LHPP-overexpression significantly inhibited U87MG and U118MG growth in vitro and in vivo. As to the mechanism, mass-spectrometric analysis indicated that the LHPP interacting proteins were mainly enriched in regulation of energy metabolism, including Carbon metabolism, Oxidative phosphorylation, and Glycolysis. Seahorse assay and metabolites detection confirmed that LHPP-overexpression obviously impeded glycolysis and respiration in U87MG and U118MG cells. For the further study, western blot assay showed that the protein level of PKM2 at dimeric, tetrameric, and total protein, were all decreased significantly, and its enzymatic activity was decreased as well. ChIP and RNAseq integrated analysis indicated that the decreased protein level of PKM2 was independent of PKM2 transcription, and LHPP did not reprogram transcription level of metabolic genome. Co-IP and immunofluorescence assay manifested that LHPP interacted with PKM2, and this interaction interfered the protein stability, then induced ubiquitin-mediated degradation of PKM2. Rescue assay confirmed that restoring the expression of PKM2 effectively reversed the restrained energy metabolism and the inhibited cancer cell growth caused by LHPP-overexpression in U87MG and U118MG cells. Taking together, we demonstrated that LHPP impedes the glycolysis and respiration during energy metabolic process via inducing ubiquitin-mediated degradation of PKM2, thus inhibits the growth of glioblastoma.

Atypical extraventricular neurocytoma: A case report.

Atypical extraventricular neurocytoma (EVN) is a rare condition characterized by diffuse tumor cell hyperplasia, increased neovascularization, increased necrosis, and aggressive characteristics. A case of a 25-year old man who presented with atypical EVN in his left parietal - occipital flaps is reported. Magnetic resonance imaging (MRI) revealed a well-defined globular mass with heterogeneous signals in the left parietal lobe, and mild perilesional edema. After left parietal craniotomy and tumor excision, pathologic examination of the resected tissue revealed that the lesion was localized mainly in the white matter and imbued with tumor cells possessing round hyperchromatic nuclei with perinuclear halos and increased microvascular proliferation. The patient underwent radiotherapy at 21st postoperative day. Over the past 26 months, the patient has been regularly followed up, and so far no neurologic deficits have been observed. The latest MRI showed that the tumor bed was stable with slight peritumoral edema. The results of clinical, histopathological and immunohistochemical examinations indicate that atypical EVN is a rare neoplasm with unique radiographic and pathologic characteristics. It possesses more aggressive properties than typical EVN.

Store-operated Ca2+ channels blockers inhibit lipopolysaccharide induced astrocyte activation.

The destruction of calcium homeostasis is an important factor leading to neurological diseases. Store-operated Ca(2+) (SOC) channels are essential for Ca(2+) homeostasis in many cell types. However, whether SOC channels are involved in astrocyte activation induced by lipopolysaccharide (LPS) still remains unknown. In this study, we used LPS as an exogenous stimulation to investigate the role of SOC channels in astrocyte activation. Using calcium imaging technology, we first found that SOC channels blockers, 1-[h-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole (SKF-96365) and 2-aminoethyldiphenyl borate (2-APB), inhibited LPS induced [Ca(2+)]i increase, which prompted us to speculate that SOC channels may be involved in LPS induced astrocyte activation. Further experiments confirmed our speculation shown as SOC channels blockers inhibited LPS induced astrocyte activation characterized as cell proliferation by MTS and BrdU assay, raise in glial fibrillary acidic protein expression by immunofluorescence and Western Blot and secretion of interleukin 6 (IL-6) and interleukin 1ß (IL-1ß) by ELISA. So, our studies showed that SOC channels are involved in LPS-induced astrocyte activation.

ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation.

Neuregulin 1 (NRG1) is a trophic factor that acts by stimulating ErbB receptor tyrosine kinases and has been implicated in neural development and synaptic plasticity. In this study, we investigated mechanisms of its suppression of long-term potentiation (LTP) in the hippocampus. We found that NRG1 did not alter glutamatergic transmission at SC-CA1 synapses but increased the GABA(A) receptor-mediated synaptic currents in CA1 pyramidal cells via a presynaptic mechanism. Inhibition of GABA(A) receptors blocked the suppressing effect of NRG1 on LTP and prevented ecto-ErbB4 from enhancing LTP, implicating a role of GABAergic transmission. To test this hypothesis further, we generated parvalbumin (PV)-Cre;ErbB4(-/-) mice in which ErbB4, an NRG1 receptor in the brain, is ablated specifically in PV-positive interneurons. NRG1 was no longer able to increase inhibitory postsynaptic currents and to suppress LTP in PV-Cre;ErbB4(-/-) hippocampus. Accordingly, contextual fear conditioning, a hippocampus-dependent test, was impaired in PV-Cre;ErbB4(-/-) mice. In contrast, ablation of ErbB4 in pyramidal neurons had no effect on NRG1 regulation of hippocampal LTP or contextual fear conditioning. These results demonstrate a critical role of ErbB4 in PV-positive interneurons but not in pyramidal neurons in synaptic plasticity and support a working model that NRG1 suppresses LTP by enhancing GABA release. Considering that NRG1 and ErbB4 are susceptibility genes of schizophrenia, these observations contribute to a better understanding of how abnormal NRG1/ErbB4 signaling may be involved in the pathogenesis of schizophrenia.