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Abstract: Adenovirus-mediated virotherapy is one of the promising therapeutic approaches for glioma treatment. However, its replication efficiency and specificity still failed to meet the requirements for clinical treatment. To improve the anti-tumor activity and specificity of oncolytic adenoviruses (OA), we applied multiple miRNA response elements (MREs) of miR-124, miR-128, miR-146b and miR-218, whose expressions were downregulated in glioma cells, to enable OA to be specific to glioma. Adenoviral E1A protein regulated by these 4 MREs (OA-4MREs) was shown to be highly expressed in glioma cells, but not in normal cells. The selective E1A expression led to glioma-specific replication and cytotoxicity of OA-4MREs. Animal experiments also showed that OA-4MREs exhibited improved anti-tumor activities for both subcutaneous and intracranial glioma xenografts, without significant toxicity to normal brain and liver tissues. Collectively, we demonstrated that oncolytic adenovirus, whose replication was regulated by MREs, may be promising biological agents for glioma treatment. [Copyright &y& Elsevier]

Since anoctamin 1 ANO1 ( TMEM16A) was found to be a molecular component of Ca2+-activated Cl− channels, its role in tumorigenesis has gained attention at a fast pace. ANO1 overexpression frequently occurs in the cancer tissues along with 11q13 chromosome amplification. Poor prognosis of many types of cancers has been closely correlated with ANO1 gene amplification and protein overexpression. ANO1 is now considered an excellent biomarker for certain cancers. Recent research suggests that it is the channel function of ANO1 that is involved in the tumorigenesis. However, how the overexpression of the functional ANO1 causes malignant transformation of tissues via signaling pathways, for example, MAPK remains to be investigated. Clarification of the reasons in future will avail to make ANO1 as a target for cancer treatment. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinases/Extracellular signal-regulated kinase (MAPK/ERK) pathway is essential for migration and invasion of malignant glioma. It is efficient to inhibit migration and invasion of glioma cells by targeting this pathway. Oleanolic acid (OA) has been well demonstrated to suppress survival, growth and angiogenesis of glioma cells. However, it is still unknown if OA affects the migration and invasion of glioma cells. We utilized U-87 MG glioma cell lines and primary glioma cells from patients to study the effect of OA on migration and invasion of glioma cells with multidisciplinary approaches. In this study, we found that OA significantly decreased the ability of glioma cells to migrate and invade. Epithelial-mesenchymal transition (EMT) of glioma cells was also suppressed by OA treatment. Furthermore, MAPK/ERK pathway was greatly inhibited in glioma cells under OA treatment. MAPK/ERK reactivation induced by a recombinant lentiviral vector, Lv-MEK, was able to rescue the inhibitory effect of OA on migration and invasion of glioma cells. Taken together, we provided evidences that OA was a MAPK/ERK pathway-targeting anti-tumor agent. Although the concentrations we used exceeded its physiological level, OA may be used to prevent migration and invasion of glioma cells by developing its derivatives with enhanced bioactivity. [ABSTRACT FROM AUTHOR]

Cerebral ischemic stroke may cause a number of adverse neurological complications or behavioral disorders. Moreover, cerebral ischemic stroke is a prevalent disease with limited treatment strategies and may increase chances of developing neurodegenerative diseases, e.g., Alzheimer's disease, in the future. Therefore, alternative strategies are highly needed for improving the therapy for ischemic stroke. Human bone marrow stroma stem cells, also known as mesenchymal stem cells (hMSC), have a demonstrative role in treating transient cerebral ischemia, yet whether immortalized hMSC may have a better effect than hMSC is unknown. Here, we addressed this question. A rat cerebral ischemia reperfusion (IR) model was used to compare the effects of hMSC and an immortalized hMSC by human telomerase reverse transcriptase (hMSC-TERT). We found that both hMSC and hMSC-TERT similarly attenuated the elevation of serum neuron specific enolase levels after IR. Transplantation with hMSC alleviated cerebral infarction, alleviated brain edema, improved neural function, and reduced brain cell apoptosis, in a significantly better degree than transplantation with hMSC. Thus, these data suggest that immortalized hMSC may have an advantage over hMSC in treatment of transient cerebral ischemia. [ABSTRACT FROM AUTHOR]

Yangmai-13 (YM13) is a wheat cultivar with weak gluten fractions. In contrast, Zhenmai-168 (ZM168) is an elite wheat cultivar known for its strong gluten fractions and has been widely used in a number of breeding programs. However, the genetic mechanisms underlying the gluten signatures of ZM168 remain largely unclear. To address this, we combined RNA-seq and PacBio full-length sequencing technology to unveil the potential mechanisms of ZM168 grain quality. A total of 44,709 transcripts were identified in Y13N (YM13 treated with nitrogen) and 51,942 transcripts in Z168N (ZM168 treated with nitrogen), including 28,016 and 28,626 novel isoforms in Y13N and Z168N, respectively. Five hundred and eighty-four differential alternative splicing (AS) events and 491 long noncoding RNAs (lncRNAs) were discovered. Incorporating the sodium-dodecyl-sulfate (SDS) sedimentation volume (SSV) trait, both weighted gene coexpression network analysis (WGCNA) and multiscale embedded gene coexpression network analysis (MEGENA) were employed for network construction and prediction of key drivers. Fifteen new candidates have emerged in association with SSV, including 4 transcription factors (TFs) and 11 transcripts that partake in the post-translational modification pathway. The transcriptome atlas provides new perspectives on wheat grain quality and would be beneficial for developing promising strategies for breeding programs. [ABSTRACT FROM AUTHOR]

Background: EGFR is an important signal involved in tumor growth that can induce tumor metastasis and drug resistance. Exploring targets for effective EGFR regulation is an important topic in current research and drug development. Inhibiting EGFR can effectively inhibit the progression and lymph node metastasis of oral squamous cell carcinoma (OSCC) because OSCC is a type of cancer with high EGFR expression. However, the problem of EGFR drug resistance is particularly prominent, and identifying a new target for EGFR regulation could reveal an effective strategy. Methods: We sequenced wild type or EGFR-resistant OSCC cells and samples from OSCC patients with or without lymph node metastasis to find new targets for EGFR regulation to effectively replace the strategy of directly inhibiting EGFR and exert an antitumor effect. We then investigated the effect of LCN2 on OSCC biological abilities in vitro and in vivo through protein expression regulation. Subsequently, we elucidated the regulatory mechanism of LCN2 through mass spectrometry, protein interaction, immunoblotting, and immunofluorescence analyses. As a proof of concept, a reduction-responsive nanoparticle (NP) platform was engineered for effective LCN2 siRNA (siLCN2) delivery, and a tongue orthotopic xenograft model as well as an EGFR-positive patient-derived xenograft (PDX) model were applied to investigate the curative effect of siLCN2. Results: We identified lipocalin-2 (LCN2), which is upregulated in OSCC metastasis and EGFR resistance. Inhibition of LCN2 expression can effectively inhibit the proliferation and metastasis of OSCC in vitro and in vivo by inhibiting EGFR phosphorylation and downstream signal activation. Mechanistically, LCN2 binds EGFR and enhances the recycling of EGFR, thereby activating the EGFR-MEK-ERK cascade. Inhibition of LCN2 effectively inhibited the activation of EGFR. We translated this finding by systemic delivery of siLCN2 by NPs, which effectively downregulated LCN2 in the tumor tissues, thereby leading to a significant inhibition of the growth and metastasis of xenografts. Conclusions: This research indicated that targeting LCN2 could be a promising strategy for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

Purpose: Aplysin, a natural brominate compound from marine organisms, has been demonstrated to exhibit anti-tumor activity, mainly by inducing apoptosis and cell cycle arrest. However, its effect on glioma is still unknown. In this study, we evaluated the effects of aplysin on the malignant properties of glioma cells and its enhancing effect on temozolomide (TMZ) action against drug-resistant glioma cell lines. Methods: We employed several human glioma cell lines and primary glioma cells to address this issue with multidisciplinary approaches. Results: The combined application of aplysin and TMZ significantly sensitizes glioma cells to TMZ action, compared with TMZ alone. miRNA profile analysis revealed that the abundance of miR-181, an important glioma tumor suppressors believed to enhance TMZ effect, was greatly elevated in aplysin-treated glioma cell lines. The aplysin-induced TMZ sensitivity is dependent on MEK1 in glioma cells. Overexpression of MEK1 was able to abolish the effect of aplysin on glioma cells. Conclusions: We found that aplysin can enhance the effect of TMZ on glioma cells by increasing miR-181 expression. [ABSTRACT FROM AUTHOR]

N The cell colony formation assay showed that the colony formation of OSCC cells increased signifcantly when LCN2 was overexpressed. F The cell colony formation test showed that after inhibiting LCN2 in ER-resistant cells, the colony formation of OSCC cells decreased signifcantly. [Extracted from the article]

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s00280-020-04166-1. [ABSTRACT FROM AUTHOR]

Persistent neuropathic pain (NP) causes future development of neurodegenerative diseases, e.g., Alzheimer' disease, and thus needs to be optimally treated. Surgically-induced neuropathic pain (SNPP) is a persistent pain that occurs in nearly half of the individuals after common operations. Here, we showed that specific activation of 5-hydroxytryptamine (5-HT) type 2A receptors by systemic administration of TCB-2 [(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide] improved the function of potassium chloride cotransporter 2 (KCC2), resulting in reduction in neuropathic pain after chronic constriction injury (CCI), a rat model that mimics SNPP. Moreover, TCB-2 administration attenuated both mechanical and thermal hyperalgesia, likely through augmentation of dorsal horn KCC2 levels, since this effect was abolished by intrathecal provision of dihydroindenyl oxy alkanoic acid (DIOA), which blocked the effects of KCC2. Furthermore, TCB-2-mediated re-activation of KCC2 likely reduces future development of neurodegeneration in rats. Together, our data support further studies on the possibility of using this strategy to reduce postoperative pain and future neurodegenerative disorders in clinic. [ABSTRACT FROM AUTHOR]

Background An uncommon disorder, adult-onset leukoencephalopathy with calcifications and cysts (ALCC) has been recognized clinically for approximately a decade. Its typical radiologic signs and pathologic characteristics have been investigated thoroughly and described fully in a series of cases. However, little attention has focused on the propensity of hemorrhage in this entity, and the etiology of cyst occurrence in ALLC remains uncertain. To the best of our knowledge, there is a lack of relevant articles addressing the relationship between hemorrhage and cyst development in ALCC. Case Description A 30-year-old woman presented with headache, diminishing eyesight, and face numbness over the course of 16 months. Repeat radiologic examination showed the formation of a new cyst and the enlargement of former cyst after hemorrhage. She was diagnosed formerly with ALCC with the triad of leukoencephalopathy, calcifications, and cyst in imaging. Staging gross total resections of cyst were achieved with neurologic improvement postoperatively. Histologic examination revealed angiomatous vessels, Rosenthal fiber formation, microcalcification, and deposits of hemosiderin, and ALCC was confirmed pathologically. Conclusions After analyzing the clinical data about the hemorrhage and cysts in our case and all 15 reported ALCC cases in the literature, we conclude that intermittent hemorrhage and cysts development are 2 outstanding features for ALCC and that hemorrhage is a probable mechanism for the formation and expansion of cyst. [ABSTRACT FROM AUTHOR]

Highlights: [•] 7,8-DHF as a selective TrkB agonist is neuroprotective. [•] 7,8-DHF has been proved to have antioxidant activity. [•] 7,8-DHF could protect PC12 cells against 6-OHDA-induced toxicity. [•] The protection by 7,8-DHF is due to eliminating ROS and improving SOD activity. [ABSTRACT FROM AUTHOR]

Aberrant expression of microRNAs hae been shown to be closely associated with glioblastoma cell proliferation, apoptosis and drug resistance. However, mechanisms underlying the role of mcroRNAs in glioblastoma cell growth and apoptosis are not fully understood. In this study, we report that miR-503 is overexpressed in glioblastoma tissue compared with normal human brain tissue. Mechanistically, miR-503 can be induced by TGF-β1 at the transcriptional level by binding the smad2/3 binding elements in the promoter. Ectopic overexpression of miR-503 promotes cell growth and inhibits apoptosis by targeting PDCD4. In contrast, inhibition of miR-503 reduces cell growth. Furthermore, miR-503 inhibitor augments the growth inhibitory effect of temozolomide in glioblastoma cells. These results establish miR-503 as a promising molecular target for glioblastoma therapy. [ABSTRACT FROM AUTHOR]