N 6 -Methyladenosine (m6A) is the most prevalent internal modification that occurs in the mRNA of eukaryotes and plays a vital role in the post-transcriptional regulation. Recent studies highlighted the biological significance of m6A modification in the nervous system, and its dysregulation has been shown to be related to degenerative and neurodevelopmental diseases. Parkinson's disease (PD) is a common age-related neurological disorder with its pathogenesis still not fully elucidated. Reports have shown that epigenetic mechanisms including DNA methylation and histone acetylation, which alter gene expression, are associated with PD. In this study, we found that global m6A modification of mRNAs is down-regulated in 6-OHDA-induced PC12 cells and the striatum of PD rat brain. To further explore the relationship between m6A mRNA methylation and molecular mechanism of PD, we decreased m6A in dopaminergic cells by overexpressing a nucleic acid demethylase, FTO, or by m6A inhibitor. The results showed that m6A reduction could induce the expression of N-methyl-D-aspartate (NMDA) receptor 1, and elevate oxidative stress and Ca 2+ influx, resulting in dopaminergic neuron apoptosis. Collectively, m6A modification may play a vital role in the death of dopaminergic neuron, which provides a novel view of mRNA methylation to understand the epigenetic regulation of Parkinson's disease.
Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a derivate of dopamine, is suspected to be the most probable neurotoxin in the degeneration of dopaminergic neurons. Numerous hypotheses regarding its pathophysiological roles have been raised, especially related to Parkinson's disease and alcohol addiction. In the mammalian brain, salsolinol may be enzymatically synthesized by salsolinol synthase from dopamine and acetaldehyde. However, the direct evidence of its biosynthesis was still missing. In this study, we purified salsolinol synthase from rat brain by a systematical procedure involving acid precipitation, ultrafiltration, and hydrophilic interaction chromatography. The molecular weight of salsolinol synthase determined by MALDI-TOF MS is 8622.29 Da, comprising 77 amino acids (MQIFVKTLTG KTITLEVEPS DTIKNVKAKI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN IQKKSTLHLV LRLRVDY). Homology analysis showed that the enzyme is a ubiquitin-like protein, with a difference of four amino acids, which suggests it is a novel protein. After it was overexpressed in eukaryotic cells, the production of salsolinol was significantly increased as compared with control, confirming the catalytic function of this enzyme. To our knowledge, it is the first systematic purification and sequencing of salsolinol synthase. Together, this work reveals a formerly anonymous protein and urges further exploration of its possible prognostic value and implications in Parkinson's disease and other related disorders.
Background There is an urgent need for targeted biological therapies for prostate cancer with greater efficacy and less toxicity, particularly for metastatic disease, where current therapies are not curative. Therapeutic adenoviral vectors or oncolytic adenoviruses offer the possibility of a competent, nontoxic therapeutic alternative for prostate cancer. However, free viral particles must be delivered locally, an approach that does not address metastatic disease, and they display poor tumor penetration. To fully exploit the potential of these vectors, we must develop methods that improve intratumoral dissemination and allow for systemic delivery. This study establishes a proof-of-principle rationale for a novel human mesenchymal stem (stromal) cell-based approach to improving vector delivery to tumors. Methods/results We have generated mesenchymal stem cell-derived packaging cells for adenoviruses (E1-modified mesenchymal stem cells) by modifying human mesenchymal stem cells with the adenovirus (type C) E1A/B genes needed for viral replication. Using cell-based assays, we have demonstrated that two adenoviral vectors, replication-defective adenovirus expressing p14 and p53 or conditionally replicating oncolytic adenovirus, packaged by E1A/B-modified mesenchymal stem cells, suppress the growth of prostate cancer cells in culture. Using subcutaneous xenograft models for human prostate cancer in mice, we have shown that E1A/B-modified mesenchymal stem cells display tumor tropism in tumor-bearing nude mice, that E1A/B-modified mesenchymal stem cells disseminate well within tumors, and that replication-defective adenovirus expressing p14 and p53 or conditionally replicating oncolytic adenovirus-loaded E1-modified mesenchymal stem cells suppresses tumor growth in mice. Conclusion The results show that this approach, if optimized, could circumvent the obstacles to efficient gene delivery encountered with current gene delivery approaches and provide an effective, nontoxic therapeutic alternative for metastatic disease.
Objective: Trigeminal nerve injury is one of the most problematic complications of dental/oral surgical procedures with significant consequences for patients, including neuropathy and facial pain. This presentation demonstrates the results of a cross-sectional survey studying the impact of nerve injury on patients' quality of life. Method: Thirty patients attending a specialist nerve injury clinic at Manchester Dental Hospital were asked to complete an Oral Impact on Daily Performance (ODIP) questionnaire. Five further patients took part in semi-structured interviews. Each interview was recorded and responses were thematically analysed. Results: Eighteen patients had an inferior alveolar nerve injury and 12 had lingual nerve injuries. There was no significant difference in mean ODIP scoreand therefore effect on quality of life, for gender or type of nerve injured (P < 0.05). Nerve injury most affected patients who enjoyed social contact with other people, their ability to eat and enjoy food. It also affected their capacity to maintain an emotional state without becoming irritable. The majority (70%) of nerve injuries were caused by dental extractions. There was also some evidence to show that patients who had sustained a nerve injury following the surgical removal of a wisdom tooth had a worse quality of life when compared to the other injury groups (P < 0.05, 95% CI). Results of the interviews further demonstrated a universal dissatisfaction of how the patient was initially managed following injury. Conclusion: Iatrogentic trigeminal nerve injury still remains a significant complication in dentistry with significant impact on patients' quality of life. Managing patients appropriately after nerve injury may help to improve the overall care given to this patient group. Clinical relevanceScientific rationale for study Nerve injury is a rare but serious complication of oral surgical procedures. Current studies evaluate the quantitative aspects of nerve injury without considering the effect on patients' quality of life. This cross-sectional study evaluates how nerve injuries impact on patients' quality of life utilising both quantitative and qualitative data. Principal findingsAbout 70% of intraoral nerve injuries were due to dental extractions. Quality of life was significantly affected following injury to the inferior alveolar and lingual nerve. Practical implicationsClinicians must be adept in recognising nerve injuries and managing patients appropriately. Management should focus on both the physiological and psychological impact of the injury.
Objective. Conditionally replicating adenoviruses (CRAds) have been proven potent oncolytic viruses in previous studies. They selectively replicate in the tumor cells because of incorporated survivin promoter and ultimately lead to their killing with minimal side effects on normal tissue. Chemotherapy with cisplatin is commonly employed for treating tumors, but its cytotoxic effects and development of resistance remained major concerns to be dealt with. The aim of this study was to explore the anticancer potential of survivin regulated CRAd alone or in combination with cisplatin in the A549 lung cancer cell line and cisplatin-resistant lung cancer cell line, A549-DDPR.Methods. CRAd was genetically engineered in our laboratory by removing its E1B region and adding survivin promoter to control its replication. A549, H292, and H661 lung cancer cell lines were procured from the CAS-China. The anti-tumor effectiveness of combined treatment (cisplatin plus CRAd) was evaluated in vitro through MTS assays and in vivo through mouse model experimentation. RT- PCR was used to assess MDR gene and mRNA expression of coxsackie adenoviral receptor (CAR).Results. Results of in vitro studies established that A549 lung cancer cells were highly sensitive to cisplatin showing dose-dependent inhibition. The resistant cells of A549-DDPR exhibited very less sensitivity to cisplatin but were infected with CRAd more efficiently as compared to A549. A549-DDPR cells exhibited higher expression of MDR gene and CAR in the RT-PCR analysis. The nearly similar rise in the CAR expression was seen when lung cancer cell lines received cisplatin in combined treatment (cisplatin plus CRAd). Combined anti-cancer therapy (cisplatin plus oncolytic virus) proved more efficient than monotherapy in the killing of cancer cells. Results of in vivo experiments recapitulated nearly similar tumor inhibition activities.Conclusion. This study highlighted the significant role of survivin in gene therapy as it has the potential to render CRAd more tumor specific. It also establishes that higher CAR expression plays a vital role in the success of adenovirus-based therapies. Furthermore, a careful combination of chemotherapy drugs and oncolytic viruses can culminate in significant therapeutic achievements against cancer.
Glioblastoma (GB) is the most common and aggressive brain malignancy, characterized by heterogeneity and drug resistance. PTEN, a crucial tumor suppressor, exhibits phosphatase-dependent (PI3K-AKT-mTOR pathway)/independent (nucleus stability) activities to maintain the homeostatic regulation of numerous physiological processes. Premature and absolute loss of PTEN activity usually tends to cellular senescence. However, monoallelic loss of PTEN is frequently observed at tumor inception, and absolute loss of PTEN activity also occurs at the late stage of gliomagenesis. Consequently, aberrant PTEN homeostasis, mainly regulated at the post-translational level, renders cells susceptible to tumorigenesis and drug resistance. Ubiquitination-mediated degradation or deregulated intracellular localization of PTEN hijacks cell growth rheostat control for neoplastic remodeling. Functional inactivation of PTEN mediated by the overexpression of ubiquitin ligases (E3s) renders GB cells adaptive to PTEN loss, which confers resistance to EGFR tyrosine kinase inhibitors and immunotherapies. In this review, we discuss how glioma cells develop oncogenic addiction to the E3s-PTEN axis, promoting their growth and proliferation. Antitumor strategies involving PTEN-targeting E3 ligase inhibitors can restore the tumor-suppressive environment. E3 inhibitors collectively reactivate PTEN and may represent next-generation treatment against deadly malignancies such as GB.
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