Transient receptor potential ion channels and cerebral stroke.

METHODS: The databases Pubmed, and the National Library of Medicine were searched for literature. All papers on celebral stroke and transient receptor potential ion channels were considered. RESULTS: Stroke is the second leading cause of death and disability, with an increasing incidence in developing countries. About 75 per cent of strokes are caused by occlusion of cerebral arteries, and substantial advances have been made in elucidating mechanisms how stroke affects the brain. Transient receptor potential (TRP) ion channels are calcium-permeable channels highly expressed in brain that drives Ca2+ entry into multiple cellular compartments. TRPC1/3/4/6, TRPV1/2/4, and TRPM2/4/7 channels have been implicated in stroke pathophysiology. CONCLUSIONS: Although the precise mechanism of transient receptor potential ion channels in cerebral stroke is still unclear, it has the potential to be a therapeutic target for patients with stroke if developed appropriately. Hence, more research is needed to prove its efficacy in this context.

TRPC5 mediates TMZ resistance in TMZ-resistant glioblastoma cells via NFATc3-P-gp pathway.

P-glycoprotein (P-gp) acts as a pump to transport cytotoxic drugs out of cells and is upregulated in cancer cells. Suppressing the expression of P-gp is an effective strategy to overcome multidrug resistance in cancer chemotherapy. Temozolomide (TMZ) is the recommended drug for the standard treatment of patients with glioblastoma, but its clinical application is restricted due to drug resistance. Transient receptor potential channel-5 (TRPC5), a Ca2+-permeable channel, has been attributed to a different drug resistance mechanism except DNA repair system; therefore, we aimed to elucidate the mechanism regarding the role of TRPC5 in TMZ resistance. TRPC5 and P-glycoprotein (P-gp) are upregulated in TMZ-resistant glioblastoma cell lines. The downregulation of TRPC5 inhibited P-gp expression and led to a significant reversal of TMZ resistance in TMZ-resistant cell lines. TRPC5-siRNA restricted the growth of tumour xenografts in an athymic nude mouse model of TMZ-resistant cells. In specimens from patients with recurrent glioblastoma, TRPC5 was found to be highly expressed, accompanied by the upregulation of P-gp expression. The nuclear factor of activated T cell isoform c3 (NFATc3), which acts as a transcriptional factor, bridges TRPC5 activity to P-gp induction. In conclusion, these results demonstrate the functional role of the TRPC5-NFATc3-P-gp signalling pathway in TMZ resistance in glioblastoma cells.

TRPC5­induced autophagy promotes the TMZ­resistance of glioma cells via the CAMMKß/AMPKα/mTOR pathway.

Temozolomide (TMZ) is the first choice chemotherapy agent against glioblastoma, but the TMZ chemotherapy resistance has restricted the clinical application. Although autophagy is considered an adaptive response for cell survival under the pressure of chemotherapy and associated with chemotherapy resistance, its initiator and the precise molecular mechanism remains unknown. In the present study, it was determined that TMZ increases the transient receptor potential cation channel subfamily C member 5 (TRPC5) protein expression and the basal autophagy level, and the upregulation of autophagy is mediated by TRPC5 in glioma cells. Additionally, knockdown of TRPC5 upregulated the chemotherapy sensitivity in vitro and in vivo. Furthermore, TRPC5­small interfering RNA and pharmacological inhibition indicated that the Ca2+/calmodulin dependent protein kinase ß (CaMKKß)/AMP­activated protein kinase α (AMPKα)/mechanistic target of rapamycin kinase (mTOR) pathway mediates cell survival autophagy during TMZ treatment. In addition, TMZ­resistant U87/TMZ cells retained a high basal autophagy level, while silence of TRPC5 expression or inhibition of autophagy reversed TMZ resistance. Thus, the present study revealed that TRPC5, an initiator of autophagy, upregulated TMZ resistance via the CaMKKß/AMPKα/mTOR pathway and this indicated a novel therapeutic site for drug resistance in glioma chemotherapy.

MicroRNA-320 inhibits cell proliferation in glioma by targeting E2F1.

MicroRNAs (miRs) are a class of small non-coding RNAs that are involved in the regulation of gene expression, and in cancer development and progression. In the present study, miR-320 expression was found to be significantly reduced in glioma tissue in comparison with that in adjacent healthy tissues. In the present study, in vitro analyses demonstrated that overexpression of miR-320 inhibited cell proliferation and metastasis, while antisense miR-320 oligonucleotides enhanced cell proliferation and migration in U251 and SHG-44 glioma cell lines, compared with that in negative control cells. Protein expression of E2F1, a cell-cycle regulator, was negatively regulated by miR-320. Therefore, the present study provides novel insights into the association between miR-320 and glioma development.

MicroRNA-210 overexpression predicts poorer prognosis in glioma patients.

MicroRNA-210 (miR-210) levels are elevated in many tumor types, are frequently associated with hypoxia induction, and are correlated with poor prognosis in many solid tumors. miR-210 regulates cell growth, angiogenesis, invasion, and apoptosis of many human tumors. In this study, we investigated the clinical significance of miR-210 expression in common brain tumors, or human gliomas. Glioma samples and normal brain tissues were analyzed using real-time quantitative reverse transcriptase polymerase chain reaction to characterize the expression patterns of miR-210. The association of miR-210 expression with clinicopathological parameters and prognosis of glioma patients was statistically analyzed. Gliomas were further divided by grade: pilocytic astrocytoma (World Health Organization [WHO] grade I), diffuse astrocytomas (WHO grade II), anaplastic astrocytomas (WHO grade III), and glioblastoma (WHO grade IV). There was a significantly higher expression level of miR-210 amongst the glioma tissues as compared with normal brain tissues (p<0.001). Increased expression of miR-210 in glioma tissues was significantly associated with advanced pathological grade (p<0.001) and low Karnofsky Performance Score (p=0.014). In addition, increased miR-210 levels were also associated with poor progression-free survival (PFS) and overall survival (OS) rates when compared to the normal control (both p<0.001), as calculated by Kaplan-Meier survival and Cox regression analyses. Furthermore, subgroup analyses showed that miR-210 expression was significantly associated with poor PFS and OS of glioma patients with high pathological grades (III-IV: both p<0.001). miR-210 is highly expressed in human gliomas and confers a poor prognosis in glioma patients. These findings may bring the development of novel, tailored pharmacological therapies for glioma patients.

Microsurgical treatment assisted by intraoperative ultrasound localization: a controlled trial in patients with hypertensive basal ganglia hemorrhage.

This study investigated the clinical value of performing microsurgical treatment on hypertensive basal ganglia hemorrhage assisted by intraoperative ultrasound localization (IUL). A total of 107 patients with hypertensive basal ganglia hemorrhage were randomly separated into two groups for this controlled clinical trial. In the IUL group, 51 patients with hypertensive basal ganglia hemorrhage were operated on with the support of ultrasonic imaging; 56 patients underwent conventional microsurgery to evacuate the hemorrhage. The results of the two methods were evaluated according to the rate of hematoma evacuation, re-hemorrhage, mortality, complications, and activities of daily living (ADL). A greater quantity of the hemorrhage was removed from patients in the IUL group, with over 90% of masses being eliminated from the brain in 78.43% of these patients (40 out of 51 patients) compared with 60.71% of patients in the control group (34 out of 56 patients). The IUL group experienced a lower rate of re-hemorrhage after the operation (7.84%, 4 out of 51 patients) compared with the control group (17.86%, 10 out of 56 patients). A significant difference in the ADL score was recorded between the two groups, with ADL scores of the IUL group exceeding 60 (indicating good recovery) at 6 months after the operative procedure (P < 0.05). In conclusion, the microsurgical treatment of hypertensive basal ganglia hemorrhage assisted by IUL improved the precision of the operation. This procedure removed the hemorrhage and reduced the changes of re-occurrence, as well as elevated the quality of life of patients after the operation.