[Show abstract][Hide abstract] ABSTRACT: Background:
Acute post-traumatic cerebral hemispheric brain swelling (ACHS) is a serious disorder that occurs after traumatic brain injury, and it often requires immediate treatment. The aim of our clinical study was to assess the effects of stepwise intracranial decompression combined with external ventricular drainage (EVD) catheters on the prognosis of ACHS patients.
A retrospective study was performed on 172 cases of severe craniocerebral trauma patients with ACHS. The patients were divided into two groups: unilateral stepwise standard large trauma craniectomy (S-SLTC) combined with EVD catheter implants (n = 86) and unilateral routine frontal temporal parietal SLTC (control group, n = 86).
No significant differences in age, sex, or pre-operative Glasgow Coma Scale score were observed between groups (P < 0.05). There were no significant differences in the ipsilateral subdural effusion incidence rates between the S-SLTC + EVD treatment group and the routine SLTC group. However, the incidence rates of intraoperative acute encephalocele and contralateral epidural and subdural hematoma in the S-SLTC + EVD group were significantly lower than those in the SLTC group (17.4 and 3.5 vs. 37.2 and 23.3%, respectively). The mean intracranial pressure (ICP) values of patients in the S-SLTC + EVD group were also lower than those in the SLTC group at days 1 through 7 (P < 0.05). A positive neurological outcome [Glasgow Outcome Scale (GOS) score 4-5, 50.0%] and decreased mortality (15.1%) was observed in the S-SLTC + EVD group compared to the neurological outcome (GOS score 4-5, 33.8%; 36.0%) in the SLTC group (P < 0.05).
Our data suggest that S-SLTC + EVD is more effective for controlling ICP, improving neurological outcome, and decreasing mortality rate compared with routine SLTC.
Frontiers in Human Neuroscience 09/2015; 9. DOI:10.3389/fnhum.2015.00535 · 3.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glioblastoma is the most aggressive malignant primary brain tumor in humans. The activation of PI3K/Akt1 signaling pathway is involved in the proliferation of glioblastoma; however, the underlying mechanism of Akt1 activation during the development of glioblastoma remains largely unclear. Recently, the modification of molecular molecules at protein level such as acetylation has been shown to be related to the function of these molecules. Thus, in our present studies, the acetylation of Akt1 molecule and its role in the proliferation of glioblastoma cells was explored. The results showed that Akt1 was markedly acetylated in glioblastoma cells compared to normal human astrocytes. Mechanistically, PCAF-mediated Akt1 acetylation enhanced Akt1 phosphorylation at both sites of Thr308 and Ser473 and further promoted the proliferation of glioblastoma cells. Together, these data implicate that, as a post-translational regulation, PCAF-mediated Akt1 acetylation plays an important role in the proliferation of human glioblastoma, suggesting a novel target for clinical application.
[Show abstract][Hide abstract] ABSTRACT: Temozolomide, an alkylating agent, is a promising chemotherapeutic agent for treating glioblastoma. Although chemotherapy with temozolomide may restrain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells maintaining these tumors persist. Previous research has shown that temozolomide can inhibit the proliferation of human glioblastoma stem cells (GSCs); however, no research has focused on the invasion of GSCs, which is an important factor for glioblastoma recurrence. Accumulating evidence indicates that microRNA (miR)-125b over-expression in GSCs may increase their invasiveness.
Our objective was to identify the effects and mechanism of action of an miR-125b inhibitor combined with temozolomide in the invasive pathogenesis of GSCs.
We modified the levels of miR-125b expression in primary GSCs in order to observe the effect on sensitivity to temozolomide on invasion, and we further analyzed the differences in mechanism between miR-125b treatment alone and treatment with miR-125b plus temozolomide using the Cancer PathwayFinder PCR Array.
Our results demonstrated that either an miR-125b inhibitor or temozolomide could modestly inhibit the invasiveness of GSCs. Furthermore, GSCs that were pre-transfected with an miR-125b inhibitor, then treated with temozolomide, showed significantly decreased invasiveness when compared with GSCs treated with an miR-125b inhibitor or temozolomide alone. Further research into the underlying mechanism demonstrated that the miR-125b inhibitor enhanced the invasion-prevention activity of temozolomide in GSCs through targeting PIAS3 (protein inhibitor of activated STAT [signal transducer and activator of transcription]), which contributed to reduced STAT3 transcriptional activity and subsequent decreased expression of matrix metalloproteinase (MMP)-2 and -9.
miR-125b could play a role in the development of temozolomide resistance in GSCs. Inhibition of miR-125b expression may enhance sensitivity of GSCs to temozolomide by targeting PIAS3 on cell invasion.
[Show abstract][Hide abstract] ABSTRACT: Malignant gliomas are treated with a combination of surgery, radiation, and temozolomide (TMZ), but these therapies ultimately fail due to tumor recurrence. In this study, we aimed to identify the combined effects of miR-125b and TMZ involved in the invasive pathogenesis of glioblastoma cells. The effects of miR-125b and TMZ on cell invasion were analyzed by Transwell assays. Unexpectedly, either overexpression or downregulation of miR-125b has no function on glioblastoma cell invasion. However, knockdown of miR-125b could enhance the effects of TMZ on glioblastoma cell invasion. Conversely, overexpression of miR-125b could decrease such effects of TMZ. Further research on the mechanism demonstrated that such function of miR-125b knockdown on enhancing the effects of TMZ was involved in downregulation of Notch1. Notch1 was overexpressed in glioblastoma cells, and found by us that downregulation of Notch1 expression decreased the cell invasion of glioblastoma cells. Knockdown of miR-125b combined with TMZ enhancely downregulated Notch1 and inhibited cell invasion of malignant glioblastoma. These findings indicate that the combination of miR-125b inhibitor and TMZ treatment could effectively inhibit the glioblastoma cell invasion by inhibiting Notch1 expression.
[Show abstract][Hide abstract] ABSTRACT: Meningiomas, one of the most common benign brain tumors in humans, arise from arachnoid cells in the brain meninges. Our investigations have revealed that miR-335 is a typical microRNA overexpressed in meningiomas in humans. Characterization of the effects of miR-335 overexpression in meningiomas demonstrated that elevated levels of miR-335 increased cell growth and inhibited cell cycle arrest in the G0/G1 phase in vitro; in addition, reduction of the miR-335 levels had the opposite effect on tumor growth and progression. Further, previous studies have shown that the mechanism of effect of miR-335 on the proliferation of meningioma cells is associated with alterations in the expression of human retinoblastoma 1 (Rb1). Our results indicate that miR-335 plays an essential role in the proliferation of meningioma cells by directly targeting the Rb1 signaling pathway. Thus, our results highlight a novel molecular interaction between miR-335 and Rb1, and miR-335 may represent a potential novel therapeutic agent to target the proliferation of meningioma cells.
Journal of Neuro-Oncology 08/2012; 110(2):155-62. DOI:10.1007/s11060-012-0951-z · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) are small noncoding RNAs whose function as modulators of gene expression is crucial for the proper control of cell development, differentiation, and homeostasis. The total number and composition of miRNAs expressed per cell at different stages of development varies widely, and the same miRNA may function differently at different stages of development. In this prospective study, we evaluated the function of miR-125b at different developmental stages of glioblastoma cells, such as primary glioblastoma cells and the corresponding stem cells. CD133 is an important surface marker in glioblastoma stem cells. We found that the upregulation of miR-125b had no effects on the invasion of primary glioblastoma CD133-negative cells but that it could inhibit the invasion of corresponding CD133-positive cells; however, the downregulation of miR-125b also had no effects on the invasion of primary glioblastoma CD133-negative cells but promoted the invasion of CD133-positive cells. Further research into the underlying mechanism demonstrated that the effects of miR-125b on the invasion of glioblastoma CD133-positive cells were associated with the alteration of the expression of MMPs (MMP-2 and MMP-9) and corresponding inhibitors (RECK and TIMP3). Our results demonstrate that miR-125b expression plays an essential role in the invasion of glioblastoma CD133-positive cells but not CD133-negative cells. Therefore, miR-125b may represent a novel target for therapy targeting the invasion of glioblastoma stem cells in the future.
Neuromolecular medicine 06/2012; 14(4). DOI:10.1007/s12017-012-8188-8 · 3.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. In mammals, their function mainly represses the target mRNA transcripts via imperfect complementary sequences in the 3'UTR of target mRNAs. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some upregulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. Temozolomide (TMZ), an alkylating agent, is a promising chemotherapeutic agent for treating glioblastoma. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells maintaining these tumors persist. Previous research showed that TMZ could inhibit the proliferation of human glioblastoma stem cells (GSC), but not induced apoptosis, which could supply the chance for glioblastoma recurrence. Accumulating evidence indicated that downregulation of miR-21 in glioblastoma cells caused repression of growth and increased apoptosis, all of which could theoretically enhance the chemotherapeutic effects of cancer therapy. In this study, we aimed to explore whether miR-21 downregulation could enhance the chemotherapeutic effects of TMZ and induce apoptosis on GSC. Interestingly, the results demonstrated that either miR-21 inhibitor or TMZ could not induce apoptosis on GSC. However, miR-21 inhibitor combined with TMZ significantly enhanced GSC apoptosis. Taken together, a combination of miR-21 inhibitor and TMZ could be an effective therapeutic strategy for GSC apoptosis to prevent potential glioblastoma recurrence.
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. miR-125b, one of the neuronal miRNAs, was recently found to be necessary for stem cell fission and for making stem cells insensitive to chemotherapy signals. Temozolomide (TMZ) is a promising chemotherapeutic agent for treating glioblastomas. However, resistance develops quickly and with a high frequency. Given the insensitivity of some glioblastomas to TMZ and the hypothesis that glioma stem cells cause resistance to drug therapy, exploring the functions and mechanisms of miR-125b action on TMZ-treated glioblastoma stem cells would be valuable. In this study, we found that miR-125b-2 is overexpressed in glioblastoma multiforme tissues and the corresponding stem cells (GBMSC); downregulation of miR-125b-2 expression in GBMSC could allow TMZ to induce GBMSC apoptosis. Additionally, the expression of the anti-apoptotic protein Bcl-2 was decreased after the TMZ+miR-125b-2 inhibitor treatment, while the expression of the proapoptotic protein Bax was increased. Further research demonstrated that the induction of apoptosis in GBMSC is also associated with increased cytochrome c release from mitochondria, induction of Apaf-1, activation of caspase-3 and poly-ADP-ribose polymerase (PARP). Taken together, these results suggest that miR-125b-2 overexpression might confer glioblastoma stem cells resistance to TMZ.
International Journal of Oncology 08/2011; 40(1):119-29. DOI:10.3892/ijo.2011.1179 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. In mammal animals, their function mainly represses the target mRNAs transcripts via imperfectly complementary to the 3'UTR of target mRNAs. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some up-regulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. Temozolomide (TMZ), an alkylating agent, is a promising chemotherapeutic agent for treating glioblastoma. However, resistance develops quickly and with high frequency. To explore the mechanism of resistance, we found that miR-21 could protect human glioblastoma U87MG cells from TMZ induced apoptosis. Our studies showed that TMZ markedly enhanced apoptosis in U87MG cells compared with untreated cells (P<0.05). However, over-express miR-21 in U87MG cells could significantly reduce TMZ-induced apoptosis (P<0.05). Pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins are known to regulate the apoptosis of glioma cells. Bcl-2, resistance to induction of apoptosis, constitutes one major obstacle to chemotherapy in many cancer cells. Bax is shown to correlate with an increased survival of glioblastoma multiforme patients. Further research demonstrated that the mechanism was associated with a shift in Bax/Bcl-2 ratio and change in caspase-3 activity. Compared to control cells, cells treated with TMZ showed a significant increase in the Bax/Bcl-2 ratio and caspase-3 activity (P<0.01). However, such effect was partly prevented by treatment of cells with miR-21 overexpression before, which appeared to downregulate the Bax expression, upregulate the Bcl-2 expression and decrease caspase-3 activity. Taken together, these results suggested that over-express miR-21 could inhibit TMZ-induced apoptosis in U87MG cells, at least in part, by decreasing Bax/Bcl-2 ratio and caspase-3 activity, which highlighted the possibility of miR-21 overexpression in the clinical resistance to chemotherapeutic therapy of TMZ.
Brain research 09/2010; 1352:255-64. DOI:10.1016/j.brainres.2010.07.009 · 2.84 Impact Factor