Efficacy of Anti-VEGF Drugs Based Combination Therapies in Recurrent Glioblastoma: Systematic Review and Meta-Analysis.

BACKGROUND: Recurrent glioblastoma multiforme (rGBM) has a grim prognosis with current therapies offering no survival benefit. Several combination therapies involving anti-VEGF agents have been studied with mixed results. METHODS: A systematic search was performed using five electronic databases: PubMed, Scopus, ISI, Embase, and the Cochrane Library without language limitations. The primary outcome of interest was progression free survival (PFS). Secondary outcomes were overall survival (OS), objective response ratio (ORR), and grade ≥ 3 adverse events. Estimates for PFS, OS were calculated as random effects hazard ratio (HR) with 95% confidence intervals (CIs) using the generic inverse variance method. Estimates for ORR, grade ≥ 3 adverse events were calculated using a random-effects risk ratio (RR) with 95% confidence intervals (CIs) using the Mantel-Haenszel method. RESULTS: Thirteen studies met the inclusion criteria and a total of 1994 patients have been included in the analysis. There was no statistically significant improvement in PFS (HR 0.84; 95% CI (0.68, 1.03); I2=81%), OS (HR 0.99; 95% CI (0.88, 1.12); I2=0%), ORR (RR 1.36; 95% CI (0.96, 1.92); I2=61%) in the combination therapy group when compared to the control group. Significantly higher grade ≥ 3 adverse events (RR 1.30; 95% CI (1.14, 1.48); I2=47%) were seen in the combination therapy when compared to the control group. CONCLUSION: Our analysis showed that the use of combination therapy with anti-VEGF agents did not offer any benefit in PFS, OS, or ORR. In contrast, it had significantly higher grade 3-5 adverse events. Further studies are needed to identify effective therapies in rGBM that can improve survival.

The Effectiveness of Nanoparticles on Gene Therapy for Glioblastoma Cells Apoptosis: A Systematic Review.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and fatal type of glioma. Nanoparticles (NPs) are used in new approaches for the delivery of gene therapy in the treatment of GBM. INTRODUCTION: The purpose of this article was to review the efficacy of NPs as the targeted carriers in the gene therapy aimed at apoptosis in GBM. METHODS: The appropriate keywords such as nanoparticle, glioblastoma, gene therapy, apoptosis, and related words were used to search from PubMed, ISI Web of Science, and Scopus for relevant publications up to September 4, 2020, with no language restrictions. The present systematic review was performed based on PRISMA protocol and reviewed the articles evaluating the effects of nanoparticles, carriers of various gene therapies essentials, on GBM cells apoptosis in vitro and in vivo. The selected articles were considered using specific scores on the quality of the articles. Data extraction and quality evaluation were performed by two reviewers. RESULTS: Of 101 articles retrieved, forty-two met the inclusion criteria and were, therefore, subjected to the final deduction. The most widely used NP in GBM gene therapy studies is polyamidoamine (PAMAM). The most common gene therapy approach for apoptosis in GBM is using siRNAs. CONCLUSION: In conclusion, these studies validated that NPs could be a practical choice to enhance the efficiency and specific delivery in gene therapies for GBM cell apoptosis. However, the choice of NP type and gene therapy mechanism affect the GBM cell apoptotic efficiency.

Transcriptome analysis evinces anti-neoplastic mechanisms of hypericin: A study on U87 glioblastoma cell line.

AIMS: Hypericin (HYP) from Hypericum perforatum has cytotoxic effects on a variety of malignant cell types, but the pattern of gene expression mediating the effect is largely unknown. Here we sought to analyze the response of U87 glioblastoma (GBM) cell lines in response to HYP. MATERIALS AND METHODS: U87 cell line was treated by HYP. Cytotoxicity was assessed using MTT and Annexin V/PI assays. Gene expression profile was obtained using high-throughput sequencing. Enrichment analysis was performed on differentially expressed genes (DEGs). Upstream transcription factors and microRNAs regulating DEGs were predicted. The effects of DEGs on survival of GBM patients were calculated. Protein-protein interaction analysis was conducted to obtain key altered genes. The possible effect of HYP treatment on immunity response was evaluated. KEY FINDINGS: The IC50 of HYP on U87 cell line was determined to be 1.5 µg/ml. The main type of cell death was apoptosis. A total of 312 DEGs were found. Affected Gene Ontology terms and pathways were identified. Analysis of upstream modulators of DEGs pointed out to transcription factors that significantly overlap with GBM stem cell transcription factor. Survival analysis suggested that HYP works best for the mesenchymal subtype patients. Tumor infiltration analysis predicted that HYP may affect Treg and macrophage infiltration in vivo. Using expression pattern of GBM patients and HYP-induced DEGs we suggested Fedratinib as a complementary drug to HYP. SIGNIFICANCE: Our study represents the response of U87 cell line to HYP, with analyses on survival, transcription factors and personalization according to GBM subtype.

Nanoparticle-Based Gene Therapy Intervention for Stroke Treatment: A Systematic Review.

Ischemic stroke is one of the main causes of mortality in advanced societies. Although gene therapy can be helpful, delivering gene therapy agents is challenging. Nanotechnology can enhance the potential therapeutic effects and the efficiency of gene therapy for some brain disorders. The present systematic review was conducted based on the PRISMA protocol to investigate the possible therapeutic effects of nanoparticles as the carriers of gene therapy agents in stroke therapy. Relevant keywords were used to search from ISI Web of Science, PubMed, and Scopus for relevant publications up to April 24, 2020. The selected articles were assessed using certain scores on the quality of the articles. Data extraction and quality judgment were carried out by the present reviewers. Of 130 articles retrieved, seven met the inclusion criteria and were, therefore, included in the final analysis. The outcome of the reviewing process revealed that depending on the selection of the target genes, stroke gene therapies have acceptable therapeutic consequences. The nanoparticles could be used to carry the gene therapy agents that are efficient targeting in stroke treatment. Also, it appears that the use of nanoparticles such as PEGylation and PAMAM, can be a valuable option to intensify the efficiency and specific targeting of stroke location. In conclusion, due to the inability of brain regeneration and the importance of genes in stroke-related complications, gene therapy seems to be a suitable treatment strategy. The use of suitable nanoparticles for transportation ensures the efficiency and usefulness of this method.

Oral and Intra-nasal Administration of Nanoparticles in the Cerebral Ischemia Treatment in Animal Experiments: Considering its Advantages and Disadvantages.

BACKGROUND: Over the past few decades, nanotechnology has dramatically advanced; from the precise strategies of synthesizing modern nanostructures to methods of entry into the body. Using nanotechnology in diagnosis, drug delivery, determining signaling pathways, and tissue engineering is great hope for the treatment of stroke. The drug-carrying nanoparticles are a way to increase drug absorption through the mouth or nose in treating the stroke. OBJECTIVE: In this article, in addition to explaining pros and cons of oral and intra-nasal administration of nanoparticles in the brain ischemia treatment of animal models, the researchers introduce some articles in this field and briefly mentioned their work outcomes. METHODS: A number of relevant published articles 183 were initially collected from three popular databases including PubMed, Google Scholar, and Scopus. The articles not closely related to the main purpose of the present work were removed from the study process. The present data set finally included 125 published articles. RESULTS: Direct delivery of the drug to the animal brain through the mouth and nose has more therapeutic effects than systemic delivery of drugs. The strategy of adding drugs to the nanoparticles complex can potentially improve the direct delivery of drugs to the CNS. CONCLUSION: Despite the limitations of oral and intra-nasal routes, the therapeutic potential of oral and intra-nasal administration of nano-medicines is high in cerebral ischemia treatment.

GABAB receptors within the central nucleus of amygdala may involve in the morphine-induced incentive tolerance in female rats.

OBJECTIVES: Central nucleus of amygdala (CeA) is the most important region for morphine-induced reward, and GABAergic system plays an important role on morphine reinforcement. The influence of CeA administration of GABAB receptor agonist and antagonist on the expression and acquisition of morphine-induced incentive tolerance using conditioned place preference (CPP) paradigm was investigated in the present study. Our purpose was to evaluate the role of CeA GABAB receptors in morphine tolerance. MATERIALS AND METHODS: Seven days after surgery and cannulation, the experiments were begun. Subcutaneous (SC) injections of morphine induced CPP. Administration of one daily dose of morphine (12.5 mg/kg) for 3 days in order to develop tolerance to the drug reduced the conditioning induced by morphine (7.5 mg/kg, SC). GABAB receptor agonist, baclofen (1.5, 6 and 12 µg/rat) or GABAB receptor antagonist, CGP35348 (1.5, 6 and 12 µg/rat) were injected into the CeA 5 min before the experiments in the test day (expression of tolerance) or 5 min before each injection of morphine (12.5 mg/kg) (acquisition of tolerance). RESULTS: It was shown that injections of baclofen (1.5 and 12 µg/rat) reduced acquisition, whereas the dose of 6 µg/rat of the drug exacerbated the acquisition of morphine tolerance. Baclofen at all doses significantly increased the expression of tolerance to morphine. Administration of CGP35348 (1.5, 6 and 12 µg/rat) reduced the acquisition and expression of morphine tolerance. CONCLUSION: These results confirmed the importance of GABAB receptors with in the CeA in morphine tolerance in female rats.

Intervention of the Gamma-Aminobutyric Acid Type B Receptors of the Amygdala Central Nucleus on the Sensitivity of the Morphine-Induced Conditionally Preferred Location in Wistar Female Rats.

BACKGROUND: The amygdala is one of the nerve centers involved in drug reward. It is suggested that the central nucleus of the amygdala (CeA) is involved in morphine dependency. The CeA gamma-aminobutyric acid-ergic (GABAergic) system is a mediator of morphine rewarding effects. In this research, the effects of stimulation or inhibition of CeA GABA type B (GABAB) receptors on sensitization acquisition to morphine-induced reward was evaluated in Wistar female rats using conditioned place preferential (CPP) method. METHODS: Wistar female rats provided by Shahid Beheshti University, Tehran, Iran, were allocated into 17 groups including 7 groups of determining morphine dose-response, 2 groups of sensitivity and control, and 8 groups of different doses of agonists and antagonists in the acquisition stage (n = 7 in each group). Various quantities of morphine (0.5, 1, 2.5, 5, 7.5, 10 mg/kg of animal weight) were used to determine the effective and neutral doses of morphine. After 5 days from the start of the surgery, sensitization was induced. After the end of the sensitization period, CPP was conducted. Baclofen and CGP35348, as an agonist and antagonist of GABAB respectively, with the dose of 1.5, 6 and 12 µg/rat were inserted to the CeA, ten minutes before taking morphine. FINDINGS: Administration of baclofen had no significant effect on the acquisition of morphine sensitization. In contrast, injection of CGP35348 reduced the sensitivity to morphine. CONCLUSION: GABA receptors can be effective in reducing morphine tendency by specific receptors, so these sites can be important therapeutic targets in counteracting the effects of drug abuse.

The role of protein kinase C in ischemic tolerance induced by hyperoxia in rats with stroke.

Recent studies suggest that normobaric hyperoxia (HO) protects the rat brain from ischemia reperfusion (IR) injury. Protein kinase C (PKC) is a key signaling molecule involved in protection against IR injury but its role in protective effect of HO in brain injury in unknown. In this study we attempted to see if PKC is involved in the effect of HO. Rats were divided into four main experimental groups. The first two were exposed to 95 % oxygen (HO) in a chamber 4 h/day for 6 consecutive days. Each of these groups had a control group exposed to 21 % oxygen. To investigate the role of PKC during HO, chelerythrin chloride (CHEL, 1 mg/kg/day), a PKC inhibitor, or its vehicle was given to animals for 6 days. After 24 h, the rats were subjected to 60 min of right middle cerebral artery occlusion (MCAO). After 24 h reperfusion neurological deficit scores, infarct volume, brain edema and blood-brain Barrier (BBB) permeability were assessed. HO decreased the infarct volume and brain edema in comparison with controls. PKC inhibition was associated with a significant increase in infarct size in both HO and control animals. PKC inhibition was unable to change brain edema in the experimental groups. Both HO and PKC inhibition reduced the BBB permeability within 24 h post occlusion of middle cerebral artery. Although both HO and PKC inhibition were associated with inhibition of BBB permeability during ischemic brain injury in rats, the neuroprotective effect of HO was independent of PKC in the MCAO model.