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Tailoring drug co-delivery nanosystem for mitigating U-87 stem cells drug resistance

Behrooz AB, Vazifehmand R, Tajudin AA, Masarudin MJ, Sekawi Z, Masomian M, et al.

Drug Deliv Transl Res, 2021 Aug 17.
PMID: 34405338 DOI: 10.1007/s13346-021-01017-1

Glioblastoma multiforme (GBM) is the most prevalent form of brain tumor, which generally has a poor prognosis. According to consensus, recurrence of the tumor and chemotherapy resistance acquisition are the two distinguishing features of GBM originated from glioblastoma stem cells (GSCs). To eliminate these obstacles inherent in GBM chemotherapy, targeting GSCs through a smart drug delivery system has come to the front position of GBM therapeutics. In this study, B19 aptamer (Apt)-conjugated polyamidoamine (PAMAM) G4C12 dendrimer nanoparticles (NPs), called Apt-NPs, were formulated for the co-delivery of paclitaxel (PTX) and temozolomide (TMZ) to U-87 stem cells. These drugs were loaded using a double emulsification solvent evaporation method. As a result, drug-loaded Apt-NPs significantly inhibited the tumor growth of U-87 stem cells, by the initiation of apoptosis via the downregulation of autophagic and multidrug resistance (MDR) genes. Additionally, by their downregulation by qPCR of CD133, CD44, SOX2, and the canonical Wnt/β-catenin pathway, cell proliferation has substantially decreased. Altogether, the results demonstrate that this intelligent drug co-delivery system is capable of effectively transferring PTX and TMZ to U-87 stem cells and without any toxic effect on Apt-NPs alone to U-87 stem cells. Furthermore, the designed dendrimer-based pharmaceutical system along with single-stranded B19 aptamer might be utilized as a new therapeutic strategy for the treatment of U-87 stem cells drug resistance in the GBM.
The evaluation expression of non-coding RNAs in response to HSV-G47∆ oncolytic virus infection in glioblastoma multiforme cancer stem cells

Vazifehmand R, Ali DS, Othman Z, Chau DM, Stanslas J, Shafa M, et al.

J Neurovirol, 2022 Dec;28(4-6):566-582.
PMID: 35951174 DOI: 10.1007/s13365-022-01089-w

Glioblastoma multiforme is the most aggressive astrocytes brain tumor. Glioblastoma cancer stem cells and hypoxia conditions are well-known major obstacles in treatment. Studies have revealed that non-coding RNAs serve a critical role in glioblastoma progression, invasion, and resistance to chemo-radiotherapy. The present study examined the expression levels of microRNAs (in normoxic condition) and long non-coding RNAs (in normoxic and hypoxic conditions) in glioblastoma stem cells treated with the HSV-G47∆. The expression levels of 43 miRNAs and 8 lncRNAs isolated from U251-GBM-CSCs were analyzed using a miRCURY LNA custom PCR array and a quantitative PCR assay, respectively. The data revealed that out of 43 miRNAs that only were checked in normoxic condition, the only 8 miRNAs, including miR-7-1, miR-let-7b, miR-130a, miR-137, miR-200b, miR-221, miR-222, and miR-874, were markedly upregulated. The expression levels of lncRNAs, including LEF1 antisense RNA 1 (LEF1-AS1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), long intergenic non-protein coding RNA 470 (LINC00470), tumor suppressor candidate 7 (TUSC7), HOX transcript antisense RNA (HOTAIR), nuclear paraspeckle assembly transcript 1 (NEAT1), and X inactive specific transcript (XIST), were markedly downregulated in the hypoxic microenvironment, and H19-imprinted maternally expressed transcript (H19) was not observed to be dysregulated in this environment. Under normoxic conditions, LEF1-AS1, MALAT1, LINC00470, H19, HOTAIR, NEAT1, and XIST were downregulated and TUSC7 was not targeted by HSV-G47∆. Overall, the present data shows HSVG47Δ treatment deregulates non-coding RNA expression in GBM-CSC tumor microenvironments.
Fulltext Analysis of serum circulating MicroRNAs level in Malaysian patients with gestational diabetes mellitus

Jamalpour S, Zain SM, Vazifehmand R, Mohamed Z, Pung YF, Kamyab H, et al.

Sci Rep, 2022 Nov 24;12(1):20295.
PMID: 36434110 DOI: 10.1038/s41598-022-23816-3

Gestational diabetes mellitus (GDM) is a severe global issue that requires immediate attention. MicroRNA expression abnormalities are possibly disease-specific and may contribute to GDM pathological processes. To date, there is limited data on miRNA profiling in GDM, especially that involves a longitudinal study. Here, we performed miRNA expression profiling in the entire duration of pregnancy (during pregnancy until parturition and postpartum) using a miRNA- polymerase chain reaction array (miRNA-PCRArray) and in-silico analysis to identify unique miRNAs expression and their anticipated target genes in Malay maternal serum. MiRNA expression levels and their unique potential as biomarkers were explored in this work. In GDM patients, the expression levels of hsa-miR-193a, hsa-miR-21, hsa-miR-23a, and hsa-miR-361 were significantly increased, but miR-130a was significantly downregulated. The area under the curve (AUC) and receiver operating characteristic (ROC) curve study demonstrated that hsa-miR-193a (AUC = 0.89060 ± 04,470, P = 0.0001), hsa-miR-21 (AUC = 0.89500 ± 04,411, P = 0.0001), and miR-130a (AUC = 0.6939 ± 0.05845, P = 0.0025) had potential biomarker features in GDM. In-silico analysis also revealed that KLF (Kruppel-Like family of transcription factor), ZNF25 (Zinc finger protein 25), AFF4 (ALF transcription elongation factor 4), C1orf143 (long intergenic non-protein coding RNA 2869), SRSF2 (serine and arginine rich splicing factor 2), and ZNF655 (Zinc finger protein 655) were prominent genes targeted by the common nodes of miR23a, miR130, miR193a, miR21, and miR361.Our findings suggest that circulating microRNAs in the first trimester has the potential for GDM screening in the Malay population.
Fulltext Author Correction: Analysis of serum circulating MicroRNAs level in Malaysian patients with gestational diabetes mellitus

Jamalpour S, Zain SM, Vazifehmand R, Mohamed Z, Pung YF, Kamyab H, et al.

Sci Rep, 2023 Mar 29;13(1):5121.
PMID: 36991146 DOI: 10.1038/s41598-023-32260-w
Effects of HSV-G47Δ Oncolytic Virus on Telomerase and Telomere Length Alterations in Glioblastoma Multiforme Cancer Stem Cells Under Hypoxia and Normoxia Conditions

Vazifehmand R, Ali DS, Homaie FM, Jalalvand FM, Othman Z, Deming C, et al.

Curr Cancer Drug Targets, 2024;24(12):1262-1274.
PMID: 38357955 DOI: 10.2174/0115680096274769240115165344

BACKGROUND: Due to the existence of tumor stem cells with tumorigenicity properties and resistance patterns, treatment of glioblastoma is not easy. Hypoxia is a major concern in glioblastoma therapy. Telomerase activity and telomere length alterations have been known to play a critical role in glioblastoma progression and invasion.
OBJECTIVE: This study aimed to investigate the effects of HSV-G47Δ oncolytic virus on telomerase and telomere length alterations in U251GBMCSCs (U251-Glioblastoma cancer stem cells) under hypoxia and normoxia conditions.
METHODS: U251-CSCs were exposed to the HSV-G47Δ virus in optimized MOI (Multiplicity of infection= 1/14 hours). An absolute telomere length and gene expression of telomerase subunits were determined using an absolute human telomere length quantification PCR assay. Furthermore, a bioinformatics pathway analysis was carried out to evaluate physical and genetic interactions between dysregulated genes with other potential genes and pathways.
RESULTS: Data revealed that U251CSCs had longer telomeres when exposed to HSV-G47Δ in normoxic conditions but had significantly shorter telomeres in hypoxic conditions. Furthermore, hTERC, DKC1, and TEP1 genes were significantly dysregulated in hypoxic and normoxic microenvironments. The analysis revealed that the expression of TERF2 was significantly reduced in both microenvironments, and two critical genes from the MRN complex, MER11 and RAD50, were significantly upregulated in normoxic conditions. RAD50 showed a significant downregulation pattern in the hypoxic niche. Our results suggested that repair complex in the telomeric structure could be targeted by HSV-G47Δ in both microenvironments.
CONCLUSION: In the glioblastoma treatment strategy, telomerase and telomere complex could be potential targets for HSV-G47Δ in both microenvironments.