International Journal of Molecular and Cellular Medicine最新文献

Recent improvements in molecular treatment and gene therapy led to discovering novel cancer remedies. Antisense LNA GapmeRs is a state-of-the-art molecular research field for diagnosing and treating various cancer types. Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy defined by the rapid accumulation and malignant proliferation of immature myeloid progenitors. SOX12 is a new potential target for acute myeloid leukemia. In this study, SOX12 was blocked by antisense LNA GapmeRs (ALG) in human AML cell lines (KG1 and M07e). Cells were transfected with Gapmer anti-SOX12 at 24, 48, and 72 h post-transfection. Transfection efficiency was assessed by a fluorescent microscope. Furthermore, evaluation of SOX12, TWIST1, CTNNB1, CASP3, and CASP9 expression was performed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Cell viability was determined by MTT assay. SOX12 expression was decreased remarkably in the ALG group. Moreover, SOX12 knockdown was associated with a decrease in TWIST1 and CTNNB1 expression. Besides, downregulation of SOX12 in both cell lines could induce apoptosis, probably through upregulation of CASP3 and CASP9. The findings reveal that SOX12 knockdown could be a new target for reducing AML cells proliferation through antisense therapy approach.

Oral squamous cell carcinoma (OSCC) is the most common malignant epithelial cancer occurring in the oral cavity, where it accounts for nearly 90% of all oral cavity neoplasms. The c-MYC transcription factor plays an important role in the control of programmed cell death, normal-to-malignant cellular transformation, and progression of the cell cycle. However, the role of c-MYC in controlling the proliferation of OSCC cells is not well known. In this study, c-MYC gene was silenced in OSCC cells (ORL-136T), and molecular and cellular responses were screened. To identify the pathway through which cell death occurred, cytotoxicity, colony formation, western blotting, caspase-3, and RT-qPCR analyzes were performed. Results indicated that knockdown of c-MYC has resulted in a significant decrease in the cell viability and c-MYC protein synthesis. Furthermore, caspase-3 was shown to be upregulated leading to apoptosis via the intrinsic pathway. In response to c-MYC knockdown, eight cell proliferation-associated genes showed variable expression profiles: c-MYC (-21.2), p21 (-2.5), CCNA1(1.8), BCL2 (-1.4), p53(-3.7), BAX(1.1), and CYCS (19.3). p27 expression was dramatically decreased in c-MYC-silenced cells in comparison with control, and this might indicate that the relative absence of c-MYC triggered intrinsic apoptosis in OSCC cells via p27 and CYCS.

Despite the remarkable decrease in cervical cancer incidence due to the availability of the HPV vaccine and implementation of screening programs for early detection in developed countries, this cancer remains a major health problem globally, especially in developing countries where most of the cases and mortality occur. Therefore, more understanding of molecular mechanisms of cervical cancer development might lead to the discovery of more effective diagnosis and treatment options. Research on long noncoding RNAs (lncRNAs) demonstrates the important roles of these molecules in many physiological processes and diseases, especially cancer. In the present review, we discussed the significance of lncRNAs altered expression in cervical cancer, highlighting their roles in regulating highly conserved signaling pathways, such as mitogen-activated protein kinase (MAPK), Wnt/β-catenin, Notch, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways and their association with the progression of cervical cancer in order to bring more insight and understanding of this disease and their potential implications in cancer diagnosis and therapy.

Mesenchymal stem cells (MSCs) as undifferentiated cells are specially considered in cell-based cancer therapy due to unique features such as multi-potency, pluripotency, and self-renewal. A multitude of cytokines secreted from MSCs are known to give such multifunctional attributes, but details of their role are yet to be unknown. In the present study, MSCs were cultured, characterized and co-cultured with Molt-4 cells as acute lymphoblastic leukemia cell line in a trans-well plate. Then, cultured Molt-4 alone and Molt-4 co-cultured with MSCs (10:1) were collected on day 7 and subjected to real time-PCR and Western blotting for gene and protein expression assessment, respectively. Ki-67/caspase-3 as well as telomere length were investigated by flow cytometry and real time-PCR, respectively. The results showed that MSCs caused significant decrease in telomere length as well as hTERT gene expression of Molt-4 cells. Also, gene and protein expression of BAD and P53 were significantly increased. Furthermore, the flow cytometry analysis indicated the decrease and increase of the Ki-67 and caspaspase-3 expression, respectively. It was concluded that MSCs co-cultured with Molt-4 cells could be involved in the promotion of Molt-4 cell apoptosis via caspase-3, BAD, and P53 expression. In addition, the decrease of telomere length is another effect of MSCs on Molt-4 leukemic cells.

The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine-protein kinase that senses and combines various environmental signals to regulate the growth and homeostasis of human cells. This signaling pathway synchronizes many critical cellular processes and is involved in an increasing number of pathological conditions such as diabetes, cancer, obesity, and metabolic syndrome. Here, we review different complications of diabetes that are associated with mTOR complex 1 imbalance. We further discuss pharmacological approaches to treat diabetes complications linked to mTOR deregulation.

Aberrant protein glycosylation is known to be associated with the development of various cancers. Although fucosylation is essential for normal biological functions, alterations in fucosylation are strongly implicated in cancer and increasing metastatic potential. Altered fucosyltarnsferases (FUTs) and fucosidases are found to be involved in many types of malignancies. In this study, we examined the mRNA expressions of fucosidase (FUCA1) and FUTs (FUTs (FUT3, FUT4, FUT5, FUT6, FUT8) in human oral cancer tissues. All FUTs and FUCA1 were significantly (P ≤0.05) down-regulated in malignant tissues in comparison with their adjacent normal tissues. The relationship between the clinicopathological parameters and the expression of FUTs and FUCA1 revealed that higher mRNA levels of FUT4, FUT5, and FUT8 and lower levels of FUT3 were associated with progression of disease and lymph node metastasis in oral carcinoma indicating their role in oral cancer progression. Collectively, results suggest that elevated mRNA levels of FUT4, FUT5 and FUT8 may be used as worst prognostic indicators for oral carcinoma.

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) and antioxidants opened the way for many effective therapeutic experiments against damaged organs like kidneys. Nephrotoxicity is the main complication of chemotherapeutic drugs. Therefore, the present study aimed to investigate the efficacy of BM-MSCs and hesperidin to treat cisplatin-induced nephrotoxicity in rats. Fifty rats were divided into five equal groups of 10 each. Group-I served as a control group, group-II received a single dose of cisplatin (7.5 mg/kg) intraperitoneally to induce nephrotoxicity, group-III received a daily dose of hesperidin (40 mg/kg) orally for four weeks, and on the 5^th day cisplatin was administered an hour before hesperidin administration. Group-IV consisted of cisplatin-treated rats that were intravenously injected with 1х10⁶ BM-MSCs cells/rat once per week. Group V contained cisplatin-treated rats that received a combination of hesperidin and BM-MSCs with the same dosage regimes. After four weeks, serum and kidney samples were collected for biochemical, histological, and immunohistochemical examinations were performed. Cisplatin administered rats showed deteriorated biochemical parameters and severe degenerative changes in renal tissue. Both single and combined hesperidin and BM-MSCs treatments restored the renal biochemical parameters. Histologically, the renal tissues significantly improved in the BM-MSCs treated group in comparison with the hesperidin treated group. Moreover, combined treatment (i.e., group V) showed complete restoration of the normal architecture in the renal tissue. Our data suggest that the combined treatment of BM-MSCs and hesperidin has a potent renoprotective efficacy against cisplatin-induced nephrotoxicity rather than the single treatment.

Docetaxel is widely used in the treatment of metastatic breast cancer. However, its effectiveness is limited due to chemoresistance and its undesirable side effects. The combination of chemotherapeutic agents and natural compounds is an effective strategy to overcome drug resistance and the ensuing inevitable toxicities. Quercetin is a natural flavonoid with strong antioxidant and anticancer activities. This study aimed to evaluate the cytotoxic and modulatory effects of combined docetaxel and quercetin on the MDA-MB-231 human breast cancer cell line. The cell viability was assessed by MTT assay. The induction of apoptosis was examined using flow cytometry. The role of p53 in the apoptotic process was evaluated via qRT-PCR. The levels of BAX, BCL2, ERK1/2, AKT, and STAT3 proteins were measured by Western blot analysis. The results showed that the single-agent treatment with docetaxel or quercetin leads to a decrease in the viability of the MDA-MB-231 cells at 48 h. Furthermore, the combination of docetaxel (7 nM) and quercetin (95 μM) displayed the greatest synergistic effects with a combination index value of 0.76 accompanied by the up regulation of p53 and a significant increase in BAX level, as well as decrease in the levels of BCL2, pERK1/2, AKT, and STAT3 proteins (P < 0.05). The concomitant use of docetaxel and quercetin leads to the cell growth inhibition associated with the induction of apoptosis and inhibition of cell survival. Therefore, this study provides a promising therapeutic approach to enhance the efficacy of docetaxel in a less-toxic manner.

Toxoplasma gondii, an obligate intracellular parasite, infects more than 30% of world's population. This parasite is considered to be neurotropic, and has high tropism for the central nervous system, and potentially induces cryptogenic epilepsy by no clear mechanism. The current study aimed to investigate the alteration of the main components of the endocannabinoid signaling systems in T. gondii-infected mice. For this purpose, the levels of mRNA expression of monoacylglycerol lipase (MAGL), diacylglycerol lipase (DAGL) and cannabinoid receptor-1 (CB1), were measured by quantitative real time PCR.The mRNA expression level of MAGL was increased by ~ 8-fold in the brains of the Toxoplasma-infected group in comparison with non-infected mice (P<0.0001). The mRNA expression of CB1 gene in the brain of the infected mice was ~ 2 times higher than that measured in control group (P<0.01). The mRNA expression level of DAGL remained unchanged in the infected mice. Overall a substantial increase in MAGL and CB1 expression without any changes in DAGL, in the brain of infected mice suggests that T. gondii disturbs the endocannabinoid signaling pathways, which are known as neurotransmitter modulators involved in epilepsy.

Bipolar disorder (BD) is a major health care concern worldwide. There are some reports showing an association between genes and their variants involved in circadian rhythm; clock and clock related genes function and development of BD in patients. Therefore, the aim of this study was to investigate the possible association of rs534654 variant on TMEM165 (transmembrane protein 165) gene with the risk of BD. Genotyping of the rs534654 was carried out using the tetra primers- amplification refractory mutation system-PCR (4P-ARMS-PCR) method in 203 patients with BD type 1 and their healthy and normal counterpart. The frequency of the G and A alleles of rs534654 polymorphism was 53% and 47%, respectively in patients. Genotype frequency in patients in comparison with control subjects was 5.4% vs 2.5% for the AA homozygous; 11.3% vs 80.8% for the GG homozygous; and 83.3% vs 16.7% for the heterozygous AG. Statistical analysis showed a significant difference in frequencies between the control and patient groups (P = 0.001). Based on this finding, it is possible to conclude that the impairment in the rs534654 single nucleotide polymorphism in TMEM165 gene is associated with the risk of BD development.