International Journal of Molecular and Cellular Medicine最新文献

The neurogenesis can occur in two regions of the adult mammalian brain throughout the lifespan: the subgranular zone of the hippocampal dentate gyrus, and the subventricular zone of the lateral ventricle. The proliferation and maturation of neural progenitor cells are tightly regulated through intrinsic and extrinsic factors. The integration of maturated cells into the circuitry of the adult hippocampus emphasizes the importance of adult hippocampal neurogenesis in learning and memory. There is a large body of evidence demonstrating that alteration in the neurogenesis process in the adult hippocampus results in an early event in the course of Alzheimer's disease (AD). In AD condition, the number and maturation of neurons declines progressively in the hippocampus. Innovative therapies are required to modulate brain homeostasis. Mesenchymal stem cells (MSCs) hold an immense potential to regulate the neurogenesis process, and are currently tested in some brain-related disorders, such as AD. Therefore, the aim of this review is to discuss the use of MSCs to regulate endogenous adult neurogenesis and their significant impact on future strategies for the treatment of AD.

Lung cancer is the second most common cancer and has high morbidity and mortality worldwide with non-small cell lung cancer (NSCLC) accounting for 85% of the cases. Over-expression of epidermal growth factor receptor (EGFR) has been clarified in different cancers, and has been shown to have a crucial role in tumor progression. In this study, we evaluated long non-coding RNA small NF90-associated RNA (snaR) expression in different EGFR-statue cell lines. Knockdown experiments were conducted to analyze snaR expression in selected cell lines. MTT and transwell assays were respectively employed to evaluate the proliferative and invasive abilities of NSCLC cells. The expression of snaR was remarkably up-regulated in SPC-A1 and A549 wild-type EGFR cell lines. Down regulation of snaR with small interfering RNA significantly inhibited cell invasion as well as proliferation of SPC-A1 and A549 cells. Our results indicate that snaR may be a potential therapeutic biomarker for NSCLC.

Cell signaling is a vital part of biological life. It helps coordinating various cellular processes including cell survival, cell growth, cell death, and cell interaction with the microenvironment and other cells. In general, cell signaling involves the attachment of signaling molecules known as ligands to specific receptors on cell surface, which then activate downstream events that dictate the cell's response. One of the most studied ligands is transforming growth factor-beta (TGF-β). TGF-β signaling is mainly mediated by suppressor of mothers against decapentaplegic (Smad) proteins, but it also interacts with other pathways such as the Ras and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, TGF-β can have a dual role depending on the cellular and microenvironmental context, in which it can act as either a growth promoter or a growth inhibitor. It has been known that TGF-β can self-induce its ligand production, thereby prolonging and amplifying its effect on cells and their microenvironment. The aim of this review is to discuss the regulation and signaling of TGF-β autoinduction, which still remain to be elucidated. Several factors have been found to facilitate TGF-β autoinduction, which include the activator protein-1 (AP1) complex, Smad3-dependent signaling, and non-Smad signaling pathways. On the other hand, the LIM (Lin11, Isl-1 and Mec-3) domain only 7 (LMO7) protein can suppress TGF-β autoinduction by interfering with the activities of AP-1 and Smad3. Since TGF-β autoinduction is implicated in various pathological conditions, better understanding of its regulation and signaling can provide new directions for therapy.

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.

Malignant brain tumors proliferate aggressively and have a debilitating outcome. Surgery followed by chemo-radiotherapy has been the standard procedure of care since 2005 but issues of therapeutic toxicity and relapse still remain unaddressed. Repurposing of drugs to develop novel combinations that can augment existing treatment regimens for brain tumors is the need of the hour. Herein, we discuss studies documenting the use of curcumin as an adjuvant to conventional and alternative therapies for brain tumors. Comprehensive analysis of data suggests that curcumin together with available therapies can generate a synergistic action achieved through multiple molecular targeting, which results in simultaneous inhibition of tumor growth, and reduced treatment-induced toxicity as well as resistance. The review also highlights approaches to increase bioavailability and bioaccumulation of drugs when co-delivered with curcumin using nano-cargos. Despite substantial preclinical work on radio-chemo sensitizing effects of curcumin, to date, there is only a single clinical report on brain tumors. Based on available lab evidence, it is proposed that antibody-conjugated nano-curcumin in combination with sub-toxic doses of conventional or repurposed therapeutics should be designed and tested in clinical studies. This will increase tumor targeting, the bioavailability of the drug combination, reduce therapy resistance, and tumor recurrence through modulation of aberrant signaling cascades; thus improving clinical outcomes in brain malignancies.

Myelodysplastic Syndromes (MDS) are clonal haematological stem cell disorders. The molecular basis of MDS is heterogeneous and the molecular mechanisms underlying biology of this complex disorder are not fully understood. Genetic variations (GVs) occur in about 90% of patients with MDS. It has been shown that in addition to the single nucleotide variations, insertions and deletions (indels) in the key genes that are known to drive MDS, could also play a role in pathogenesis of MDS. However, only a few genetic studies have analyzed indels in MDS. The present study reports indels of bone marrow (BM) derived CD34⁺ haematopoietic stem/progenitor cells of 20 newly diagnosed de novo MDS patients using next generation sequencing.A total of 88 indels (9 insertions and 79 deletions) across 28 genes were observed. The genes that showed more than five indels are BCOR (N=6), RAD21 (N=6), TP53 (N=8), ASXL1 (N=9), TET2 (N=9) and BCORL1 (N=10). Deletion in the BCORL1 gene (c.3957_3959delGGA, TGAG>TGAG/T) was the most recurrent deletion and was observed in 4/20 patients. The other recurrent deletions reported were EZH2 (W15X, N=2) and RAD21 (G274X, N=3). The recurrent insertions were detected in the FLT3 (E598DYVDFREYE, N=3) and in the NPM1 (L287LCX, N=3) genes. The findings of this study may have a diagnostic, prognostic and a therapeutic value for MDS after validation using a larger cohort.

The opportunistic pathogen Pseudomonas aeruginosa (Pa) is a major concern for immunocompromised and cystic fibrosis patients. Chronic lung infections caused by Pa are generally considered incurable, in part, due to the bacteria's ability to form persister cells. These variants are categorized as being phenotypically dormant and highly tolerant to antibiotic treatment. Currently, the mechanisms involved in Pa persister cell formation is poorly understood. One promising candidate is the Pa filamentation induced by cAMP (FIC) domain containing toxin (PaFicT), which like other FIC toxins transiently inhibits cell growth. Genetic knockout and complementation by single copy chromosomal insertion was used to characterize paficT involvement in Pa persister cell formation. Toxicity and the PaFicT active site were examined by overexpression of wild-type and mutant protein variants. Antibiotic tolerance of PaFicT-induced Pa persister cells, was measured by minimum inhibitory concentration (MIC) analysis and compared to parental mostly non-persister populations. Deletion of paficT resulted in a 7.2-fold reduction in persister cell formation, which was fully complemented by re-insertion of the gene. Expression of PaFicT significantly increased persister cell formation by 5.9-fold, and this phenotype required a functional FIC active site motif. Unlike growing cell populations, PaFicT-induced persister cells were unaffected by 4 h treatment with 10 × MIC meropenem and showed an increased survival of 6.2 × 10⁵-fold to tobramycin under the same conditions. Alternatively, survival of both persisters and parental, mostly non-persister, populations were below detectable levels following amikacin treatment. Results indicate a potential major involvement of PaFicT in Pa persister cell formation and multidrug tolerance.

Colorectal cancer (CRC) is one of the most prevalent diagnosed cancers and a common cause of cancer-related mortality. Despite effective clinical responses, a large proportion of patients undergo resistance to radiation therapy. Therefore, the identification of efficient targeted therapy strategies would be beneficial to overcome cancer radioresistance. Doublecortin-like kinase 1 (DCLK1) is an intestinal and pancreatic stem cell marker that showed overexpression in a variety of cancers. The transfection of DCLK1 siRNA to ‎normal HCT-116 cells was performed, and then cells were irradiated with X-rays. The effects of DCLK1 inhibition on cell survival, apoptosis, cell cycle, DNA damage response (ATM and γH2AX proteins), epithelial-mesenchymal transition (EMT) related genes (vimentin, N-cadherin, and E-cadherin), cancer stem cells markers (CD44, CD133, ALDH1, and BMI1), and β-catenin signaling pathway (β-catenin) were evaluated. DCLK1 siRNA downregulated DCLK1 expression in HCT-116 cells at both mRNA and protein levels (P <0.01). Colony formation assay showed a significantly reduced cell survival in the DCLK1 siRNA transfected group in comparison with the control group following exposure to 4 and 6 Gy doses of irradiation (P <0.01). Moreover, the expression of cancer stem cells markers (P <0.01), EMT related genes (P <0.01), and DNA repair proteins including pATM (P <0.01) and γH2AX (P <0.001) were significantly decreased in the transfected cells in comparison with the nontransfected group after radiation. Finally, the cell apoptosis rate (P <0.01) and the number of cells in the G0/G1 phase in the silencing DCLK1 group was increased (P <0.01). These findings suggest that DCLK1 can be considered a promising therapeutic target for the treatment of radioresistant human CRC.

Thyroid cancer is the most prevalent type of endocrine malignancy with the highest incidence rate among women under 45 years old. Ethinylestradiol (EE) and levonorgestrel (LNG) are two steroid components of low-dose oral contraceptives used all over the world. In this study, we aimed to examine the possible effects of the combination of these two steroids on metastasis and angiogenic factors in BCPAP papillary thyroid cancer (PTC) cell line. After treatment of BCPAP cells with the combination of 20 nM EE and 90 nM LNG, mRNA expression levels of long noncoding RNAs HOTAIR and MALAT1, angiogenic and antiangiogenic gene markers VEGFA and THBS1, and epithelial-mesenchymal transition (EMT) biomarkers CDH1, CDH2, FN1, and VIM were analyzed by real-time PCR. Additionally, the protein expression of VEGFA was semiquantified by Western blotting. Results showed that the combination of LNG and EE significantly elevated the level of VEGFA protein and mRNA expression of VEGFA, MALAT1, HOTAIR, CDH2, FN1, and VIM genes while decreased CDH1 gene expression but had no marked effect on the expression of THBS1 gene in comparison with the control group. Also, our results suggest that LNG and EE may increase the metastatic and migratory properties of BCPAP cells via modulating angiogenic and EMT biomarkers. These data may highlight the potential of exogenous steroids in the advancement of PTC tumors.