Combination of Etoposide and quercetin-loaded solid lipid nanoparticles Potentiates apoptotic effects on MDA-MB-231 breast cancer cells.

Background: Breast cancer is a major global cancer, for which radiation and chemotherapy are the main treatments. Natural remedies are being studied to reduce the side effects. Etoposide (ETO), a chemo-drug, and quercetin (QC), a phytochemical, are considered potential factors for adaptation to conventional treatments. Objectives: The anticancer effect of the synergy between ETO and Quercetin-loaded solid lipid nanoparticles (QC-SLNs), was investigated in MDA-MB-231 cells. Methods: We developed QC-SLNs for efficient cellular delivery, characterizing their morphology, particle size, and zeta potential. We assessed the cytotoxicity of QC-SLNs and ETO on breast cancer cells via the MTT assay. Effects on apoptosis intensity in MDA-MB-231 cells have been detected utilizing annexin V-FITC, PI, and caspase activities. Real-time PCR assessed Bax gene and Bcl-2 gene fold change expression, while Western blot analysis determined p53 and p21 protein levels. Results: Spherical, negatively charged QC-SLNs, when combined with ETO, significantly enhanced inhibition of MDA-MB-231 cell proliferation compared to ETO or QC-SLNs alone. The combined treatment also notably increased the apoptosis pathway. QC-SLNs + ETO increased the Bax/Bcl-2 gene ratio, elevated p53 and p21 proteins, and activated caspase 3 and 9 enzymes. These results indicate the potential for QC-SLNs + ETO as a strategy for breast cancer treatment, potentially overcoming ETO-resistant breast cancer chemoresistance. Conclusion: These results suggest that QC-SLN has the potential to have a substantial impact on the breast cancer cure by improving the efficacy of ETO. This enhancement could potentially help overcome chemoresistance observed in ETO-resistant breast cancer.

Circulating Nucleic Acids in Colorectal Cancer: Diagnostic and Prognostic Value.

Colorectal cancer (CRC) is the third most prevalent cancer in the world and the fourth leading cause of cancer-related mortality. DNA (cfDNA/ctDNA) and RNA (cfRNA/ctRNA) in the blood are promising noninvasive biomarkers for molecular profiling, screening, diagnosis, treatment management, and prognosis of CRC. Technological advancements that enable precise detection of both genetic and epigenetic abnormalities, even in minute quantities in circulation, can overcome some of these challenges. This review focuses on testing for circulating nucleic acids in the circulation as a noninvasive method for CRC detection, monitoring, detection of minimal residual disease, and patient management. In addition, the benefits and drawbacks of various diagnostic techniques and associated bioinformatics tools have been detailed.

Circular RNAs and cervical cancer: friends or foes? A landscape on circRNA-mediated regulation of key signaling pathways involved in the onset and progression of HPV-related cervical neoplasms.

Cervical cancer (CC) is a common gynecologic malignancy, accounting for a significant proportion of women death worldwide. Human papillomavirus (HPV) infection is one of the major etiological causes leading to CC onset; however, genetic, and epigenetic factors are also responsible for disease expansion. Circular RNAs (circRNAs), which are known as a particular subset of non-coding RNA (ncRNA) superfamily, with covalently closed loop structures, have been reported to be involved in the progression of diverse diseases, especially neoplasms. In this framework, abnormally expressed circRNAs are in strong correlation with CC pathogenesis through regulating substantial signaling pathways. Also, these RNA molecules can be considered as promising biomarkers and therapeutic targets for CC diagnosis/prognosis and treatment, respectively. Herein, we first review key molecular mechanisms, including Wnt/ß-catenin, MAPK, and PI3K/Akt/mTOR signaling pathways, as well as angiogenesis and metastasis, by which circRNAs interfere with CC development. Then, diagnostic, prognostic, and therapeutic potentials of these ncRNA molecules will be highlighted in depth.

Association of Interleukin-17A rs2275913 Polymorphism with Recurrent Miscarriage: A Systematic Review and Meta-Analysis Study.

Recurrent miscarriage (RM) is a condition defined as having three or more consecutive pregnancy losses before the 20 weeks of pregnancy. The present study was undertaken to investigate association of Interleukin-17A (IL-17A) rs2275913 polymorphism with RM. To this end, we searched the international databases (Web of Science, PubMed, Embase, and Scopus) and extracted studies investigating the association of IL-17A rs2275913 polymorphism with RM using the appropriate keywords. The collected data were analyzed with the random-effects model and STATA (version 14). A total of five studies met the eligibility criteria, and total sample size was 998 subjects. Mean age of the cases and controls were 31.41 ± 4.16 and 30.56 ± 3.5 years, respectively. Our results disclosed a significant relationship of the IL-17A rs2275913 AA genotype [odds ratio (OR)=1.68; 95% confidence interval (CI)=1.16- 2.43; I2=19; P=0.294) with RM. There was no statistically significant correlation between IL-17Ars2275913 GG genotype (OR=1.04; 95% CI=0.64-1.7; I2=59.5; P=0.042) and GA genotype (OR=0.85; 95% CI=0.65-1.12; I2=19.1; P=0.293) with RM. Our findings revealed that the IL-17A rs2275913 polymorphism is associated with RM, and the AA genotype of this polymorphism increased possibility of being involved in RM.

Insilco prediction of the role of the FriZZled5 gene in colorectal cancer.

INTRODUCTION: In this study, we aimed to elucidate the crosstalk between the Wnt/ß-catenin signaling pathway and colorectal cancer (CRC) associated with inflammatory bowel disease (IBD) using a bioinformatics analysis of putative common biomarkers and a systems biology approach. MATERIALS AND METHODS: The following criteria were used to search the GEO and ArrayExpress databases for terms related to CRC and IBD: 1. The dataset containing the transcriptomic data, and 2. Untreated samples by medications or drugs. A total of 42 datasets were selected for additional analysis. The GEO2R identified the differentially expressed genes. The genes involved in the Wnt signaling pathway were extracted from the KEGG database. Enrichment analysis and miRNA target prediction were conducted through the ToppGene online tool. RESULTS: In CRC datasets, there were 1168 up- and 998 down-regulated probes, whereas, in IBD datasets, there were 256 up- and 200 down-regulated probes. There were 65 upregulated and 57 downregulated genes shared by CRC and IBD. According to KEGG, there were 166 genes in the Wnt pathway. FriZZled5 (FZD5) was a down-regulated gene in both CRC and IBD, as determined by the intersection of CRC- and IBD-related DEGs with the Wnt pathway. It was also demonstrated that miR-191, miR-885-5p, miR-378a-3p, and miR-396-3p affect the FriZZled5 gene expression. CONCLUSION: It is possible that increased expression of miR-191 and miR-885-5p, or decreased expression of miR-378a -3p and miR396-3, in IBD and CRC results in decreased expression of the FZD5 gene. Based on the function of this gene, FZD5 may be a potential therapeutic target in IBD that progresses to CRC.

Methylation-mediated silencing of miR-125a-5p facilitates breast cancer progression by inducing autophagy.

BACKGROUND: microRNA-125a-5p (miR-125a) is a tumor suppressor gene whose role in autophagy remains poorly understood. In the current study, we aimed to investigate the methylation status of miR-125a, its transfection into SK-BR3 cells, and its effects on autophagy. METHODS: Sixty samples of tumor and non-tumor adjacent tissue were collected and the methylation status of miR-125a was evaluated by methylation-specific PCR (MSP). The effect of 5-Aza-dC on miR-125a expression was investigated in the SK-BR3 cells. Cells were also transfected with miR-125a mimic/antimiR. The expression of miR-125a and its target genes was evaluated by Real-Time PCR. Protein levels of ATG5 and LC3 were assessed by Western blotting. HER2 expression was investigated by immunocytochemistry (ICC). RESULTS: The data showed that the miR-125a promoter CpG Island was significantly hypermethylated in breast cancer tissues (p < 0.01) and in SK-BR3 cells. The 5-Aza-dC could significantly increase miR-125a expression by decreasing its methylation (p < 0.05). In addition, Western blot analysis indicated the expression of ATG5 and LC3 II/ LC3I, as autophagy biomarkers, was significantly reduced in SK-BR3 cells transfected with miR-125a (p < 0.05). CONCLUSIONS: Our data showed miR-125a expression was significantly decreased in tumor tissues due to its promoter hypermethylation. Overexpression of miR-125a was associated with a reduction in autophagy, which could provide a new therapeutic avenue for advanced-stage breast cancer treatment.

Enhancing autophagy in Alzheimer's disease through drug repositioning.

Alzheimer's disease (AD) is one of the biggest human health threats due to increases in aging of the global population. Unfortunately, drugs for treating AD have been largely ineffective. Interestingly, downregulation of macroautophagy (autophagy) plays an essential role in AD pathogenesis. Therefore, targeting autophagy has drawn considerable attention as a therapeutic approach for the treatment of AD. However, developing new therapeutics is time-consuming and requires huge investments. One of the strategies currently under consideration for many diseases is "drug repositioning" or "drug repurposing". In this comprehensive review, we have provided an overview of the impact of autophagy on AD pathophysiology, reviewed the therapeutics that upregulate autophagy and are currently used in the treatment of other diseases, including cancers, and evaluated their repurposing as a possible treatment option for AD. In addition, we discussed the potential of applying nano-drug delivery to neurodegenerative diseases, such as AD, to overcome the challenge of crossing the blood brain barrier and specifically target molecules/pathways of interest with minimal side effects.

KRAS mutation and abnormal expression of Cripto-1 as two potential candidate biomarkers for detection of colorectal cancer development.

Colorectal cancer (CRC), regardless of standard procedures of treatment and screening, is still considered one of the deadliest cancers in the Western world, and in economically developed Asian countries, especially Iran. The current study was undertaken to investigate whether changes in the level of Cripto-1 (CR-1) expression and KRAS mutations have a cumulative effect on the onset and progression of CRC. Fifty colorectal tissue samples, including 35 colorectal carcinomas with matching adjacent mucosa, and 15 colorectal adenomas, were chosen for analysis. Twenty-five CRC biopsies and 15 adenoma were analyzed for KRAS mutations by DNA sequencing (Sanger sequencing), and all 50 patients (35 CRCs and 15 adenomas) were evaluated by immunohistochemistry for the CR-1 protein expression. The inducible somatic KRAS mutation (G12D) was observed in nine (36%) of CRC patients, and in two (13.3%) of adenoma patients. The CR-1 expression level in both adenomas (P < .05) and carcinomas (P < .001), were significantly different, compared with the matching adjacent mucosa. The intensity of CR-1 staining in adenomas was less than the intensity of staining, detected in the CRCs (P < .001). The G12D KRAS mutation and CR-1 abnormalities are significantly associated as two signature biomarkers with potential clinical characteristics for the detection of CRC development.

Altered miR-21, miRNA-148a Expression in Relation to KRAS Mutation Status as Indicator of Adenoma-Carcinoma Transitional Pattern in Colorectal Adenoma and Carcinoma Lesions.

Sporadic colorectal cancer (CRC) is a fatal disease, mostly known as the silent killer, due to the fact that this disease is asymptomatic before diagnosis in advanced stage. Screening and the early detection of CRC and colorectal adenoma (CRA) by non-aggressive molecular biomarkers' signature is useful for improvement of survival rate in CRC patients. To achieve such a goal, a better understanding of distinct molecular abnormalities as candidate biomarkers in CRC development is crucial. In this study, seventy-five archived FFPE CRC samples, including colorectal adenocarcinoma, adenomatous polyps (adenoma), and adjacent non-neoplastic mucosa were collected for the investigation by Sanger sequencing at the DNA level and by real-time PCR at the RNA level. The results of the KRAS mutational analysis have shown that the majority of somatic mutations in the KRAS affect only one codon, mainly codon 12(p.G12D) with low frequency in adenomas (13.3%) versus CRCs (36%). The results of dysregulated epigenetic changes of miR-21 clearly showed upregulation of expression in colorectal adenocarcinoma, compared to non-neoplastic mucosa, in colorectal adenoma vs non-neoplastic mucosa: (p < 0.001) and in CRC versus adenoma (p < 0.001); while miR-148a expression were significantly downregulated in CRC, compared to non-neoplastic mucosa, in colorectal adenoma vs non-neoplastic mucosa, and in adenoma vs CRC (p < 0.001). Our findings support the important role of miR-21 in stages I-II of CRC, and the KRAS G12D mutant, and differential miR-148a expression, in advanced stages of CRC.

Effects of Different Concentrations of Opium on the Secretion of Interleukin-6, Interferon-γ and Transforming Growth Factor Beta Cytokines from Jurkat Cells.

BACKGROUND: The risk of infectious, autoimmune and immunodeficiency diseases and cancers rise in opioid addicts due to changes in innate and acquired immune responses. Three types of opioid receptors (К-δ-µ) are expressed on the surface of lymphocytes and mononuclear phagocytes. The present study was designed to examine the effects of different concentrations of opium on the secretion of some cytokines produced by lymphocyte cells. METHODS: Jurkat cells were exposed to different concentrations of opium for periods of 6, 24 and 72 h in cell culture medium. The amount of interleukin-6 (IL-6), interferon-γ (IFN-γ) and transforming growth factor-b (TGF-ß) were then measured using enzyme-linked immunosorbent assay (ELISA) method. FINDINGS: The results showed that opium increases the secretion of IL-6 in different concentration of opium in 6 h. The amount of IFN-γ decreased in 6 h and increased in 24 h significantly compared with control. On the other hand, opium had an inhibitory effect on the TGF-ß secretion in 6, 24 and 72 h. CONCLUSION: Overall, the study showed that opium stimulates pro-inflammatory and suppressed anti-inflammatory cytokine secretion in Jurkat cells. This may account for the negative effect of opium on the immune system leading to chronic inflammation and a base for many disorders in opium addicts.

Opium induces apoptosis in jurkat cells.

BACKGROUND: The direct effect of some opioids on immune cells has been demonstrated. The aim of this study was to assess the apoptotic effect of opium on Jurkat T lymphocyte cells. METHODS: Different concentrations of opium (2.86 × 10-3 to 2.86 × 10-11 g/ml) were added to 24-well plates containing 5 × 105 Jurkat cells. Apoptotic events were assessed after 6, 24, and 72 hours by flow-cytometric detection of surface phosphatidylserine. FINDINGS: Significant differences in apoptosis of Jurkat cells were seen at 24 and 72 hours in different concentrations of opium (P < 0.05). After 72 hours, significant increase in necrosis of Jurkat cells was seen in opium concentration of 2.85 × 10-3 g/ml compared to cells without opium (control) (P < 0.05). CONCLUSION: These results showed that opium directly increases apoptosis and necrosis of T lymphocytes. This effect may play a role in immune dysfunction in opium addicts.