The protective effect of resveratrol on diazinon-induced oxidative stress and glucose hemostasis disorder in rats' liver.

This study was intended to assess the possible protective effect of resveratrol (Res) against oxidative stress and glucose hemostasis disorder in rats exposed to diazinon (DZN) for 4 weeks. Totally 25 Sprague-Dawley rats were divided randomly into five groups: Control (orally received corn oil), DZN group (orally received 70 mg/kg/day), and Res groups (received DZN 70 mg/kg/day plus Res doses of 5, 10, and 20 mg/kg bodyweight/-day), respectively. DZN significantly inhibited serum acetylcholinesterase enzyme (Ach E), serum and liver catalase, glutathione peroxidase activities, also total antioxidant capacities. On the other hand, DZN increased serum and liver malondialdehyde. DZN significantly increased Forkhead box protein O1 (Foxo1) expression and decreased phosphatase and tensin homolog (PTEN) and sirtuin 1 (Sirt-1) expression. DZN impaired glucose hemostasis. Instead, Res treatment significantly reversed status of oxidative stress and antioxidant enzymes activities induced by DZN. Also, Res improved glucose hemostasis. Res increased PTEN and Sirt-1 expression and reduced Foxo1 expression. Res administration ameliorated liver histopathological changes induced by DZN. These data confirmed that DZN significantly enhances oxidative stress and impairs glucose hemostasis. While Res showed a protective effect against the toxicity induced by DZN in rats.

Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy.

In recent decades, a new method of cellular immunotherapy was introduced based on engineering and empowering the immune effector cells. In this type of immunotherapy, the immune effector cells are equipped with chimeric antigen receptor (CAR) to specifically target cancer cells. In much of the trials and experiments, CAR-modified T cell immunotherapy has achieved very promising therapeutic results in the treatment of some types of cancers and infectious diseases. However, there are also some considerable drawbacks in the clinical application of CAR-T cells although much effort is in progress to rectify the issues. In some conditions, CAR-T cells initiate over-activated and strong immune responses, therefore, causing unexpected side-effects such as systemic cytokine toxicity (i.e., cytokine release syndrome), neurotoxicity, on-target, off-tumor toxicity, and graft-versus-host disease (GvHD). To overcome these limitations in CAR-T cell immunotherapy, NK cells as an alternative source of immune effector cells have been utilized for CAR-engineering. Natural killer cells are key players of the innate immune system that can destroy virus-infected cells, tumor cells, or other aberrant cells with their efficient recognizing capability. Compared to T cells, CAR-transduced NK cells (CAR-NK) have several advantages, such as safety in clinical use, non-MHC-restricted recognition of tumor cells, and renewable and easy cell sources for their preparation. In this review, we will discuss the recent preclinical and clinical studies, different sources of NK cells, transduction methods, possible limitations and challenges, and clinical considerations.

CAR T cells in solid tumors: challenges and opportunities.

BACKGROUND: CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal. MAIN BODY: Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as "living drugs" presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion. CONCLUSION: Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.

The effect of combined miR-200c replacement and cisplatin on apoptosis induction and inhibition of gastric cancer cell line migration.

One of the major obstacles in the treatment of cancer is resistance to standard chemotherapeutic drugs. According to the numerous reports, miR-200c is involved in many cancers, especially gastric cancer, and also miR-200c has been known as an effective factor in the elimination of chemotherapy resistance. The purpose of this study was to explore the potential function and mechanism of miR-200c and cisplatin in the inhibition of migration and induction of apoptosis in gastric cancer cells. In this study, first, miR-200c mimics and LNA-anti-miR-200c were transfected into KATOIII cells. Moreover, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay results revealed that increased miR-200c expression and cisplatin can more inhibited the proliferation of KATOIII cells. MiR-200c overexpression inhibited the movement of KATOIII cells in wound healing assay. Subsequently, miR-200c/cisplatin could suppress colony formation in KATOIII cells. To identify a potential miR-200c target, we investigated the effect of miR-200c modulation on RhoE, PTEN, VEGFR, and MMP9 expression levels. Increased miR-200c expression caused a reduction in VEGFR and MMP9 mRNA and protein, suggesting that VEGFR and MMP9 are targets of miR-200c. In addition, reverse-transcription polymerase chain reaction assays showed that RhoE is target gene of miR-200c and LNA-anti-miR-200c suppressed the expression of PTEN. Flow cytometry and 4',6-diamidino-2-phenylindole staining analysis indicated that miR-200c increased the cisplatin-induced apoptosis which may be associated with suppression of RhoE expression in KATOIII cells, also cell-cycle analysis showed the arrest of cell-cycle progression at the G2 phase. These data demonstrated that miR-200c functioned as a suppressor gene in KATOIII cells. Also, miR-200c can be a potential therapeutic approach to overcome chemoresistance during cisplatin chemotherapy.

MicroRNAs in cancer drug resistance: Basic evidence and clinical applications.

Development of drug resistance has considerably limited the efficacy of cancer treatments, including chemotherapy and targeted therapies. Hence, understanding the molecular mechanisms underpinning the innate or the acquired resistance to these therapies is critical to improve drug efficiency and clinical outcomes. Several studies have implicated microRNAs (miRNA) in this process. MiRNAs repress gene expression by specific binding to complementary sequences in the 3' region of target messenger RNAs (mRNAs), followed by target mRNA degradation or blocked translation. By targeting molecules specific to a particular pathway within tumor cells, the new generation of cancer treatment strategies has shown significant advantages over conventional chemotherapy. However, the long-term efficacy of targeted therapies often remains poor, because tumor cells develop resistance to such therapeutics. Targeted therapies often involve monoclonal antibodies (mAbs), such as those blocking the ErB/HER tyrosine kinases, epidermal growth factor receptor (cetuximab) and HER2 (trastuzumab), and those inhibiting vascular endothelial growth factor receptor signaling (e.g., bevacizumab). Even though these are among the most used agents in tumor medicine, clinical response to these drugs is reduced due to the emergence of drug resistance as a result of toxic effects in the tumor microenvironment. Research on different types of human cancers has revealed that aberrant expression of miRNAs promotes resistance to the aforementioned drugs. In this study, we review the mechanisms of tumor cell resistance to mAb therapies and the role of miRNAs therein. Emerging treatment strategies combine therapies using innovative miRNA mimics or antagonizers with conventional approaches to maximize outcomes of patients with cancer.

Downregulation of miR-146a promotes cell migration in Helicobacter pylori-negative gastric cancer.

microRNAs (miRs) are short noncoding RNAs that post-transcriptionally suppress gene expression. miR-146a acts as an oncogene or a tumor suppressor in various cancers, including gastric cancer, but it is unclear what determines whether miR-146a is oncogenic or tumor suppressive and the molecular mechanisms are still largely unknown. The aim of this study was to investigate the role of miR-146a in gastric cancer, by focusing on its expression in patients who were negative for Helicobacter pylori and its reduced and increased expression effect in vitro. Twenty gastric cancer patients who were negative for H. pylori infection were selected and the expression levels of miRNA-146a in these gastric tumors, in their matched normal gastric tissues and in gastric cancer cell lines with varying tumorigenic potential was measured. Further, the impact of increased and decreased miR-146a expression levels on the expression of predicted target genes, cell migration, viability, proliferation, and apoptosis was examined, respectively. Our results for the first time indicated that miR-146a is downregulated in H. pylori-negative gastric cancers and suggests that H. pylori infection determines whether miR-146a acts as an oncogene or tumor suppressor. The level of miR-146a expression inversely correlates with the tumorigenicity of three gastric cancer cell lines and low miR-146a expression predicts poor recurrence-free survival. It was also found that miR-146a reduces the expression levels of the prometastatic genes and suppresses MKN-45 cell migration. Functional studies showed that miR-146a acts as a tumor suppressor miR and identifies miR-146a as a candidate for antimetastatic miRNA replacement therapy for gastric cancer patients.

microRNA-193a-5p inhibits migration of human HT-29 colon cancer cells via suppression of metastasis pathway.

PURPOSE: Altered expression of microRNAs (miRNAs) is indicated strongly in colorectal cancer (CRC). This study aims to evaluate the inhibitory role of miR-193a-5p on epithelial-mesenchymal transition markers in CRC lines. The cellular effects and potential mechanisms of miR-193a-5p were also examined. METHODS: Quantitative reverse-transcription polymerase chain reaction (RT-PCR) was performed to determine the expression of miR-193a-5p in three CRC cell lines (HCT-116, SW-480, and HT-29) and its impact on metastasis-related genes ( vimentin and CXCR4) before and after mimic transfection. Of those, the cell line with the highest changes was selected for the next upcoming experiments such as wound-healing assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and annexin-V staining tests. RESULTS: Our results revealed that miR-193a-5p was significantly downregulated in three CRC cell lines and that HT-29 displayed the most decrease ( P < 0.0001). The restoration of miR-193a-5p in human HT-29 cell line inhibited cell migration. But, miR-193a-5p transfection did not affect cell viability and had no significant effect on apoptosis induction. Also, the quantitative RT-PCR analysis of miR-193a-5p mimic transfected cells revealed a significant increase in miR-193a-5p messenger RNA (mRNA) expression level ( P < 0.0001) with reduction of vimentin and CXCR4 mRNA expression levels in HT-29 cell line ( P < 0.01 and < 0.05, respectively). CONCLUSION: Our results indicated that miR-193a-5p acts as a tumor suppressor miRNA and its downregulation plays an important role in metastasis via upregulation of metastasis-related genes in CRC. Therefore, it can be considered as a potential therapeutic target for applying in CRC management in the future.

Association analysis of ERAP1 gene single nucleotide polymorphism in susceptibility to ankylosing spondylitis in Iranian population.

Background Ankylosing spondylitis (AS) is a debilitating spondyloarthropathy that has been associated with variation in several genes. Human leukocyte antigen (HLA)-B27 constructs an impaired structure, culminating in recognition and activation of immune system. Impaired function of Endoplasmic reticulum aminopeptidase (ERAP) 1, which primes peptides to be loaded in HLA molecules, has strongly been associated with AS proneness. Here, we intended to investigate the possible association of ERAP1 gene single nucleotide polymorphisms (SNPs) with AS susceptibility in Iranian patients. Methods Two-hundred and twenty AS patients and 220 healthy controls were enrolled in this study. DNA was extracted from blood samples and then was genotyped for rs27044, rs17482078, and rs10050860 polymorphism by SSP-PCR approach. Results It was seen that G allele and GG genotype of rs27044 SNP significantly increased the risk of AS that was even stronger in HLA-B27 positive patients. Moreover, the T allele and TT genotype of rs10050860 polymorphism were associated with increased risk of the disease in both all and HLA-B27 positive AS group. Two haplotypes were associated with the risk of AS and there was linkage disequilibrium between SNPs. Two SNPs were associated with clinicopathological manifestations of AS subjects. Conclusions This association study replicated the role ofERAP1 gene polymorphisms with the risk of AS in an Iranian population.

MicroRNAs as novel biomarkers for colorectal cancer: New outlooks.

Colorectal cancer is one of the most prevalent cancers with high mortality in the world. MicroRNAs are a class of small non-coding RNAs that regulate gene expression through targeting mRNAs. MicroRNAs involve in many biological and pathological processes such as cell growth, differentiation, apoptosis. etc. Dysregulation of miRNAs expression patterns have been reported in many tumors including Colorectal Cancer. Various studies indicate that miRNAs can be utilized as diagnostic and prognostic biomarkers for evaluation of tumor initiation, development, invasion, metastasis and response to chemotherapeutic drugs. Numerous investigations have also shown dysregulation of miRNAs in tissue samples and body fluids such as serum, plasma and fecal samples from CRC patients. Recently, several studies have demonstrated that miRNAs have regulatory roles in response to anti-cancer drugs and suggested them as predictive factors for successful treatment. In this review, we highlight the facts concerning tumor suppressor miRNAs and oncomiRs in CRC; by emphasizing their importance in different signaling pathways such as the Wnt/ß catenin activation, EGFR pathway, (TGF-ß) and the TP53 network and then their potential as biomarker and targets for cancer treatment.

MiR-146a functions as a small silent player in gastric cancer.

Gastric cancer is responsible for approximately one million annual deaths worldwide. Recently, the important roles of miRNAs as vital factors in malignancy processes such as metastasis have identified. They involve in the regulation of different biological procedures such as proliferation, invasion, metastasis and cell survival. MiR-146a has an aberrant expression in different tumors and has different expressions in the gastric cancer cell lines. This microRNA can act as a tumor suppressor and/or oncogene in gastric cancer related cases. Most of the studies have confirmed that miR-146a is downregulated in human gastric cancer cell lines and tissues, significantly and that it has tumor suppressor effects in gastric cancers. On the other hand, the role of miR-146a as an oncogene has been studied in an in-vitro experiment and results showed that over- an expression of miR-146a in gastric cancer tissues inhibits apoptosis and improves cell proliferation of gastric cancer cell. MiR-146a also has been a candidate for diagnosis and prognosis in gastric cancer cases. In this review, we focus on the important roles of miR-146a in tumor genesis of gastric tissues, emphasizing on the involvement of this microRNA in diagnosis, prognosis, chemotherapy response and finally, potential therapeutic applications as an anticancer agent in inhibition of gastric cancer cell metastasis and invasion.