The critical role and functional mechanism of microRNA-146a in doxorubicin-induced apoptosis in breast cancer cells.

BACKGROUND: Breast cancer among women is the most frequently diagnosed cancer and the leading cause of death worldwide. There many advances in diagnosing and treating this disease, early diagnosis and treatment are still a significant challenge in the early stages. In recent years, microRNAs have attracted much attention in cancer diagnosis and treatment. However, the role of miR-146a in breast cancer is still controversial. We aimed to investigate the roles of miR-146a in apoptosis in breast cancer cells. METHODS: A microarray dataset from the GEO database was selected, and using the GEO2R tool, the gene expression profile of this dataset was extracted. Then, the target scan database was used to explore the miR-146a target genes. The link between the signaling pathways was collected. We used miR-146a mimic, which was transfected to the MCF-7 cells to investigate the miR-146a roles in the apoptosis. The expression levels of miR-146a and BAX, BCL-2, and p-21(most essential genes in the apoptosis) were quantified by qPCR and western blot analysis. RESULTS: Our findings indicated that doxorubicin induces miR-146a expression. In addition, overexpression of miR-146a affected MCF-7 cell viability, induced apoptosis, and led to reduced expression levels of BCL-2 and P-21, as well as increased BAX expression levels. CONCLUSION: Considering the role of doxorubicin in inducing apoptosis and increasing the expression of miR-146a, it can be suggested that this miR is involved in inducing apoptosis in BC cells. In addition, miR-146a can be considered a therapeutic candidate.

Combination therapy of metformin and morin attenuates insulin resistance, inflammation, and oxidative stress in skeletal muscle of high-fat diet-fed mice.

Lipid accumulation, inflammation, and oxidative stress are the most important causes of muscle insulin resistance. The aim of this study was to investigate the single and combined treatment effects of metformin (MET) and morin (MOR) on lipid accumulation, inflammation, and oxidative stress in the skeletal muscle of mice fed a high-fat diet. The mice were supplemented with MET (230 mg/kg diet), MOR (100 mg/kg diet), and MET + MOR for 9 weeks. Our results revealed that single treatment with MET or MOR, and with a stronger effect of MET + MOR combined treatment, reduced body weight gain, improved glucose intolerance and enhanced Akt phosphorylation in the muscle tissue. In addition, plasma and muscle triglyceride levels were decreased after treatment with MET and MOR. The expression of genes involved in macrophage infiltration and polarization and pro-inflammatory cytokines showed that MET + MOR combined treatment, significantly reduced inflammation in the muscle. Furthermore, combined treatment of MET + MOR with greater efficacy than the single treatment improved several oxidative stress markers in the muscle. Importantly, combined treatment of MET and MOR could increase the expression of nuclear factor erythroid 2-related factor 2, the master regulator of the antioxidant response. These findings suggest that combination of MET with MOR might ameliorate insulin resistance, inflammation, and oxidative stress in the skeletal muscle of mice fed high-fat diet.

Exosomal long non-coding RNAs in glioblastoma.

Glioblastoma multiforme (GBM) is the most prevalent primary tumor found in the central nervous system, accounting for 70% of all adult brain tumors. The median overall survival rate is one year post-diagnosis with treatment, and only four months without treatment. Current GBM diagnostic methods, such as magnetic resonance imaging (MRI), surgery, and brain biopsies, have limitations. These include difficulty distinguishing between tumor recurrence and post-surgical necrotic regions, and operative risks associated with obtaining histological samples through direct surgery or biopsies. Consequently, there is a need for rapid, inexpensive, and minimally invasive techniques for early diagnosis and improved subsequent treatment. Research has shown that tumor-derived exosomes containing various long non-coding RNAs (lncRNAs) play critical regulatory roles in immunomodulation, cancer metastasis, cancer development, and drug resistance in GBM. They regulate genes that enhance cancer growth and progression and alter the expression of several key signaling pathways. Due to the specificity and sensitivity of exosomal lncRNAs, they have the potential to be used as biomarkers for early diagnosis and prognosis, as well as to monitor a patient's response to chemotherapy for GBM. In this review, we discuss the role of exosomal lncRNAs in the pathogenesis of GBM and their potential clinical applications for early diagnosis.

Critical involvement of circular RNAs in virus-associated cancers.

Virus-related cancer is cancer where viral infection leads to the malignant transformation of the host's infected cells. Seven viruses (e.g., human papillomavirus (HPV), Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human T-lymphotropic virus (HTLV), and Merkel cell polyomavirus (MCV)) that infect humans have been identified as an oncogene and have been associated with several human malignancies. Recently, growing attention has been attracted to exploring the pathogenesis of virus-related cancers. One of the most mysterious molecules involved in carcinogenesis and progression of virus-related cancers is circular RNAs (circRNA). These emerging non-coding RNAs (ncRNAs), due to the absence of 5' and 3' ends, have high stability than linear RNAs and are found in some species across the eukaryotic organisms. Compelling evidence has revealed that viruses also encode a repertoire of circRNAs, as well as dysregulation of these viral circRNAs play a critical role in the pathogenesis and progression of different types of virus-related cancers. Therefore, understanding the exact role and function of the virally encoded circRNAs with virus-associated cancers will open a new road for increasing our knowledge about the RNA world. Hence, in this review, we will focus on emerging roles of virus-encoded circRNAs in multiple cancers, including cervical cancer, gastric cancer, Merkel cell carcinoma, nasopharyngeal carcinoma, Kaposi cancer, and liver cancer.

The Anti-Adhesion Effect of Nisin as a Robust Lantibiotic on the Colorectal Cancer Cells.

Background: Bacteriocins are a type of antimicrobial peptide that are produced by probiotics. They have been studied as possible therapeutic drugs and have been used to suppress bacterial development in foods. Nisin is a potent bacteriocin having the anti-microbial and anti-cancer characteristics produced by Lactococcus lactis. The aim of the present paper is to evaluate the influence of Nisin on cell adhesion and its two related genes, mmp-2 and mmp-9, in the colorectal cancer cell line. Materials and Methods: For this purpose, HT-29 cells were treated with various concentrations of Nisin and the cell cytotoxicity, cell adhesion, and gene expression were evaluated using the MTT assay, cell adhesion assay, and real-time PCR. Results: Our findings showed that 32 to 1024 µg/ml of Nisin resulted in a significant reduction in cell viability (P < 0.05). Furthermore, 128 and 256 µg/ml of Nisin significantly reduced the cell adhesion, and mmp-2 and mmp-9 gene expressions (P < 0.05). Conclusion: Our findings suggested that Nisin could prevent metastasis and cancer progression.

The critical role of circular RNAs in drug resistance in gastrointestinal cancers.

Nowadays, drug resistance (DR) in gastrointestinal (GI) cancers, as the main reason for cancer-related mortality worldwide, has become a serious problem in the management of patients. Several mechanisms have been proposed for resistance to anticancer drugs, including altered transport and metabolism of drugs, mutation of drug targets, altered DNA repair system, inhibited apoptosis and autophagy, cancer stem cells, tumor heterogeneity, and epithelial-mesenchymal transition. Compelling evidence has revealed that genetic and epigenetic factors are strongly linked to DR. Non-coding RNA (ncRNA) interferences are the most crucial epigenetic alterations explored so far, and among these ncRNAs, circular RNAs (circRNAs) are the most emerging members known to have unique properties. Due to the absence of 5' and 3' ends in these novel RNAs, the two ends are covalently bonded together and are generated from pre-mRNA in a process known as back-splicing, which makes them more stable than other RNAs. As far as the unique structure and function of circRNAs is concerned, they are implicated in proliferation, migration, invasion, angiogenesis, metastasis, and DR. A clear understanding of the molecular mechanisms responsible for circRNAs-mediated DR in the GI cancers will open a new window to the management of GI cancers. Hence, in the present review, we will describe briefly the biogenesis, multiple features, and different biological functions of circRNAs. Then, we will summarize current mechanisms of DR, and finally, discuss molecular mechanisms through which circRNAs regulate DR development in esophageal cancer, pancreatic cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma.

Multiple novel functions of circular RNAs in diabetes mellitus.

Circular RNAs (circRNAs), as an emerging group of non-coding RNAs (ncRNAs), have received the attention given evidence indicating that these novel ncRNAs are implicated in various biological processes. Due to the absence of 5' and 3' ends in circ-RNAs, their two ends are covalently bonded together, and they are synthesised from pre-mRNAs in a process called back-splicing, which makes them more stable than linear RNAs. There is accumulating evidence showing that circRNAs play a critical role in the pathogenesis of diabetes mellitus (DM). Moreover, it has been indicated that dysregulation of circRNAs has made them promising diagnostic biomarkers for the detection of DM. Recently, increasing attention has been paid to investigate the mechanisms underlying the DM process. It has been demonstrated that there is a strong correlation between the expression of circRNAs and DM. Hence, our aim is to discuss the crosstalk between circRNAs and DM and its complications.

Effect of Capparis spinosa Fruit Hydroalcoholic Extract on Paraquat-Induced Pulmonary Fibrosis in the Rat.

Pulmonary fibrosis (PF) is a lethal inflammatory disease and there has been no effective medication for this progressive disease up to now. Paraquat is commonly used in agricultural settings to control weed growth and is one of the important risk factors for PF. Additionally, emerging evidence has demonstrated Capparis spinosa (C. spinose) fruit extract has anti-fibrotic, anti-inflammatory, and antioxidant properties. We aimed to evaluate whether C. spinose fruit hydroalcoholic extract has a positive effect against Paraquat-induced PF in rats. 30 male Wistar rats were randomly divided into 5 groups, which included: a control group, a Paraquat control group, a C. spinose group with a dose of 20 mg/kg, a C. spinose group with a dose of 30 mg/kg, a C. spinose group with a dose of 50 mg/kg. After 21 days of the treatment, levels of hydroxyproline and malondialdehyde (MDA) in lung tissue were assessed and lung indices and semi-quantitative histopathological changes were determined. The results showed that treatment with C. spinose, led to increased weight gain, whereas reduced lung weight. C. spinose demonstrated a decreasing effect on levels of MDA, and hydroxyproline in lung tissue. Moreover, histopathological data and the number of lung indices indicated the preventive role of C. spinose Paraquat-induced PF in rats.

Melatonin: A smart molecule in the DNA repair system.

DNA repair is an important pathway for the protection of DNA molecules from destruction. DNA damage can be produced by oxidative reactive nitrogen or oxygen species, irritation, alkylating agents, depurination and depyrimidination; in this regard, DNA repair pathways can neutralize the negative effects of these factors. Melatonin is a hormone secreted from the pineal gland with an antioxidant effect by binding to oxidative factors. In addition, the effect of melatonin on DNA repair pathways has been proven by the literature. DNA repair is carried out by several mechanisms, of which homologous recombination repair (HRR) and non-homologous end-joining (NHEJ) are of great importance. Because of the importance of DNA repair in DNA integrity and the anticancer effect of this pathway, we presented the effect of melatonin on DNA repair factors regarding previous studies conducted in this area.

Gene therapy: A promising approach for breast cancer treatment.

Breast cancer (BC) is the most prevalent malignancy and the second leading cause of death among women worldwide that is caused by numerous genetic and environmental factors. Hence, effective treatment for this type of cancer requires new therapeutic approaches. The traditional methods for treating this cancer have side effects, therefore so much research have been performed in last decade to find new methods to alleviate these problems. The study of the molecular basis of breast cancer has led to the introduction of gene therapy as an effective therapeutic approach for this cancer. Gene therapy involves sending genetic material through a vector into target cells, which is followed by a correction, addition, or suppression of the gene. In this technique, it is necessary to target tumour cells without affecting normal cells. In addition, clinical trial studies have shown that this approach is less toxic than traditional therapies. This study will review various aspects of breast cancer, gene therapy strategies, limitations, challenges and recent studies in this area.

50-bp insertion/deletion polymorphism of the superoxide dismutase-1 is associated with bladder cancer risk in an Iranian population.

Bladder cancer (BC) is considered the sixth prevalent malignancy in men and the ninth leading cause of malignancy-related worldwide. Superoxide dismutase (SOD) is an antioxidant enzyme in the defense system against oxidative stress. Hence, we aimed to investigate whether the 50 bp Insertion/Deletion(Ins/Del) polymorphism of the SOD1 associated with the risk of BC. The study was conducted on 158 BC patients and 153 age-matched healthy subjects. Genomic DNA from all individuals was screened for the 50-bp SOD1 promoter deletion using PCR assay. Our results demonstrated an association between SOD1 Ins/Del (45% vs. 32%) genotype and risk of BC and this genotype elevated the susceptibility to BC (OR = 1.80, 95% CI: (1.10-2.90), P = 0.01). In addition, the Del allele of the SOD1 variation was detected to be more prevalent in the BC patients with the frequency of 28% and 20% in cases and healthy groups, correspondingly (OR = 1.61, 95% CI: (1.10-2.36), P = 0.01). It seems that SOD1 50-bp Ins/Del genotype, as well as Del, allele, is associated with an increased risk of BC in an Iranian population. However, further investigations in more diverse populations are necessary to assess the value of the novel biomarkers as a risk stratification biomarker for BC.

Design and evaluation of scFv-RTX-A as a novel immunotoxin for breast cancer treatment: an in silico approach.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in breast cancer (BC) patients. Hence, immunotherapy is a proper treatment option for HER2-positive BC patients. Accumulating evidence has indicated that immunotoxin therapy is a novel approach to improve the potency of targeted therapy. Immunotoxins are antibodies or antibody fragments coupled with a toxin. We designed an immunotoxin. The physicochemical properties were evaluated using ProtParam servers and secondary structure was examined by PROSO II and GORV. Using I-TASSER, a 3D model was built and refined by GalaxyRefine. The model was validated using PROCHECK and RAMPAGE. To predict immunotoxin allergenicity and mRNA stability, AlgPred server and RNAfold were used. Furthermore, the immunotoxin and HER2 were docked by ZDOCK. The scFv+RTX-A could be a non-allergenic and stable chimeric protein, and the secondary structure of its components did not alter, and this protein had a proper 3D structure that might have stable mRNA structure which could bind to HER2. Given the fact that the designed immunotoxin was a non-allergenic and stable chimeric protein and that it could bind with high affinity to HER2 receptors, we proposed that this chimeric protein could be a useful candidate for HER-2 positive BC patients.

Shelterin Complex at Telomeres: Implications in Ageing.

Different factors influence the development and control of ageing. It is well known that progressive telomere shorting is one of the molecular mechanisms underlying ageing. The shelterin complex consists of six telomere-specific proteins which are involved in the protection of chromosome ends. More particularly, this vital complex protects the telomeres from degradation, prevents from activation of unwanted repair systems, regulates the activity of telomerase, and has a crucial role in cellular senescent and ageing-related pathologies. This review explores the organization and function of telomeric DNA along with the mechanism of telomeres during ageing, followed by a discussion of the critical role of shelterin components and their changes during ageing.

Comparison of the calcium-related factors in Parkinson's disease patients with healthy individuals.

BACKGROUND: Parkinson's disease (PD) is one of the most common neurodegenerative diseases (ND). Studies have demonstrated that biochemical markers have an association with PD. We aimed to investigate an association of biochemical markers including calcium, vitamin D, alkaline phosphatase (ALP), parathormone (PTH), and phosphorous with PD. METHODS: This study was conducted on 139 PD patients and 100 healthy individuals. Serum levels of calcium, phosphorous, ALP, PTH and vitamin D were evaluated. Furthermore, student's t-test and logistic regression models were used by SPSS. RESULTS: The mean levels of calcium (9.4±0.7 and 9.0±0.8 ) and vitamin D (29.7±22.1 and 25.8±23.7) were higher in PD patients as compared with healthy controls, which only status of calcium being significantly different in the two groups (P<0.001). Levels of ALP (202.4±96.7 and 242.9±142.4) and phosphorous (3.6±0.6 and 4.22±1.1) were significantly different comparing PD patients with healthy subjects (P<0.01, P<0.001, respectively). ALP and phosphorous were significantly different in the two groups (OR=0.996, [CI 95%, 0.994-0.999], P<0.001, OR=0.475, [CI 95%, 0.325-0.694], P<0.001, respectively). Furthermore, increased levels of calcium resulted in an elevated risk of PD (OR=2.175, [CI 95% 1.377-3.435], P<0.001). CONCLUSION: Results show that mean levels of calcium are higher in PD patients relative to healthy controls. Thereby, higher levels of calcium may be associated with PD.

Association of serum magnesium levels with risk factors, severity and prognosis in ischemic and hemorrhagic stroke patients.

BACKGROUND: Stroke is the third leading cause of mortality worldwide. One of the factors that affect the occurrence of stroke can be attributed to changes in the levels of trace elements. Accumulating evidence has been shown that magnesium, as an important element, is a new predictor of stroke. We aimed to determine the levels of Mg in ischemic stroke patients in comparison with those having the hemorrhagic type. METHODS: This study was conducted on 447 stroke patients. Demographic characteristics of patients, stroke severity, and risk factors such as hypertension, ischemic heart disease, diabetes mellitus, and hyperlipidemia were recorded. Stroke was diagnosed based on the neurological examination and neuroimaging findings e.g. computed tomography (CT) or magnetic resonance imaging (MRI). The colorimetric technique was used to determine the concentration of Mg at 450 nm according to the commercial kit. RESULTS: The mean of magnesium levels in ischemic patients was significantly higher than that in the hemorrhagic patients (P=0.001). Difference in magnesium status was associated with gender in thrombotic patients (P<0.05), while hyperlipidemia was associated with the status of magnesium in embolic patients (P=0.012). Furthermore, magnesium levels were correlated with ischemic heart disease in embolic (P=0.011) and sub-arachnoid hemorrhagic (SAH) patients (P=0.012), and with diabetes mellitus in thrombotic patients (P=0.012). Magnesium status was associated with the severity of ischemic stroke at the time of discharge in ischemic patients (P<0.001). Mg levels had the best area under curve (AUC) for the discrimination of ischemic patients from hemorrhagic ones. CONCLUSION: Magnesium levels were higher in ischemic patients compared to hemorrhagic ones, and these levels were associated with many risk factors contributing to a stroke. Magnesium may be used as a new predictor of stroke in ischemic patients as opposed to hemorrhagic ones.

Modulation of cancer cell signaling by long noncoding RNAs.

Cellular signaling pathways play a very important role in almost all molecular processes in the cell, and are generally composed of a complex set of cascades in which enzymes and proteins play a key role. These signaling pathways include different types of cellular signaling classified based on their receptors and effector proteins such as enzyme-linked receptors, cytokine receptors, and G-protein-coupled receptors each of which is subdivided into different classes. Signaling pathways are tightly controlled by different mechanisms mostly thorough inhibiting/activating their receptors or effector proteins. In the last two decades, our knowledge of molecular biology has changed dramatically and today we know that more than 85% of the human genome expresses noncoding RNAs most of which are crucial in the cellular and molecular mechanisms of cells. One of these noncoding RNAs are long noncoding RNAs (lncRNA) containing more than 200 nucleotides. LncRNAs participate in the progression of cancer growth through several mechanism including signaling pathways. In this review, we summarize some of the most important of lncRNAs and their effect on important signaling pathways.

The crosstalk between trace elements with DNA damage response, repair, and oxidative stress in cancer.

DNA damage response (DDR) is a regulatory system responsible for maintaining genome integrity and stability, which can sense and transduce DNA damage signals. The severity of damage appears to determine DDRs, which can include damage repair, cell-cycle arrest, and apoptosis. Furthermore, defective components in DNA damage and repair machinery are an underlying cause for the development and progression of various types of cancers. Increasing evidence indicates that there is an association between trace elements and DDR/repair mechanisms. In fact, trace elements seem to affect mediators of DDR. Besides, it has been revealed that oxidative stress (OS) and trace elements are associated with cancer development. In this review, we discuss the role of some critical trace elements in the risk of cancer. In addition, we provide a brief introduction on DDR and OS in cancer. Finally, we will further review the interactions between some important trace elements including selenium, zinc, chromium, cadmium, and arsenic, and DDR, and OS in cancer.