The potential therapeutic effect of melatonin in oxaliplatin combination therapy against chemoresistant colorectal cancer cells.

BACKGROUND: Oxaliplatin is one of the main therapeutics in colorectal cancer (CRC) chemotherapy. However, in light of multidrug resistance (MDR) phenotype development, the efficacy of oxaliplatin has decreased. This study aimed to assess the potential therapeutic effect of melatonin in oxaliplatin combination therapy for drug-resistant colorectal cancer cells. METHODS AND RESULTS: Initially, the oxaliplatin-resistant cell line was created of LS174T (LS174T/DR) by using the oxaliplatin IC50 concentration and resting cycles. MTT assays and flow cytometry were applied for assessing cell viability and apoptotic cells. The mRNA expression level of Bax, Bcl2, MT1, MT2, and ABCB1 as well as protein levels of ABCB1, Bcl2, BAX were measured by the qRT-PCR and western blot techniques respectively. P-gp activity was assessed by Rho123 staining. The IC50 concentration of oxaliplatin in resistant cells was increased from 500.7 ± 0.2 nM to 7119 ± 0.1 nM. Bcl2, MT1, MT2, and ABCB1 mRNA plus protein expression levels of Bcl2 and ABCB1 were significantly reduced in resistant cells, along with a marked increase in Bax mRNA and protein levels compared to parental cells. Rho 123 staining revealed a marked reduction in P-gp activities in the combination-treated group compared to the oxaliplatin-treated group. CONCLUSIONS: The results of cytotoxicity assays, MTT, and flow cytometry revealed that the combination of melatonin and oxaliplatin exerts synergistic effects on induction of oxaliplatin's cytotoxicity in CRC. Our research suggests that combining the treatments of melatonin and oxaliplatin may be considered as a new approach to overcoming oxaliplatin resistance in CRC patients.

An update of Nrf2 activators and inhibitors in cancer prevention/promotion.

NF-E2-related factor 2 (Nrf2) protein is a basic-region leucine zipper transcription factor that defends against endogenous or exogenous stressors. By inducing several cytoprotective and detoxifying gene expressions, Nrf2 can increase the sensitivity of the cells to oxidants and electrophiles. Transient Nrf2 activation, by its specific activators, has protective roles against carcinogenesis and cancer development. However, permanent activation of Nrf2 promotes various cancer properties, comprising malignant progression, chemo/radio resistance, and poor patient prognosis. Taken together, these findings suggest that reaching an optimal balance between paradoxical functions of Nrf2 in malignancy may render a selective improvement to identify therapeutic strategies in cancer treatment. In this review, we describe lately discovered Nrf2 inducers and inhibitors, and their chemopreventive and/or anticancer activities.

An evaluation on potential anti-oxidant and anti-inflammatory effects of Crocin.

Crocin, an active ingredient derived from saffron, is one of the herbal components that has recently been considered by researchers. Crocin has been shown to have many anti-inflammatory and antioxidant properties, and therefore can be used to treat various diseases. It has been shown that Crocin has a positive effect on the prevention and treatment of cardiovascular disease, cancer, diabetes, and kidney disease. In addition, the role of this substance in COVID-19 pandemic has been identified. In this review article, we tried to have a comprehensive review of the antioxidant and anti-inflammatory effects of Crocin in different diseases and different tissues. In conclusion, Crocin may be helpful in pathological conditions that are associated with inflammation and oxidative stress.

The role of SOX family in cancer stem cell maintenance: With a focus on SOX2.

The role of cancer stem cells (CSCs) in cancer incidence, drug resistance, and relapse after chemotherapy has been discussed and it has been confirmed that CSCs are extremely important and so, are suitable for therapeutic targeting. Sox families play an important role in carcinogenesis and dis-regulation of SOXs molecules has been observed in different types of cancers. The members of this family have been shown to play an important role in the maintenance of CSCs. In this article, we have tried to evaluate the role of different family members in CSCs maintenance, review various studies in this field and provide a perspective view on this issue. Also, due to the important role and many studies in the field of SOX2 molecule in CSCs, we try to have more focus on this molecule and examine the potential of these molecules for therapeutic targeting.

Potential Therapeutic Effects of Melatonin Mediate via miRNAs in Cancer.

miRNAs are evolutionarily conserved non-coding ribonucleic acids with a length of between 19 and 25 nucleotides. Because of their ability to regulate gene expression, miRNAs have an important function in the controlling of various biological processes, such as cell cycle, differentiation, proliferation, and apoptosis. Owing to the long-standing regulative potential of miRNAs in tumor-suppressive pathways, scholars have recently paid closer attention to the expression profile of miRNAs in various types of cancer. Melatonin, an indolic compound secreted from pineal gland and some peripheral tissues, has been considered as an effective anti-tumor hormone in a wide spectrum of cancers. Furthermore, it induces apoptosis, inhibits tumor metastasis and invasion, and also angiogenesis. A growing body of evidence indicates the effects of melatonin on miRNAs expression in broad spectrum of diseases, including cancer. Due to the long-term effects of the regulation of miRNAs expression, melatonin could be a promising therapeutic factor in the treatment of cancers via the regulation of miRNAs. Therefore, in this review, we will discuss the effects of melatonin on miRNAs expression in various types of cancers.

Role of Nrf2 and mitochondria in cancer stem cells; in carcinogenesis, tumor progression, and chemoresistance.

Cancer stem cells (CSCs) are rare sub-population in tumor mass with self-renewal and differentiation abilities; CSCs are considered as the main cells which are responsible for tumor metastasis, cancer recurrence, and chemo/radio-resistance. CSCs are believed to contain low mitochondria in quantity, high concentration of nuclear factor erythroid 2-related factor 2 (Nrf2), and low reactive oxygen species (ROS) levels. Mitochondria regulate certain cellular functions, including controlling of cellular energetics, calcium signaling, cell growth and cell differentiation, cell cycle regulation, and cell death. Also, mitochondria are the main sources of intrinsic ROS production. Dysfunction of CSCs mitochondria due to oxidative phosphorylation is reported in several pathological conditions, including metabolic disorders, age-related diseases, and various types of cancers. ROS levels play a significant role in cellular signal transduction and CSCs' identity and differentiation capability. Nrf2 is a master transcription factor that plays critical functions in maintaining cellular redox hemostasis by regulating several antioxidant and detoxification pathways. Recently, the critical function of Nrf2 in CSCs has been revealed by several studies. Nrf2 is an essential molecule in the maintenance of CSCs' stemness and self-renewal in response to different oxidative stresses such as chemotherapy-induced elevation of ROS. Nrf2 enables these cells to recover from chemotherapy damages, and promotes establishment of invasion and dissemination. In this study, we have summarized the role of Nrf2 and mitochondria function CSCs, which promote cancer development. The significant role of Nrf2 in the regulation of mitochondrial function and ROS levels suggests this molecule as a potential target to eradicate CSCs.

Targeting cancer stem cells by melatonin: Effective therapy for cancer treatment.

Melatonin is a physiological hormone produced by the pineal gland. In recent decades, enormous investigations showed that melatonin can prompt apoptosis in cancer cells and inhibit tumor metastasis and angiogenesis in variety of malignancies such as ovarian, melanoma, colon, and breast cancer; therefore, its possible therapeutic usage in cancer treatment was confirmed. CSCs, which has received much attention from researchers in past decades, are major challenges in the treatment of cancer. Because CSCs are resistant to chemotherapeutic drugs and cause recurrence of cancer and also have the ability to be regenerated; they can cause serious problems in the treatment of various cancers. For these reasons, the researchers are trying to find a solution to destroy these cells within the tumor mass. In recent years, the effect of melatonin on CSCs has been investigated in some cancers. Given the importance of CSCs in the process of cancer treatment, this article reviewed the studies conducted on the effect of melatonin on CSCs as a solution to the problems caused by CSCs in the treatment of various cancers.

The apatinib inhibits breast cancer cell line MDA-MB-231 in vitro by inducing apoptosis, cell cycle arrest, and regulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways.

BACKGROUND AND PURPOSE: Breast cancer is one of the most common cancers and leading causes of death in the women worldwide. The evidence shows efficacy of apatinib against breast cancer. Accordingly, the present study was conducted to investigate the effect of apatinib on apoptosis, cell cycle, and Mitogen­Activated Protein Kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways in the breast cancer MDA-MB-231 cell line. METHODS: The effects of apatinib on viability, morphology, tumor spheroid, cell cycle, migration, invasion, and apoptosis of MDA-MB-231 breast cancer cells were evaluated in vitro. In addition, expression of proteins involved in NF-κB and MAPK signaling pathways was evaluated using the western blotting analysis. RESULTS: Apatinib decreased viability, tumor spheroid, migration, and invasion of MDA-MB-231 cells. Furthermore, apatinib altered morphology and regulated cell cycle which followed by apoptosis induction in MDA-MB-231 cells. Apatinib decreased expression of p-p65 and p65 proteins in NF-κB signaling pathways and increased expression of p38, p-p38, JNK, and p-JNK in MAPK signaling pathways. CONCLUSION: The results suggested that apatinib can inhibit proliferation, migration and invasion of breast cancer cell line MDA-MB-231 through inducing apoptosis, cell cycle arrest, and regulating NF-κB and MAPK signaling pathways.

Graphene Oxide: A Promising Material for Regenerative Medicine and Tissue Engineering.

Regenerative medicine and tissue engineering have been considered pioneer fields in the life sciences, with an ultimate goal of restoring or switching lost or impaired body parts. Graphene oxide (GO) is the product of graphene oxidation and presents a great opportunity to make substantial progress in the field of regenerative medicine; for example, it supports the possibility of creating a cellular niche for stem cells on a nanoparticle surface. GO creates a fascinating structure for regulating stem cell behavior, as it can potentially applied to the noninvasive chase of stem cells in vivo, the liberation of active biological factors from stem cell-containing delivery systems, and the intracellular delivery of factors such as growth factors, DNA, or synthetic proteins in order to modulate stem cell differentiation and proliferation. Due to the interesting physicochemical properties of GO and its possible usage in tissue engineering approaches, the present review aims to elaborate on the ways in which GO can improve current regenerative strategies. In this respect, the applicability of GO to the repair and regeneration of various tissues and organs, including cardiac muscle, skeletal muscle, and nervous, bone, cartilage, adipose, and skin tissues, is discussed.

Reduced Levels of miR-28 and miR-200a Act as Predictor Biomarkers of Aggressive Clinicopathological Characteristics in Gastric Cancer Patients.

BACKGROUND: MicroRNAs (miRNAs) play critical roles in different pathological processes including cancer development and progression. To find novel molecular diagnostic and prognostic markers and promising therapeutic tools for gastric cancer (GC), we aimed to investigate the relationship of the expression levels of miR-28-5p or miR-200a-3p with the clinicopathological criteria and to explore their impacts on the progression of human GC. MATERIALS AND METHODS: Quantitative RT-PCR was performed to analyze miR-28 and miR-200a expression in 60 GC and 60 non-GC tissue samples. RESULT: Our results revealed that the expressions of miR-200a and miR-28 were significantly downregulated in GC in comparison with non- GC tissues. Tumors with low miR-28 expression had larger tumor size, more advanced histological grade, and a higher incidence of lymph node and distal metastasis than the tumors with high miR-28 expressions. Furthermore, receiver operating characteristic (ROC) analyses demonstrate that the expression of miR-28 is a predictive biomarker allows predicting the histological grade, tumor size, and occurrence of nodal and distal metastases. We also found a significant inverse association between miR-200a expression and the rate of lymph node metastasis (p = 0.010, r = -0.334). CONCLUSION: Our findings suggest that the miR-28 and miR-200a have tumor-suppressor functions and may be considered as potential biomarkers for gastric cancer diagnosis and prognosis.

Epigenetics and Behçet's Disease: DNA Methylation Specially Highlighted.

Behçet's disease (BD) is a multisystem inflammatory disease with unknown etiology. Although evidence about the pathogenesis of BD is growing, the actual cause of this disease is unclear. Both genetic and epigenetic factors are claimed to play significant roles in BD. Epigenetic factors such as age, gender, smoking as well as exogenous factors like diet, infection, stress are related to the onset and clinical manifestations of BD. DNA methylation refers to a major epigenetic element which influences gene activities with catalyzing DNA using a set of DNA methyltransferases (Dnmts). DNA methylation status of many genes in patients with BD is different from that of healthy people. For example, cytoskeletal gene, Human Leukocyte Antigen (HLA) loci, Long interspersed nuclear element (LINE-1), and Arthrobacter luteus (Alu) repetitive sequences are different in the DNA methylation status in patients with BD and healthy controls. In this paper we reviewed, according to previous studies, the mechanisms of epigenetic, the epigenetic factors involved in the BD, and especially the effect of DNA methylation in the Behcet's disease. Future studies are needed to identify the capability of specific DNA methylation alterations in BD in order to predict disease manifestations, medical course, and response to treatment.

Cancer stem cells-emanated therapy resistance: Implications for liposomal drug delivery systems.

It is verified that failure in cancer therapy by conventional chemotherapeutic agents arise from cancer heterogeneity. That, a small subpopulation of cancer cells known as "cancer stem cells" (CSCs) are shown to be responsible for deriving clonal heterogeneity/diversity in tumors, which render them resistant to conventional treatment regimes. So far, efficient targeted cancer therapy by nanotechnology-based drug delivery approaches is well established. Among various introduced nanocarriers, the non-toxic nature and biocompatibility of liposome make it highly desirable for human studies. In addition, liposomal nanocarriers can be used to protect entrapped therapeutic agents against chemical and biological degradation, improve solubility of the encapsulated drugs, provide sustained drug release, extend in vivo half-life, reduce side effects, improve drug pharmacokinetic and pharmacodynamic profiles, reduce drug dosage and administration frequency. Further, multifunctional liposomes can be envisioned that are simultaneously loaded with different theranostics and chemically-modified with different tumor-specific surface ligands for targeted therapy. Such versatile nanocarrier can influence the physicochemical characteristics, immunological mechanisms, and uptake mechanisms following systemic delivery. Other strategies to improve tumor-specific tropism include delivery systems involving immune cells or their modulators. Here, we describe mechanisms by which CSC can promote drug resistance to impair the efficacy of cancer therapies. Then, we summarize the implication of each of these mechanisms as potential therapeutics ways to overcome the therapeutically-resistant CSCs. Further, we discuss the status, therapeutic potential and prospect of different liposomal drug delivery systems in overcoming CSC drug resistance in the clinic.

The MicroRNA-326: Autoimmune diseases, diagnostic biomarker, and therapeutic target.

MicroRNAs (miRNAs) are uniquely regulated in healthy, inflamed, activated, cancerous, or other cells and tissues of a pathological state. Many studies confirm that immune dysregulation and autoimmune diseases with inflammation are correlated with various miRNA expression changes in targeted tissues and cells in innate or adaptive immunity. In this review, we will explain the history and classification of epigenetic changes. Next, we will describe the role of miRNAs changes, especially mir-326 in autoimmunity, autoinflammatory, and other pathological conditions. A systematic search of MEDLINE, Embase, and Cochrane Library was presented for all related studies from 1899 to 2017 with restrictions in the English language. In recent years, researchers have concentrated on mostly those roles of miRNA that are correlated with the inflammatory and anti-inflammatory process. Latest studies have proposed a fundamental pathogenic role in cancers and autoinflammatory diseases. Studies have described the role of microRNAs in autoimmunity and autoinflammatory diseases, cancers, and so on. The miRNA-326 expression plays a significant role in autoimmune and other types of diseases.