Allelic and Genotype Frequencies of CYP2B6∗2 (64C > T) and CYP2B6∗3 (777C > A) in Three Dominant Ethnicities of the Iranian Population.

Background: Cytochrome P450 complex plays a key role in drug metabolism. CYP2B6 has an essential part in Cytochrome P450 complex metabolism. This study aims to determine the allelic distribution of CYP2B6∗2 and CYP2B6∗3 in three main Iranian ethnicities: Fars, Turk, and Kurd. Methods: The study was conducted on 174 unrelated healthy volunteers from three main Iranian ethnicities. After DNA extraction from peripheral blood samples, genotyping of CYP2B6∗2 and ∗3 was performed using tetra ARMS and ARMS PCR, respectively. Results: The average age of 174 cases was 40.69 ± 11.87 (mean ± SD) and 39.06 ± 11.63 (mean ± SD) for males and females. In the CYP2B6∗2 variant, the genotyping frequency of wild type (C/C), heterozygous (C/T), and homozygous mutant (T/T) was 8.7%, 86%, and 5.2%, respectively. The CYP2B6∗2 (c.64C > T) allele frequency was 48.2% (95% CI: (37.8-58.6)). In the CYP2B6∗3 variant, the frequency of wild type (C/C), heterozygous (C/T), and homozygous mutant (T/T) was 75.3%, 11%, and 13.6%, respectively. The CYP2B6∗3 (c.777C > A) allelic frequency was 19.1% (95% CI: (17.5-20.7)). Conclusion: Allelic distribution in three main Iranian ethnicities, i.e., Turk, Kurd, and Fars, is remarkably higher than that in other populations, even that in Southern Iran. High frequencies of CYP2B6∗2 and ∗3 in the Iranian population highly affect drug responsiveness. Understanding such variability could help to increase drug efficacy and reduce its toxicity.

Evaluation of the Effects of Nanomicellar Curcumin, Berberine, and Their Combination with 5-Fluorouracil on Breast Cancer Cells.

INTRODUCTION: Breast cancer is one of the main challenging areas in cancer treatment. Natural compounds such as curcumin and berberine have been approved with anticancer effects and are more favorable to people. Here, we investigated the potential synergistic anticancer effects of these two compounds in combination with the standard cancer drug 5-FU on the growth of MCF-7 breast cancer cells. MATERIALS AND METHODS: This study tested the effects of six different treatments on cancer cell growth: A) control; B) curcumin; C) berberine; D) 5-FU; E) curcumin + berberine; and F) curcumin + berberine + 5-FU. The IC50 concentration of each treatment on cancer cell growth was determined using the MTT assay. Invasiveness of cells grown in 3D culture was analyzed using the transwell chamber technique. Expression levels of genes involved in cancer cell growth and survival (WNT1, APC, AXIN1, CTNNB1, TCF, MTOR, AKT1, MAPK1, PTEN, BIRC5, CCNG1) were evaluated by real-time PCR. RESULTS: There was a reduction in cancer cell growth and invasion, and an increase in cellular decomposition across all treatment groups compared to the control with the strongest effects seen in the combined curcumin/berberine/5-FU group. The expression levels of all tested genes were altered in all treatment groups compared to the control, with that of WNT1, CTNNB1, TCF, MTOR, AKT1, BIRC5, and CCND1 showing the most robust changes in the combined curcumin/berberine/5-FU treatment. CONCLUSIONS: All treatment groups had anti-growth, anti-invasion, and pro-apoptotic effects on MCF-7 breast cancer cells in culture. In addition, all treatment groups showed changes in the expression of the genes involved in cancer cell growth and survival with the strongest effects found for the curcumin/berberine/5-FU combination. Therefore, curcumin and berberine may improve the anticancer effects of chemotherapy and these natural compounds should undergo further testing as potential adjuvants.

Effects of Curcumin and Its Analogues on Infectious Diseases.

Infectious diseases (IDs) are life-threatening illnesses, which result from the spread of pathogenic microorganisms such as bacteria, viruses, fungi, and parasites. IDs are a major challenge for the healthcare systems around the world, leading to a wide variety of clinical manifestations and complications. Despite the capability of frontline-approved medications to partially prevent or mitigate the invasion and subsequent damage of IDs to host tissues and cells, problems such as drug resistance, insufficient efficacy, unpleasant side effects, and high expenses stand in the way of their beneficial applications. One strategy is to evaluate currently explored and available bioactive compounds as possible anti-microbial agents. The natural polyphenol curcumin has been postulated to possess various properties including anti-microbial activities. Studies have shown that it possess pleiotropic effects against bacterial- and parasitic-associating IDs including drug-resistant strains. Curcumin can also potentiate the efficacy of available anti-bacterial and anti-parasitic drugs in a synergistic fashion. In this review, we summarize the findings of these studies along with reported controversies of native curcumin and its analogues, alone and in combination, toward its application in future studies as a natural anti-bacterial and anti-parasitic agent.

Exosomal microRNAs derived from mesenchymal stem cells: cell-to-cell messages.

Exosomes are extracellular vesicles characterized by their size, source, release mechanism and contents. MicroRNAs (miRNAs) are single stranded non-coding RNAs transcribed from DNA. Exosomes and miRNAs are widespread in eukaryotic cells, especially in mesenchymal stem cells (MSCs). MSCs are used for tissue regeneration, and also exert paracrine, anti-inflammatory and immunomodulatory effects. However, the use of MSCs is controversial, especially in the presence or after the remission of a tumor, due to their secretion of growth factors and their migration ability. Instead of intact MSCs, MSC-derived compartments or substances could be used as practical tools for diagnosis, follow up, management and monitoring of diseases. Herein, we discuss some aspects of exosomal miRNAs derived from MSCs in the progression, diagnosis and treatment of various diseases. Video Abstract.

A contemporary review on pathogenesis and immunity of COVID-19 infection.

Emerging of the COVID-19 pandemic has raised interests in the field of biology and pathogenesis of coronaviruses; including interactions between host immune reactions specific, and viral factors. Deep knowledge about the interaction between coronaviruses and the host factors could be useful to provide a better support for the disease sufferers and be advantageous for managing and treatment of the lung infection caused by the virus. At this study, we reviewed the updated information on the pathogenesis of the COVID-19 and the immune responses toward it, with a special focus on structure, genetics, and viral accessory proteins, viral replication, viral receptors, the human immune reactions, cytopathic effects, and host-related factors.

The potential therapeutic use of renin-angiotensin system inhibitors in the treatment of inflammatory diseases.

Inflammation is a normal part of the immune response to injury or infection but its dysregulation promotes the development of inflammatory diseases, which cause considerable human suffering. Nonsteroidal anti-inflammatory agents are the most commonly prescribed agents for the treatment of inflammatory diseases, but they are accompanied by a broad range of side effects, including gastrointestinal and cardiovascular events. The renin-angiotensin system (RAS) is traditionally known for its role in blood pressure regulation. However, there is increasing evidence that RAS signaling is also involved in the inflammatory response associated with several disease states. Angiotensin II increases blood pressure by binding to angiotensin type 1 (AT1 ) receptor, and direct renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) are clinically used as antihypertensive agents. Recent data suggest that these drugs also have anti-inflammatory effects. Therefore, this review summarizes these recent findings for the efficacy of two of the most widely used antihypertensive drug classes, ACE inhibitors and ARBs, to reduce or treat inflammatory diseases such as atherosclerosis, arthritis, steatohepatitis, colitis, pancreatitis, and nephritis.

Effect of curcumin on glioblastoma cells.

Curcumin is a polyphenolic compound derived from Curcumin longa L. There are growing bodies of evidence revealing the antitumor effect of curcumin in different tumors; although the molecular mechanism behind this inhibition in glioblastoma multiform (GBM) still remains unclear. Here we investigated the antitumor activity of nano micelles curcumin compared with erlotinib in U-373 cells in monolayer cell cultures and spheroids models. Furthermore, we characterized affecting cell cycle perturbation, as well as apoptosis induction in GBM cells. The antiproliferative activity of nano micelles curcumin and erlotinib were assessed in monolayer and spheroid models. The influence of the cell cycle and expression levels of nuclear factor κB (NF-κB) and Wnt/ß-catenin pathway was checked. Nano micelles curcumin suppressed cell growth in U-373 cells via modulation of Wnt and NF-κB pathways. Moreover, cells developed an early G2/M cell cycle arrest followed by sub-G1 apoptosis and apoptotic bodies formation posttreatment with nano micelles curcumin and erlotinib. In the core signaling pathways of GBM, nano micelles curcumin either significantly influences the NF-κB pathway by decreasing p-65 expression or significantly inhibits the Wnt/ß-catenin pathway by declining cyclin D1 expression. In conclusion, we have shown that nano micelles curcumin effectively prevent proliferation, and invasion of GBM cells through perturbation of Wnt/ß-catenin and NF-κB pathways, suggesting further investigations on the therapeutic application of this novel anticancer drug in in vivo models.

Circulating microRNA-133, microRNA-17 and microRNA-25 in serum and its potential diagnostic value in gastric cancer.

Gastric cancer is one of the most common malignancies in the world and is considered as the most lethal gastrointestinal cancer. microRNAs (miRNAs) can be very important in detecting a disease at an early stage. The aim of this study was to investigate the microRNA-17 (miR-17), miR-25, and miR-133b in the serum of gastric cancer subjects. Serum samples were obtained from 120 gastric cancers and 102 healthy subjects. We evaluated expression levels of miR-17, miR-25 and miR-133b by quantitative real-time polymerase chain reaction. Our results showed that in the patients with gastric cancer, the expression level of miR-17 and miR-25 were significantly increased compared with the control group (P < 0.5), while the expression level of miR-133b was significantly decreased in patient groups compared with control cases (P < 0.5). It seems that expression of miRNAs in Iranian patients with gastric cancer is similar to other patients in other populations. These findings suggested that miR-17, miR-25 and miR-133b could be introduced as potential diagnostic candidates for the detection in gastric cancer patients in the early stage.

Knockdown of Sal-like 4 expression by siRNA induces apoptosis in colorectal cancer.

Colorectal cancer (CRC) is known as the third most common malignancies among men and women and is also the second leading cause of cancer-related deaths worldwide. It has been indicated that a variety of risk factors are involved in the pathogenesis of CRC. Spalt-like transcription factor 4 (SALL4) is known as a transcription factor that plays an important role in the proliferation of cancerous cells. In this study, using a specific sequence of small interfering RNA (siRNA) against the sequence of SALL4, its activity is investigated in the CRC cell line (sw742). The CRC cells (sw742) were cultured and then, using a specific anti-SALL4 siRNA, their toxic doses were determined. Then, the gene is transfected into the cell. Proliferation and expression of the SALL4 and Bcl-2 gene were measured using the real-time polymerase chain reaction method. Cell death was evaluated by propidium iodide staining and fluorescence-activated cell sorting analysis. Our results indicated that the specific concentration of siRNA of the SALL4 gene was 62.5 nmole. Gene expression of SALL4 and Bcl-2 results showed that expression of Bcl-2 gene in the siRNA group was significantly reduced. In conclusion, our finding indicated that it could be used as a therapeutic and diagnostic biomarker in the treatment of patients with CRC.

Knockdown of sal-like 4 expression by small interfering RNA induces apoptosis in breast cancer cells.

Breast cancer is the most prevalent cancers worldwide and causes a significant amount of deaths annually. Spalt-like transcription factor 4 is known as a transcription factor, which has an important role in the proliferation of cancerous cells. Small interfering RNA (siRNA) is a short-chain molecule of 20 to 25 nucleotides that protrude on two sides of the 3', two nucleotides. In this study, using a specific sequence of siRNA against the sequence of this gene, its activity is investigated in the cell line of breast cancer. The breast cancer cells (MCF-7) were cultured and then, using a specific anti-sal-like 4 (SALL4) siRNA, their toxic doses were determined. Then, the gene is transfected into the cell. Proliferation and expression of the SALL4 and BCL-2 gene were measured using the real-time polymerase chain reaction method. The specific concentration of siRNA IC50 of the SALL4 gene was 40.35 nmole. Gene expression results indicated that the expression of the Bcl-2 gene in the siRNA group was significantly reduced ( P < 0.05). SiRNA can increase the apoptosis of breast cancer cells by reducing the gene expression of SALL4 gene and Bcl-2; it can be used as a novel targeted therapy. This strategy, in addition to increasing the specificity of the drug, also reduces the side effects when compared with conventional chemotherapy.

Vaccines for colorectal cancer: an update.

Colorectal cancer (CRC) is known as the third most common and fourth leading cancer associated death worldwide. The occurrence of metastasis has remained as a critical challenge in CRC, so that distant metastasis (mostly to the liver) has been manifested in about 20%-25% of patients. Several screening approaches have introduced for detecting CRC in different stages particularly in early stages. The standard treatments for CRC are surgery, chemotherapy and radiotherapy, in alone or combination. Immunotherapy is a set of novel approaches with the aim of remodeling the immune system battle with metastatic cancer cells, such as immunomodulatory monoclonal antibodies (immune checkpoint inhibitors), adoptive cell transfer (ACT) and cancer vaccine. Cancer vaccines are designed to trigger the intense response of immune system to tumor-specific antigens. In two last decades, introduction of new cancer vaccines and designing several clinical trials with vaccine therapy, have been taken into consideration in colon cancer patients. This review will describe the treatment approaches with the special attention to vaccines applied to treat colorectal cancer.

Expression of circulating miR-17, miR-25, and miR-133 in breast cancer patients.

One of the most lethal cancers among women is breast cancer. MicroRNAs (miRNAs) can be of great importance in the early detection of breast cancer. This study aimed to investigate some miRNAs in the serum of patients with breast cancer compared with the control group. Total RNA was extracted from the serum of patients with breast cancer and healthy volunteers. The expression levels of miRNAs and the genes were assessed using real-time reverse transcriptase-polymerase chain reaction with specific primers. Our data showed that miR-25 and miR-133 were downregulated, and miR-17 was upregulated in patients with breast cancer. Upregulation of miR-17 is related to the poor survival time and increased cell proliferation. The reduced expression of miR-133 and miR-25 is significantly associated with clinical stage, metastasis, and survival time of patients with breast cancer. Expressions of miRNAs miR-17, miR-25, and miR-133 are altered in patients with clinical stage, metastasis, poor survival time.

Evaluation of the two polymorphisms rs1801133 in MTHFR and rs10811661 in CDKN2A/B in breast cancer.

The 5,10-Methylenetetrahydrofolate reductase (MTHFR) was the rate-limiting enzyme in the methyl cycle, which was encoded by the MTHFR gene. MTHFR played a key role in homocysteine plasma level and was associated with the risk of breast cancer. The cyclin-dependent kinase (CDK) inhibitor (CDKN2A/B) was the tumor suppressor in the cell cycle regulation. The single-nucleotide polymorphism was thought to be associated with the predisposition of breast cancer and in subsequent immune response in different populations. The current study was conducted on a peripheral blood sample of 100 Iranian women with breast carcinoma and 142 cancer-free healthy female volunteers. The TaqMan real-time polymerase chain reaction technique was applied for genotyping of participants. The correlation of both variants and demographic data were investigated with the risk of breast cancer. Our data showed that the MTHFR allele T and TT genotype had the higher prevalence in patients (P < 0.0001) than the control group. The frequency of risk C allele into the CDKN2A/B rs10811661 was 72%. The correlations of menarche and underlying hormonal disorder with the risk of breast cancer were investigated; also our results showed that the menopause status was statistically significant between patients and controls (P = 0.036). Our investigations demonstrated that the MTHFR rs180113 and CDKN2A/B rs10811661 had a significant correlation with the elevated risk of breast cancer and they might be potentially valuable to apply as a prognostic factor for individual health care.

Current status and future prospects of transforming growth factor-ß as a potential prognostic and therapeutic target in the treatment of breast cancer.

The transforming growth factor-ß (TGF-ß) signaling pathway is one of the important pathways involved in the cancer cell proliferation, invasion, migration, angiogenesis, apoptosis, as well as in metastasis by agitation or invasion of metastasis-related factors, including matrix metalloproteinase (MMP), epithelial-to-mesenchymal transition (EMT), tumor microenvironment (TME), cancer stem cells (CSCs), and cell adhesion molecules (CAMs). These data suggest its potential value as a therapeutic object in the treatment of malignancies including breast cancer. Several pharmacological approaches have been established to suppress TGF-ß pathway; such as vaccines, small molecular inhibitors, antisense oligonucleotides, and monoclonal antibodies. Some of these are now approved by the US Food and Drug Administration for targeting the TGF-ß signaling pathway. This study attempts to summarize the current data about the functions of TGF-ß in cancer cells, and their probable application in the cancer therapy with a specific emphasis on recent preclinical and clinical research in the treatment of breast cancer and its prognostic value.

Chemopreventive and therapeutic potential of curcumin in esophageal cancer: Current and future status.

Esophageal cancer is a common malignant tumor with an increasing trend during the past three decades. Currently, esophagectomy, often in combination with neoadjuvant chemo- and radiotherapy, is the cornerstone of curative treatment for esophageal cancer. However, esophagostomy is related to significant risks of perioperative mortality and morbidity, as well as lengthy recovery. Moreover, the adjuvant therapies including chemotherapy and radiotherapy are associated with numerous side effects, limiting compliance and outcome. The dietary agent curcumin has been extensively studied over the past few decades and is known to have many biological activities especially in regard to the prevention and potential treatment of cancer. This review summarizes the chemo-preventive and chemotherapeutic potential of curcumin in esophageal cancer in both preclinical and clinical settings.

MicroRNAs as Diagnostic, Prognostic, and Therapeutic Biomarkers in Prostate Cancer.

Prostate cancer is the most prevalent nonskin cancer and a major cause of cancer-related deaths worldwide. Prostate-specific antigen (PSA) testing is routinely used for screening and early detection of prostate cancer; however, it does not reduce death from prostate cancer. Moreover, PSA is not specific for prostate cancer and results in high false-positive rates, and it is poorly correlated with cancer stage. Therefore, the need for another diagnostic and prognostic factor in prostate cancer is apparent. MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs which are involved in modulation of gene expression posttranscriptionally. Multiple lines of evidence indicate that miRNAs play key roles in various physiological events. Deregulation of miRNAs is related to initiation and development of various diseases such as prostate cancer. It has been shown that various miRNAs (miR-34, miR-21, miR-155, miR-221, miR-222, and let-7) exert their effects by targeting a variety of cellular and molecular pathways (c-Myc, EZH2, c-RSC, BCL2L2, E2F6, ZEB, HMGA251, and CCND2) involved in prostate cancer pathogenesis. Hence, it seems that miRNA expression profiles can be seen as potential candidates for prognosis, diagnosis, and treatment of prostate cancer. Here, we summarize various miRNAs as prognostic, diagnostic, and therapeutic biomarkers for prostate cancer therapy.

Prevalence of CCR5delta32 in Northeastern Iran.

BACKGROUND: A 32-base pair deletion (∆32) in the open reading frame (ORF) of C-C motif chemokine receptor 5 (CCR5) seems to be a protective variant against immune system diseases, especially human immunodeficiency virus type 1 (HIV-1). We aimed to assess the frequency of CCR5∆32 in the healthy Iranian population. METHODS: In this study, 400 normal samples from Khorasan, northeastern Iran, were randomly selected. The frequency of CCR5∆32 carriers was investigated using PCR analysis. Allele prevalence and the fit to the Hardy-Weinberg equilibrium were analyzed. RESULTS: The prevalence of CCR5∆32 in the northeastern population of Iran was 0.016. Four hundred samples were studied, among which one with CCR5∆32/∆32 and 11 with CCR5Wild/∆32 genotype were detected. CONCLUSION: This study was the first investigation for an assessment of the prevalence of CCR5∆32 in northeastern Iran. The low prevalence of CCR5∆32 allele in the Iranian population may result in the increased susceptibility to HIV-1. In addition, this prevalence is the same as that of reported in East Asia, while is lower than that in the Europeans.

The novel role of pyrvinium in cancer therapy.

Pyrvinium pamoate (PP) is a quinoline-derived cyanine dye which was officially approved by FDA for its anthelmintic properties and therapeutic function against animal-like protists such as Cryptosporidium parvum and Plasmodium falciparum in the 1950s. In the last 10 years, several studies have shown the novel activity of pyrvinium in tumor therapy. Some investigations have indicated that pyrvinium could delay or inhibit tumor cell proliferation in cancer models including colon, breast, lung and prostate cancer, and some hematological malignancies. In this review, we discuss multiple critical signaling pathways and mechanisms underlying the anticancer effects of PP. In details, pyrvinium acts through the following main mechanisms: (i) energy and autophagy depletion; and (ii) inhibition of Akt and Wnt-ß-catenin-dependent pathways. Interestingly, pyrvinium has also shown potent anti-cancer stem cell activity. The overwhelming insights into the mechanism of anticancer properties of PP can help establishing novel and future anti-tumor treatment strategies.

Expression of microRNAs and IRAK1 pathway genes are altered in gastric cancer patients with Helicobacter pylori infection.

Gastric cancer (GC) is among the most common cancer types in the world and one of the most lethal gastrointestinal cancers. MicroRNAs (miRNAs) can be of great importance in the early detection of GC. This study aimed to investigate some miRNAs and the genes involved in IRAK1 pathways in the serum of GC patients with Helicobacter pylori (H. pylori) infections compared to the control group. Total RNA was extracted from the serum of GC patients with H. pylori infection and healthy volunteers. The expression levels of miRNAs and the genes were assessed using Real time RT-PCR with specific primers. Our data showed that miR-146, miR-375, and Let-7 were down-regulated and miR-19 and miR-21 were up-regulated in GC patients with H. pylori infection. Other genes involved in the pathways such as RAS, MYC, NFKB, JUN, TRAF6, and IRAK4 were overexpressed; while the expression of PTEN gene was decreased compared to the control group. Expression of miRNAs and IRAK1 pathway genes are altered in patients with GC and H. pylori infection. This suggests a potential role for the above-mentioned miRNAs and genes in the diagnosis of GC.

Berberine: A potential adjunct for the treatment of gastrointestinal cancers?

Gastrointestinal cancers are among the most prevalent cancers in the general population. Despite effective early diagnostics and intervention, the gastrointestinal cancer-related mortality still remains elevated. Berberine (BBR) is a benzyl tetra isoquinoline alkaloid exracted from several plants. BBR is nontoxic to human normal cells, but suppresses the growth of different tumor cells: melanoma, epidermoid carcinoma, hepatoma, oral carcinoma, glioblastoma, prostatic carcinoma, and gastric carcinoma. In particular, BBR seems to suppress the proliferation of gastrointestinal cancers in a number of preclinical models. Several mechanisms of action have been hypothesized and demonstrated: immunomodulation, inhibition of topoisomerase enzymes, suppression of the EGF receptor, Her2/neu, and the VEGF receptor, induction of p53, Cip1/p21, Kip1/p27, Rb expression, induction of apoptosis (by regulation of MMPs pathway, caspases, Bax, and Smac/DIABLO), inhibition of arylamin N-acetyltransferase activity, and regulation of microRNAs expression. The aim of this review is to summarize the pharmacological effects of BBR on animal and human gastrointestinal cancers.