Cellular Conversations in Glioblastoma Progression, Diagnosis and Treatment.

Glioblastoma (GBM) is the most frequent malignancy among primary brain tumors in adults and one of the worst 5-year survival rates (< 7%) among all human cancers. Till now, treatments that target particular cell or intracellular metabolism have not improved patients' survival. GBM recruits healthy brain cells and subverts their processes to create a microenvironment that contributes to supporting tumor progression. This microenvironment encompasses a complex network in which malignant cells interact with each other and with normal and immune cells to promote tumor proliferation, angiogenesis, metastasis, immune suppression, and treatment resistance. Communication can be direct via cell-to-cell contact, mainly through adhesion molecules, tunneling nanotubes, gap junctions, or indirect by conventional paracrine signaling by cytokine, neurotransmitter, and extracellular vesicles. Understanding these communication routes could open up new avenues for the treatment of this lethal tumor. Hence, therapeutic approaches based on glioma cells` communication have recently drawn attention. This review summarizes recent findings on the crosstalk between glioblastoma cells and their tumor microenvironment, and the impact of this conversation on glioblastoma progression. We also discuss the mechanism of communication of glioma cells and their importance as therapeutic targets and diagnostic and prognostic biomarkers. Overall, understanding the biological mechanism of specific interactions in the tumor microenvironment may help in predicting patient prognosis and developing novel therapeutic strategies to target GBM.

Potential of natural products in the treatment of myocardial infarction: focus on molecular mechanisms.

Although conventional drugs are widely used in the prevention and treatment of cardiovascular disease (CVD), they are being used less frequently due to concerns about possible side effects over the long term. There has been a renewed research interest in medicinal plant products, and their role in protecting the cardiovascular system and treating CVD, which are now being considered as potential alternatives to modern drugs. The most important mechanism causing damage to the myocardium after heart attack and reperfusion, is increased levels of free radicals and oxidative stress. Therefore, treatment approaches often focus on reducing free radicals or enhancing antioxidant defense mechanism. It has been previously reported that bioactive natural products can protect the heart muscle in myocardial infarction (MI). Since these compounds are readily available in fruits and vegetables, they could prevent the risk of MI if they are consumed daily. Although the benefits of a healthy diet are well known, many scientific studies have focused on whether pure natural compounds can prevent and treat MI. In this review we summarize the effects of curcumin, resveratrol, quercitin, berberine, and tanshinone on MI and CVD, and focus on their proposed molecular mechanisms of action.

Are anti-inflammatory agents and nutraceuticals - novel inhibitors of PCSK9?

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease which increases the lysosomal degradation of low density lipoprotein receptor (LDLR) resulting in elevated serum LDL-cholesterol levels. Elevated LDL-cholesterol is the main risk factor for cardiovascular disease (CVD). Antibodies to PCSK9 decrease LDL-cholesterol. Recent studies have suggested a direct relationship between PCSK9 and inflammation and the potential inhibitory effects of anti-inflammatory agents against this enzyme. Nutraceuticals are natural compounds, which have numerous anti-inflammatory and lipid-lowering effects. In this review we focus on anti-inflammatory substances and nutraceuticals, which are beneficial in treatment of dyslipidemia. We also reviewed the recent findings concerning the role of PCSK9 as the main target for molecular mechanisms of these substances.

Circular RNAs: A novel biomarker for cervical cancer.

Besides messenger RNAs, recent RNA-Seq and biochemical analysis showed another type of RNAs as a product of splicing which is named circular RNA (circRNA). Evidence demonstrated that circRNAs are abundant in the cells and are able to show cell/tissue-specific expression or tissue developmental stage which suggest that circRNAs may have regulatory potentials. In recent years, researchers have focused attention on circRNAs because of their key functions in various cellular mechanisms. CircRNAs also have the potential to be as promising biomarkers for diagnosis of various diseases such as cancer. Growing up evidence has shown the various roles of circRNAs in multiple cancers. In recent years, cervical cancer as one of the main causes of cancer death in women has been interesting for molecular research. CircRNAs are one of the novel objects which have recently been evaluated in this cancer. The improvement in our knowledge of the roles of circRNAs in cervical cancer may lead to new transcription therapeutic approaches to cervical cancer inhibition. Therefore, the purpose of this review is to review many studies which examined the role of circRNAs in cervical cancer carcinogenesis and progression up till date and to summarize possible mechanisms of action of circRNAs in cervical neoplasm.

Melatonin: A promising agent targeting leukemia.

Leukemia or cancer of blood is a well-known cancer, which affects a range of people from newborns to the very old. It is a public health problem throughout the world. By way of treatment, due to the lack of specific anticancer therapies, common treatments of leukemia lead to severe side effects. Nonspecific anticancer drugs result in inhibition of normal cell growth and thereby their necrosis. Moreover, drug resistance is an additional problem, which stands in the way of leukemia treatment. Thus, finding new treatments for leukemia is essential. Melatonin, as a natural product, has been shown to be effective in a wide variety of diseases such as coronary heart disease, schizophrenia, chronic pain, and Alzheimer's disease. In addition, melatonin levels have been observed to be altered in different cancers, such as breast cancer, colorectal cancer endometrial cancer, and hematopoetical cancers. Anticancer features of melatonin such as pro-oxidation, apoptosis induction, antiangiogenesis property and metastasis and invasion inhibition suggest that this natural compound can be used as a potential agent in novel therapeutic strategies for cancers. Also, it has been reported that melatonin has positive and protective effects on different physiological reactions and in normal bone marrow cells suggesting effectiveness in leukemia therapy. Thus, the aim of our paper was to depict and summarize the main molecular targets of melatonin on leukemia models.

The effects of catechin on endothelial function: A systematic review and meta-analysis of randomized controlled trials.

The findings of trials investigating the effect of catechin on endothelial function are controversial. This meta-analysis of randomized controlled trials (RCTs) was performed to summarize the existing evidence and determine the effects of catechin supplementation on endothelial function. Two authors independently searched electronic databases including MEDLINE, EMBASE, Cochrane Library, and Web of Science from inception until March 2019, in order to find relevant RCTs. The quality of selected RCTs was evaluated using the Cochrane Collaboration risk of bias tool. Cochrane's Q test and I-square (I 2) statistic were used to determine the heterogeneity of included trials. Data were pooled using a random-effects model and weighted mean difference (WMD) was considered as the overall effect size. A total of 16 studies with 22 effect sizes were included in this meta-analysis. A significant increase in flow mediated dilation (FMD) in 10 studies was found after catechin supplementation including 13 effect sizes (WMD: 1.53; 95% CI: 0.93, 2.14). The pooled analysis of 7 effect sizes from 4 studies showed a significant reduction in pulse wave velocity (PWV) after catechin supplementation (WMD: -0.32; 95% CI: -0.44, -0.20) and combining 5 effect sizes from 3 studies in augmentation index (AI) (WMD: -3.57; 95% CI: -6.40, -0.74). Catechin supplementation significantly increased FMD, and significantly reduced PWV and AI, but did not affect other markers of endothelial function.

The effects of n-3 fatty acids from flaxseed oil on genetic and metabolic profiles in patients with gestational diabetes mellitus: a randomised, double-blind, placebo-controlled trial.

The present study was performed to evaluate the effects of n-3 fatty acids from flaxseed oil on genetic and metabolic profiles in patients with gestational diabetes mellitus (GDM). This randomised, double-blind, placebo-controlled clinical trial was performed in sixty women with GDM. Participants were randomly divided into two groups to intake either 2 × 1000 mg/d n-3 fatty acids from flaxseed oil containing 400 mg α-linolenic acid in each capsule (n 30) or placebo (n 30) for 6 weeks. n-3 Fatty acid intake up-regulated PPAR-γ (P < 0·001) and LDL receptor (P = 0·004) and down-regulated gene expression of IL-1 (P = 0·002) and TNF-α (P = 0·001) in peripheral blood mononuclear cells of subjects with GDM. In addition, n-3 fatty acid supplementation reduced fasting plasma glucose (P = 0·001), insulin levels (P = 0·001) and insulin resistance (P < 0·001) and increased insulin sensitivity (P = 0·005) when compared with the placebo. Additionally, n-3 fatty acid supplementation was associated with a decrease in TAG (P < 0·001), VLDL-cholesterol (P < 0·001), total cholesterol (P = 0·01) and total cholesterol:HDL-cholesterol ratio (P = 0·01) when compared with placebo. n-3 Fatty acid administration was also associated with a significant reduction in high-sensitivity C-reactive protein (P = 0·006) and malondialdehyde (P < 0·001), and an increase in total nitrite (P < 0·001) and total glutathione levels (P = 0·006) when compared with the placebo. n-3 Fatty acid supplementation for 6 weeks to women with GDM had beneficial effects on gene expression related to insulin, lipid and inflammation, glycaemic control, lipids, inflammatory markers and oxidative stress.

Molecular and Biological Functions of Quercetin as a Natural Solution for Cardiovascular Disease Prevention and Treatment.

Cardiovascular disease (CVD) is a worldwide health problem with growing up rates of mortality and morbidity. Many risk factors, including high blood pressure, cigarette smoking, diabetes, obesity, and dyslipidemia are responsible for CVD. CVD can be prevented by some simple and cost-effective steps such as smoking cessation, normalizing body weight, regular physical activity, and dietary changes, including decreasing saturated fats, increasing the intake of vegetables and fruits, and reducing sugar intake. In the last decades, growing up number of studies were performed to explain the possible function of non-nutrient substances from the diet which might prevent CVD. One of these natural compounds is quercetin which is widely present in vegetables, tea, fruits and wine. Many in vitro, in vivo and clinical studies have indicated the cardioprotective functions of quercetin. They can be explained by quercetin's reducing blood pressure, antioxidant potential and some other activities. This review evaluates the experimental and clinical studies that have studied the effect of quercetin in CVD and summarizes the molecular mechanisms of action as well as clinical effects of quercetin in CVD.

Association between microRNAs expression and signaling pathways of inflammatory markers in diabetic retinopathy.

Diabetic retinopathy is one of the common and serious microvascular complications of diabetes mellitus, as hyperglycemia has metabolic effects on the retina. Hyperglycemia induces increased oxidative stress, which stimulates inflammation pathways and promotes vascular dysfunction of the retina that leads to increased capillary permeability and vascular leakage. One of the main factors involving diabetic retinopathy is the inflammation signaling pathways. In contemporary times, microRNAs (miRNAs) are identified as functional biomarkers for early detection and treatment of numerous diseases specifically diabetic retinopathy. MiRNAs can modulate gene expression through regulation of transcriptional and posttranscriptional of target genes. With that, miRNAs can regulate almost every cellular and developmental process, including the regulation of instinct immune responses and inflammation. The aim of this study is to investigate the role of miRNAs in inflammation pathways and the pathogenesis of diabetic retinopathy.

Melatonin: A new inhibitor agent for cervical cancer treatment.

Cervical cancer is one of the most common cancers between women and is known as the third leading cause of female cancer related deaths annually. Its detection in early stages allows it to be a preventable and generally treatable disease. Increasing evidence revealed, a variety of internal and external factors are associated with initiation and progression of cervical cancer pathogenesis. Human papilloma virus infection is found as a major cause of cervical cancer. Other molecular and biochemical alterations as well as genetic and epigenetic changes are related cervical cancer progression. Current treatment options often have severe side effects and toxicities thus, new adjuvant agents having synergistic effects and ability to decrease different side effects and toxicities are needed. Melatonin is an indolamine compound secreted from the pineal gland which shows wide range anticancer activities. A large amount of studies indicated inhibitory effects of melatonin against various types of cancers. In addition, experimental evidence reports inhibitory effects of melatonin as an adjuvant therapy on cervical cancer by targeting a sequence of different molecular mechanisms. Herein, for first time, we summarized anticervical cancer effects of melatonin and its underlying molecular mechanisms.

Role of histone modification and DNA methylation in signaling pathways involved in diabetic retinopathy.

Retinopathy, characterized by an alteration of the retinal microvasculature, is a common complication of diabetes mellitus. These changes can cause increased permeability and alter endothelial cell proliferation, edema, and abnormal neovascularization and eventually result in blindness. The pathogenesis of diabetic retinopathy (DR) is complicated, involving many factors/mediators such as genetic susceptibility, microRNAs, and cytokines. One of the factors involved in DR pathogenesis is epigenetic changes that can have a key role in the regulation of gene expression; these include microRNAs, histone modifications, and methylation of DNA. The main epigenetic modifications are DNA methylation and posttranslational modifications of the histones. Generally, the studies on epigenetics can provide new opportunities to investigate the molecular basis of diseases with complicated pathogenesis, including DR, and provide essential insights into the potential design of strategies for its treatment. The aim of this study is an investigation of DR pathogenesis and epigenetic modifications that involve in DR development.

Molecular pathogenesis of interstitial cystitis/bladder pain syndrome based on gene expression.

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder inflammation that leads to chronic bladder pain and urinary urgency and frequency. The presentation of IC/PBS is heterogeneous, and it is classified as ulcerative IC/PBS and nonulcerative IC/PBS. The main cause of IC/PBS is thought to be a persistent inflammatory condition in the bladder, though the actual pathophysiology has not been identified yet. Although the underlying pathophysiology of IC/PBS is not completely understood, several theories for the etiology of this syndrome have been suggested, including deficiency of the glycosaminoglycan covering urothelium surface that results in leaky urothelium infection, immunological etiology, activated mast cells, neural changes, and inflammation. In addition, there are no gold standards for the detection of this disorder to date. So, determination of gene expression and its role in different signaling pathways in the pathogenesis of this heterogeneous disorder contribute to the more efficient cognition of the pathophysiology of this disease and to the design of effective treatments and molecular diagnostic methods for IC/PBS.

Melatonin as a potential inhibitor of colorectal cancer: Molecular mechanisms.

Colorectal cancer (CRC) is a prevalent disease and a major cause of mortality in the world. Several factors including population aging, poor dietary habits, obesity, insufficient physical activity, and smoking can explain its increased prevalence. CRC is a heterogeneous disease both histopathologically and in term of its molecular and genetic aspects. Melatonin a derivative of tryptophan, is synthesized and released from pineal gland but it is also found in numerous extrapineal tissues including retina, testes, lymphocytes, Harderian gland, gastrointestinal tract, etc. This molecule has several tasks which enhance physiological functions such as antioxidant, antiaging, immunomodulatory, and tumor inhibition. Multiple immunocytochemical studies reported melatonin in the intestinal mucosa where its concentration is greater than in the blood. These findings suggest that melatonin may have a potential inhibitory role in CRC progression. The purpose of this review is to examine the effects of melatonin in molecular pathogenesis and signaling pathways of CRC.

Melatonin is an appropriate candidate for breast cancer treatment: Based on known molecular mechanisms.

Breast cancer is the most prevalent cancer and one of the most important causes of death in women throughout the world. Breast cancer risk factors include smoking, alcohol consumption, personal and family history, hypertension, and hormone therapy, long-term use of nonsteroidal anti-inflammatory drugs and tobacco usage. Surgery, chemotherapy, radiotherapy, immunotherapy, and neoadjuvant therapy are the current means for breast cancer treatment. Despite hormonal agents and chemotherapy, which have beneficial effects on lowering breast cancer death rate, the reaction of different people to these treatments is still a challenging point. Melatonin (N-acetyl-5-methoxy tryptamine) is a methoxy indole compound that is mainly secreted by the pineal gland at night; it is as an antioxidant, anti-inflammatory, and oncostatic agent. On the basis of recent studies, melatonin has antitumor properties on different cancer types and it may suppress cancer development in vitro and as well as in animal models. It is suggested that melatonin inhibits the development of breast cancer by various mechanisms. This paper summarizes the roles of melatonin in breast cancer treatment from the aspect of its molecular actions.

Resveratrol is a promising agent for colorectal cancer prevention and treatment: focus on molecular mechanisms.

Colorectal cancer (CRC) is the third most common cancer and one of the main causes of cancer death entire the world. Environmental, dietary, and lifestyle factors including red meat consumption, cigarette smoking, alcohol intake and family history are the most important risk factors of CRC. Multiple pathways including inflammation, oxidative stress, and apoptosis are involved in its incidence and progression. Resveratrol, a polyphenolic compound, has different pharmacologic functions including anti-inflammation, cancer prevention, lipid-lowering effect, and hypoglycemic effect. Many studies have proved that resveratrol might also represent a chemo preventive effect on CRC. Thus, the aim of the current review is to depict the role of resveratrol in treatment of CRC in a molecular manner.

Could circRNA be a new biomarker for pre-eclampsia?

Pre-eclampsia is a devastating complication of pregnancy which is characterized by hypertension and proteinuria in pregnant women. Pre-eclampsia is important as it is the leading cause of death. Moreover, untreated pre-eclampsia might lead to other lethal complications, for both fetus and mother. Pre-eclampsia can also affect the quality of life in affected women. Despite a large number of risk factors for pre-eclampsia, these risk factors are able to detect just 30% of women who are susceptible to pre-eclampsia. Heterogeneous manifestations of pre-eclampsia necessitate the discovery of potential biomarkers required for its early detection. Circular RNAs (circRNAs) are a type of RNA which are more abundant, specific, and highly organized compared with other types of RNA. Accordingly, circRNAs have been suggested as one of the potential biomarkers for different diseases. Recently, researchers have shown interest in the effects of circRNAs in pre-eclampsia, although the current evidence is limited. The majority of obstetricians are probably not aware of circRNAs as a useful biomarker. Here, we aimed to summarize recent supporting evidence and assess the mechanisms by which circRNAs are involved in pre-eclampsia.

Targeting regulatory T cells by curcumin: A potential for cancer immunotherapy.

Immune system has critical roles in fighting against several diseases like cancer. Cancer cells evolve several ways to escape from the immune system to remain alive and trigger new phases of cancer progression. Regulatory T cells are one of the key components in tumor immune tolerance and contribute to the evasion of cancer cells from the immune system. Targeting regulatory T cells could provide new horizons in designing and development of effective therapeutic platforms for the treatment of various malignancies. Curcumin is the bioactive pigment of turmeric and a well-known phytochemical with a wide range of pharmacological activities. A growing body of evidence has demonstrated that curcumin affects manifold molecular pathways that are implicated in tumorigenesis and cancer metastasis. In this regard, some studies have indicated that this phytochemical could target regulatory T cells and convert them into T helper 1 cells, which possess anti-tumor effects. On the contrary, curcumin is able to increase the number of regulatory T cells in other conditions such as inflammatory bowel disease. Herein, we describe the anti-cancer roles of curcumin via targeting regulatory T cells. Moreover, we summarize the effects of curcumin on regulatory T cell population in other diseases.

Long-term vitamin D and high-dose n-3 fatty acids' supplementation improve markers of cardiometabolic risk in type 2 diabetic patients with CHD.

This study was performed to evaluate the effects of vitamin D and n-3 fatty acids' co-supplementation on markers of cardiometabolic risk in diabetic patients with CHD. This randomised, double-blinded, placebo-controlled trial was conducted among sixty-one vitamin D-deficient diabetic patients with CHD. At baseline, the range of serum 25-hydroxyvitamin D levels in study participants was 6·3-19·9 ng/ml. Subjects were randomly assigned into two groups either taking 50 000 IU vitamin D supplements every 2 weeks plus 2× 1000 mg/d n-3 fatty acids from flaxseed oil (n 30) or placebo (n 31) for 6 months. Vitamin D and n-3 fatty acids' co-supplementation significantly reduced mean (P = 0·01) and maximum levels of left carotid intima-media thickness (CIMT) (P = 0·004), and mean (P = 0·02) and maximum levels of right CIMT (P = 0·003) compared with the placebo. In addition, co-supplementation led to a significant reduction in fasting plasma glucose (ß -0·40 mmol/l; 95 % CI -0·77, -0·03; P = 0·03), insulin (ß -1·66 µIU/ml; 95 % CI -2·43, -0·89; P < 0·001), insulin resistance (ß -0·49; 95 % CI -0·72, -0·25; P < 0·001) and LDL-cholesterol (ß -0·21 mmol/l; 95 % CI -0·41, -0·01; P = 0·04), and a significant increase in insulin sensitivity (ß +0·008; 95 % CI 0·004, 0·01; P = 0·001) and HDL-cholesterol (ß +0·09 mmol/l; 95 % CI 0·01, 0·17; P = 0·02) compared with the placebo. Additionally, high-sensitivity C-reactive protein (ß -1·56 mg/l; 95 % CI -2·65, -0·48; P = 0·005) was reduced in the supplemented group compared with the placebo group. Overall, vitamin D and n-3 fatty acids' co-supplementation had beneficial effects on markers of cardiometabolic risk.