MiRNAs: Emerging Agents for Therapeutic Effects of Polyphenols on Ovarian Cancer.

In terms of female reproductive tract cancers, ovarian cancer remains the principal reason for mortality globally and is notably difficult to identify in its early stages. This fact highlights the critical need to establish prevention strategies for patients with ovarian cancer, look for new robust diagnostic and prognostic markers, and identify potential targets of response to treatment. MicroRNAs (miRNAs) are one of the novel treatment targets in cancer treatment. Thus, understanding the part of miRNAs in the pathogenesis and metastasis of ovarian cancer is at the center of researchers' attention. MiRNAs are suggested to play a role in modulating many essential cancer processes, like cell proliferation, apoptosis, differentiation, adhesion, epithelial-mesenchymal transition (EMT), and invasion. In two recent decades, natural polyphenols' anti-cancer features have been a focal point of research. Meanwhile, polyphenols are good research subjects for developing new cancer treatments. Polyphenols can modify miRNA expression and impact the function of transcription factors when used as dietary supplements. Multiple works have indicated the impact of polyphenols, including quercetin, genistein, curcumin, and resveratrol, on miRNA expression in vitro and in vivo. Here, we provide an in-depth description of four polyphenols used as dietary supplements: quercetin, genistein, curcumin, and resveratrol, and we summarize what is currently known about their regulatory abilities on influencing the miRNA functions in ovarian tumors to achieve therapeutic approaches.

Modulation of long non-coding RNAs by resveratrol as a potential therapeutic approach in cancer: A comprehensive review.

LncRNAs, or long non-coding RNAs, are a subset of RNAs that play a regulatory role in a wide range of biological functions, including RNA processing, epigenetic regulation, and signal transduction. Recent research indicates that lncRNAs play a key role in the development and spread of cancer by being dysregulated in the disease. In addition, lncRNAs have been linked to the overexpression of certain proteins that are involved in tumor development and progression. Resveratrol has anti-inflammatory and anti-cancer properties that it exerts through regulating different lncRNAs. By the regulation of tumor-supportive and tumor-suppressive lncRNAs, resveratrol acts as an anti-cancer agent. By downregulating the tumor-supportive lncRNAs DANCR, MALAT1, CCAT1, CRNDE, HOTAIR, PCAT1, PVT1, SNHG16, AK001796, DIO3OS, GAS5 and H19, and upregulating MEG3, PTTG3P, BISPR, PCAT29, GAS5, LOC146880, HOTAIR, PCA3, NBR2, this herbal remedy causes apoptosis and cytotoxicity. For the purpose of using polyphenols in cancer therapy, it would be helpful to have more in-depth knowledge about lncRNA modulation via resveratrol. Here, we discuss the current knowledge and future promise of resveratrol as modulators of lncRNAs in different cancers.

Role of non-coding RNAs in neuroblastoma.

Neuroblastoma is known as the most prevalent extracranial malignancy in childhood with a neural crest origin. It has been widely accepted that non-coding RNAs (ncRNAs) play important roles in many types of cancer, including glioma and gastrointestinal cancers. They may regulate the cancer gene network. According to recent sequencing and profiling studies, ncRNAs genes are deregulated in human cancers via deletion, amplification, abnormal epigenetic, or transcriptional regulation. Disturbances in the expression of ncRNAs may act either as oncogenes or as anti-tumor suppressor genes, and can lead to the induction of cancer hallmarks. ncRNAs can be secreted from tumor cells inside exosomes, where they can be transferred to other cells to affect their function. However, these topics still need more study to clarify their exact roles, so the present review addresses different roles and functions of ncRNAs in neuroblastoma.

Therapeutic effects of melatonin on endometriosis, targeting molecular pathways: Current knowledge and future perspective.

Endometriosis, the very serious disease in women creates a huge financial burden worldwide, which is comparable to diabetes mellitus. In addition to the typical pelvic pain, endometriosis is related to low life quality and decreased work efficiency; clinical consequences include mood complaints, metabolic impairments, inflammation, immunologic problems, and elevated malignancy risks. Several risk factors are correlated with endometriosis including elevated oxidative and nitrosative stress, long-lasting inflammation, raised immune tolerance, as well as autoimmunity. Melatonin is a natural molecule present throughout both the plant and animal kingdoms. It has numerous functions as an antioxidant and anti-inflammatory agent. Due to the anti-proliferative, antioxidant, anti-inflammatory, and anti-invasive features of melatonin, it performances as a beneficial agent to limit endometriosis; this involves several pathways including antiestrogenic, antioxidant, anti-inflammatory, and anti-apoptosis effects, as well as reducing the growth of E2-induced endometriotic tissue. Moreover, melatonin can favor sleep quality and decrease the unwanted signs in the patients. However, most of the data on melatonin accured from experimental works and additional clinical trials are needed. This review summarizes what is currently known regarding the influence of melatonin on endometriosis. AVAILABILITY OF DATA AND MATERIAL: Not applicable.

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.

Resveratrol and Cervical Cancer: A New Therapeutic Option.

Globally, cervical cancer is the second most common cancer and the third main cause of death related to cancer in women. The cervical cancer mortality rate is higher in underdeveloped and developing vs. developed countries. Chronic infection with human papilloma virus (HPV) can trigger cervical cancer by an interplay of a variety of pathways and molecules (i.e., inflammatory mediators, oxidative stress and apoptosis), leading to carcinogenesis and cancer progression. Cervical carcinoma is treatable in the early stages, while it progresses to metastasis at advanced stages; however, generally, it is poorly manageable with current treatment options. For future advances in the treatment of metastatic or recurrent cervical cancer carcinoma, the identification of new therapeutic platforms is necessary. A new generation of drugs, herbs and spices may provide novel opportunities for cancer therapy. Among the herb-based components, resveratrol has several beneficial effects given its anticancer activities (e.g., anti-angiogenesis, anti-proliferation, anti-metastatic and pro-apoptotic). Hence, this therapeutic agent may prove to have promising potential if clinically corroborated to possess anticancer efficacy. Here, we summarize the chemopreventive and treatment actions of resveratrol for cervical cancer as well as its mechanism of action.

CircRNAs: A Novel Strategy in Diagnosis and Treatment of Thyroid Cancer.

Thyroid cancer is one of the most frequent cancers globally, and its incidence has risen recently. The clinical behavior of thyroid cancer includes a wide range, from benign to invasive malignant tumors. Thus, precious diagnostic activities before therapeutic work are required. Circular RNAs (circRNAs) along with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are known as non-coding RNAs (ncRNAs). Large amounts of investigations have indicated that circRNAs can participate in multiple cellular processes, especially in tumorigenesis. Furthermore, circRNAs are stable in blood or plasma, as well as they are specific in different tissues. Therefore, they could serve as a potential diagnostic biomarker for cancer cells. Limited studies investigated the role of circRNAs in some processes involved in thyroid cancer. In this review, we summarized the current evidence on the potential clinical involvement of circRNAs in thyroid cancer.

Targeting Glioma Cells with Nutraceuticals: Therapeutic Effects Based on Molecular Mechanisms, New Evidence and Perspectives.

Gliomas are the most common malignant cancers of the brain that have unregulated proliferation and are known as highly invasive tumors. Hence, their relapse rate is high, and the prognosis is low. Despite remarkable advances in neuroimaging, neurosurgery, and radiation therapy, they, especially glioblastoma, are highly resistant to treatments, including radiotherapy, surgery, and temozolomide chemotherapy. The average survival rate for patients with malignant glioma is still less than two years. Accordingly, the search for new treatment options has recently become an urgent need. Today, a number of nutraceuticals have been considered because of their special role in inhibiting the angiogenic process, metastasis, and apoptosis, resulting in the inhibition of tumor growth, including glioma. Nutraceuticals can disrupt cancer cells by affecting different pathways. In fact, these compounds can reduce the growth of cancer cells, inhibit their proliferation and angiogenesis, as well as induce apoptosis in these cells and play an important role in various stages of treatment. One of the key targets of nutraceuticals may be to regulate cellular signaling pathways, such as PI3K/Akt/mTORC1, JAK/STAT, and GSK-3, or to exert their effects through other mechanisms, such as cytokine receptors and inflammatory pathways, reactive oxygen species, and miRNAs. This review refers to the results of recent studies and target molecules as well as signaling pathways affected by some nutraceuticals in glioma cells. These studies indicated that clinical trials are imminent and new approaches can be beneficial for patients.

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.

Morus Alba leaf extract affects metabolic profiles, biomarkers inflammation and oxidative stress in patients with type 2 diabetes mellitus: A double-blind clinical trial.

INTRODUCTION: Morus Alba extract, despite its special properties, has been less studied in terms of its effects on metabolic profiles in patients with type 2 diabetes mellitus (T2DM). This study was carried out to determine the effects of Morus Alba extract, known as white mulberry, on liver enzymes, biomarkers of inflammation and oxidative stress, insulin metabolism and lipid profiles in patients with T2DM. METHODS: The current randomized, double-blind, placebo-controlled trial was conducted among 60 patients with T2DM. Subjects were randomly divided into 2 groups to receive either Morus Alba extract (300 mg) (n = 30) or placebo (n = 30) twice a day. Fasting blood samples were collected at the baseline and 12 weeks after intervention to quantify related markers. RESULTS: Morus Alba extract intake significantly decreased insulin (P = 0.026) and malondialdehyde (MDA) (P < 0.001), and significantly increased HDL-cholesterol concentrations (P = 0.001) compared with the placebo. However, Morus Alba extract intake did not affect other metabolic profiles. CONCLUSIONS: The results of this study shown that the 12-week administration of Morus Alba extract among subjects with T2DM had beneficial effects on HDL-cholesterol, insulin and MDA levels, but did not affect other metabolic profiles. The present study was registered in the Iranian website for clinical trials as http://www.irct.ir: IRCT2016081312438N21.

Gynecologic Cancer, Cancer Stem Cells, and Possible Targeted Therapies.

Gynecologic cancer is one of the main causes of death in women. In this type of cancer, several molecules (oncogenes or tumor suppressor genes) contribute to the tumorigenic process, invasion, metastasis, and resistance to treatment. Based on recent evidence, the detection of molecular changes in these genes could have clinical importance for the early detection and evaluation of tumor grade, as well as the selection of targeted treatment. Researchers have recently focused on cancer stem cells (CSCs) in the treatment of gynecologic cancer because of their ability to induce progression and recurrence of malignancy. This has highlighted the importance of a better understanding of the molecular basis of CSCs. The purpose of this review is to focus on the molecular mechanism of gynecologic cancer and the role of CSCs to discover more specific therapeutic approaches to gynecologic cancer treatment.

Anti-inflammatory and antioxidative effects of thiamin supplements in patients with gestational diabetes mellitus.

OBJECTIVE: The aim of this study was to evaluate the effects of thiamin supplementation on biomarkers of inflammation and oxidative stress in patients with gestational diabetes mellitus (GDM). METHODS: This randomized, double-blind, placebo-controlled trial was conducted among 60 patients with GDM. Patients were randomly allocated into two groups to receive either 100 mg/day thiamin supplements (n = 30) or placebo (n = 30) for 6 weeks. RESULTS: Thiamin supplementation significantly decreased serum high-sensitivity C-reactive protein (hs-CRP) (ß - 0.98 mg/L; 95% CI, -1.54, -0.42; p = .001) and plasma malondialdehyde (MDA) levels (ß - 0.86 µmol/L; 95% CI, -1.15, -0.57; p < .001) when compared with the placebo. In addition, thiamin supplementation downregulated gene expression of tumor necrosis factor-alpha (TNF-α) (p = .002) in peripheral blood mononuclear cells of patients with GDM. Thiamin supplementation did not affect other biomarkers of inflammation and oxidative stress. CONCLUSION: Overall, thiamin supplementation for 6 weeks to patients with GDM significantly reduced hs-CRP and MDA levels, and gene expression of TNF-α, but did not affect other biomarkers of inflammation and oxidative stress. CLINICAL TRIAL REGISTRATION NUMBER: Clinical Trials.govIdentifier no. http://www.irct.ir: IRCT20170513033941N58.

Autophagy and gastrointestinal cancers: the behind the scenes role of long non-coding RNAs in initiation, progression, and treatment resistance.

Gastrointestinal (GI) cancers comprise a heterogeneous group of complex disorders that affect different organs, including esophagus, stomach, gallbladder, liver, biliary tract, pancreas, small intestine, colon, rectum, and anus. Recently, an explosion in nucleic acid-based technologies has led to the discovery of long non-coding RNAs (lncRNAs) that have been found to possess unique regulatory functions. This class of RNAs is >200 nucleotides in length, and is characterized by their lack of protein coding. LncRNAs exert regulatory effects in GI cancer development by affecting different functions such as the proliferation and metastasis of cancer cells, apoptosis, glycolysis and angiogenesis. Over the past few decades, considerable evidence has revealed the important role of autophagy in both GI cancer progression and suppression. In addition, recent studies have confirmed a significant correlation between lncRNAs and the regulation of autophagy. In this review, we summarize how lncRNAs play a behind the scenes role in the pathogenesis of GI cancers through regulation of autophagy.

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.

Curcumin administration and the effects on psychological status and markers of inflammation and oxidative damage in patients with type 2 diabetes and coronary heart disease.

INTRODUCTION: This study assessed the effects of curcumin intake on psychological status, markers of inflammation and oxidative damage in patients with type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD). METHOD: This randomized, double-blind, placebo-controlled trial was performed in 60 patients with T2DM and CHD, aged 45-85 years with 2- and 3-vessel CHD. Patients were randomized into two groups to receive either 1000 mg/day curcumin (n = 30) or placebo (n = 30) for 12 weeks. Using RT-PCR method, gene expression related to insulin metabolism and inflammatory markers on mononuclear cells from peripheral blood was evaluated. RESULT: Curcumin intake significantly decreased Pittsburgh Sleep Quality Index (PSQI) (ß -1.27; 95% CI, -2.27, -0.31; P = 0.01) compared to the placebo group. Curcumin intake caused a significant reduction in malondialdehyde (MDA) (ß -0.20 µmol/L; 95% CI, -0.36, -0.04; P = 0.01), significant increase in total antioxidant capacity (TAC) (ß 75.82 mmol/L; 95% CI, 3.400, 148.25; P = 0.04) and glutathione (GSH) levels (ß 63.48 µmol/L; 95% CI, 26.58, 100.37; P = 0.001) when compared with the placebo. Additionally, curcumin intake upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.01). CONCLUSION: Curcumin intake for 12 weeks in patients with T2DM and CHD had beneficial effects on PSQI, TAC, GSH, MDA values, and gene expression of PPAR-γ. This study was retrospectively registered in the Iranian website (www.irct.ir) for registration of clinical trials (http://www.irct.ir: IRCT20170513033941N63).

The Effects of Nano-curcumin on Metabolic Status in Patients With Diabetes on Hemodialysis, a Randomized, Double Blind, Placebo-controlled Trial.

INTRODUCTION: This study evaluated the effects of nano-curcumin intake on metabolic status in patients with diabetes on hemodialysis (HD). METHODS: This randomized, double-blind, placebo-controlled clinical trial was performed on 60 patients with diabetes on HD. Participants were randomly divided into two groups to take either 80 mg/d nano-curcumin (n = 30) or placebo (n = 30) for 12 weeks. RESULTS: Nano-curcumin significantly decreased fasting plasma glucose (ß = -19.68 mg/dL, 95% CI: -33.48 to -5.88; P < .05) and serum insulin levels (ß = -1.70 µIU/mL, 95% CI: -2.96 to -0.44; P < .05) when compared with patients who received placebo. Nanocurcumin treatment was associated with a significant reduction in triglycerides (ß = -16.13 mg/dL, 95% CI: -31.51 to -0.75; P < .05), VLDL-cholesterol (ß = -3.22 mg/dL, 95% CI: -6.30 to -0.15; P < .05), total cholesterol (ß = -17.83 mg/dL, 95% CI: -29.22 to -6.45; P < .05), LDL-cholesterol (ß = -15.20 mg/dL, 95% CI: -25.53 to -4.87; P < .05), and total-cholesterol/HDL-cholesterol ratio (ß = -1.15, 95% CI: -0.2.10 to -0.21; P < .05) when compared with the placebo. Nanocurcumin also resulted in a significant reduction of serum high sensitivity CRP (ß = -0.78 mg/L, 95% CI: -1.41 to -0.15; P < .05), and plasma malondialdehyde (ß = -0.25 µmol/L, 95% CI: -0.45 to -0.04; P < .05); but also with a significant increase in plasma total antioxidant capacity (ß = 52.43 mmol/L; 95% CI: 4.52 to 100.35; P < .05) and total nitrite levels (ß = 3.62 µmol/L, 95% CI: 2.17 to 5.08; P < .001) when compared with placebo. CONCLUSION: Nano-curcumin intake for 12 weeks had beneficial effects on metabolic profile in patients with diabetes on HD.

Chitosan: A compound for drug delivery system in gastric cancer-a review.

Gastric cancer is known as the fourth most common cancer and the second main cause of cancer-related deaths. Gastric cancer has some characteristics including high incidence rates of metastasis and mortality as well as low rates of early diagnosis, radical resection and 5-year survival. Radical surgery and following chemotherapy has been done for patients with early gastric cancer leading to 90 % survival rate in 5-year after operation. Besides, in advanced stage some cases don't have the chance of surgery as well as the risk of metastasis is high in these patients overally leading to poor prognosis. In recent years, finding a suitable drug delivery system for chemotherapeutic drugs in gastric cancer is an considerable subject for researchers. Chitosan is known as an appropriate compound for chemo-drug delivery in cancer treatment due to its high biodegradability and biocompatibility. Moreover, trans-mucosal drug delivery is facilitated by chitosan via its mucoadhesive and cationic features enhancing interaction with mucous membrane. In addition, a large amount of experimental evidence has reported the efficacy of chitosan for drug delivery in gastric cancer. Thus, the aim of this article was to review this evidence as well as new chitosan-based drug delivery systems investigated in gastric cancer.

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.

Circular RNAs: new genetic tools in melanoma.

Melanoma is the most lethal form of skin cancer. New technologies have resulted in major advances in the diagnosis and treatment of melanoma and other cancer types. Recently, some studies have investigated the role of circular RNAs (circRNAs) in different cancers. CircRNAs are a member of long noncoding RNA family mainly formed through back-splicing and have a closed-loop structure. These molecules affect several biological and oncogenic cascades in diverse ways via acting as microRNA sponge, interacting with RNA-binding proteins and acting as a transcription regulator. In this review, we made an insight into the impact of circRNA dysregulation in the melanoma tumorigenesis based on the presented evidences.