Mechanistic Features and Therapeutic Implications Related to the MiRNAs and Wnt Signaling Regulatory in Breast Cancer.

Breast cancer (BC) is accountable for a large number of female-related malignancies that lead to lethality worldwide. Various factors are considered in the occurrence of BC, including the deregulation of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT). Genetic factors such as microRNAs (miRs) are crucially responsible for BC progression and aggressiveness. Hence, the association of miRs and EMT regulators (e.g., Wnt signaling pathway) is of importance. In the present review, we accurately discussed this interplay (interaction between Wnt and miRs) concerning cell - invasion, -migration, -differentiation, -chemoresistance, survival, and-proliferation, and BC prognosis. The putative therapeutic agents, multidrug resistance (MDR) evade, and possible molecular targets are described as well.

The effects of Berberis vulgaris L. and Berberis aristata L. in metabolic syndrome patients: a systematic and meta-analysis study.

INTRODUCTION: This meta-analysis study assessed the effects of Berberis vulgaris L. and Berberis aristata L. in patients with metabolic syndrome. METHODS: Data were analysed through "random-effects meta-regression" performance. RESULTS: The findings indicated that LDL was 0.68 and 2.92 lower in the B. vulgaris L. and B. aristata L.-treated groups versus the controls. The HDL was 0.71-fold higher in the B. aristata L.-treated group versus the controls. The total-cholesterol levels were 1.02 and 2.25 folds lower in the B. vulgaris L. and B. aristata L.-treated groups versus the matched control groups. The triglyceride levels were 1.35 and 1.16-fold lower in the B. vulgaris L. and B. aristata L.-treated groups versus the controls. Glucose was 0.96 and 0.54 folds lower in the B. vulgaris L. and B. aristata L.-treated groups versus the control groups, respectively. CONCLUSION: B. vulgaris L. and B. aristata L. have beneficial effects in patients with metabolic syndrome.

The Protective Role of Grape Seed in Obesity and Lipid Profile: An Updated Narrative Overview of Preclinical and Clinical Studies.

Obesity and dyslipidemia are common disorders universally. According to the acquired outcomes of recent studies, dietary supplementations which have great content of phenolic compounds exert protective effects against obesity and dyslipidemia. Grape [Vitis vinifera] seeds are considered attractive sources of phenolic compounds with anti-oxidative stress and anti-inflammatory effects. There are also various experimental studies describing hepatoprotective, neuroprotective, anti-aging, cardioprotective, and anti-carcinogenic effects of polyphenols isolated from grape seed, highlighting the therapeutic and biological aspects of proanthocyanidins. The present review article first discusses pharmacological, botanical, toxicological, and phytochemical characteristics of Vitis vinifera seeds and afterward designates the protective properties which are attributed to the intake of grape seeds in obesity and hyperlipidemia. Overall valuable and updated findings of this study display that polyphenol of grape seeds has meaningful impacts on the regulation of lipid profile levels and management of obesity.

The interplay between oxidative stress and autophagy: focus on the development of neurological diseases.

Regarding the epidemiological studies, neurological dysfunctions caused by cerebral ischemia or neurodegenerative diseases (NDDs) have been considered a pointed matter. Mount-up shreds of evidence support that both autophagy and reactive oxygen species (ROS) are involved in the commencement and progression of neurological diseases. Remarkably, oxidative stress prompted by an increase of ROS threatens cerebral integrity and improves the severity of other pathogenic agents such as mitochondrial damage in neuronal disturbances. Autophagy is anticipated as a cellular defending mode to combat cytotoxic substances and damage. The recent document proposes that the interrelation of autophagy and ROS creates a crucial function in controlling neuronal homeostasis. This review aims to overview the cross-talk among autophagy and oxidative stress and its molecular mechanisms in various neurological diseases to prepare new perceptions into a new treatment for neurological disorders. Furthermore, natural/synthetic agents entailed in modulation/regulation of this ambitious cross-talk are described.

Promising Protective Effects of Chrysin in Cardiometabolic Diseases.

Cardiometabolic diseases (CMD) have caused a great burden in terms of morbidity and mortality worldwide. The vicious cycle of CMD consists of type II diabetes, hypertension, dyslipidemia, obesity, and atherosclerosis. They have interlinked pathways, interacting and interconnecting with each other. The natural flavonoid chrysin has been shown to possess a broad spectrum of therapeutic activities for human health. Herein, we did an in-depth investigation of the novel mechanisms of chrysin's cardioprotection against cardiometabolic disorders. Studies have shown that chrysin protects the cardiovascular system by enhancing the intrinsic antioxidative defense system. This antioxidant property enhanced by chrysin protects against several risk factors of cardiometabolic disorders, including atherosclerosis, vascular inflammation and dysfunction, platelet aggregation, hypertension, dyslipidemia, cardiotoxicity, myocardial infarction, injury, and remodeling, diabetes-induced injuries, and obesity. Chrysin also exhibited anti-inflammatory mechanisms through inhibiting pro-inflammatory pathways, including NF-κB, MAPK, and PI3k/Akt. Furthermore, chrysin modulated NO, RAS, AGE/RAGE, and PPARs pathways which contributed to the risk factors of cardiometabolic disorders. Taken together, the mechanisms in which chrysin protects against cardiometabolic disorder are more than merely antioxidation and anti-inflammation in the cardiovascular system.

A Concise Overview of Biosensing Technologies for the Detection of Alzheimer's Disease Biomarkers.

Alzheimer's disease (AD) is a brain-linked pathophysiological condition with neuronal degeneration and cognition dysfunctions and other debilitations. Due to the growing prevalence of AD, there is a highly commended trend to accelerate and develop analytical technologies for easy, costeffective, and sensitive detection of AD biomarkers. Biosensors are commanding analytical devices that can conduct biological responses on transducers into measurable signals. This review focuses on up-todate developmets, contests, and tendencies regarding AD biosensing principally, with the emphasis on the exclusive possessions of nanomaterials. In the last decade, remarkable advancements have been achieved to the progression of biosensors, predominantly optical and electrochemical, for the detection of AD biomarkers. These analytical devices can assist the case finding and management of AD.

An Overview of NO Signaling Pathways in Aging.

Nitric Oxide (NO) is a potent signaling molecule involved in the regulation of various cellular mechanisms and pathways under normal and pathological conditions. NO production, its effects, and its efficacy, are extremely sensitive to aging-related changes in the cells. Herein, we review the mechanisms of NO signaling in the cardiovascular system, central nervous system (CNS), reproduction system, as well as its effects on skin, kidneys, thyroid, muscles, and on the immune system during aging. The aging-related decline in NO levels and bioavailability is also discussed in this review. The decreased NO production by endothelial nitric oxide synthase (eNOS) was revealed in the aged cardiovascular system. In the CNS, the decline of the neuronal (n)NOS production of NO was related to the impairment of memory, sleep, and cognition. NO played an important role in the aging of oocytes and aged-induced erectile dysfunction. Aging downregulated NO signaling pathways in endothelial cells resulting in skin, kidney, thyroid, and muscle disorders. Putative therapeutic agents (natural/synthetic) affecting NO signaling mechanisms in the aging process are discussed in the present study. In summary, all of the studies reviewed demonstrate that NO plays a crucial role in the cellular aging processes.

An updated review on the versatile role of chrysin in neurological diseases: Chemistry, pharmacology, and drug delivery approaches.

Neurological diseases are responsible for a large number of morbidities and mortalities in the world. Flavonoids are phytochemicals that possess various health-promoting impacts. Chrysin, a natural flavonoid isolated from diverse fruits, vegetables, and even mushrooms, has several pharmacological activities comprising antioxidant, anti-inflammatory, antiapoptotic, anticancer, and neuroprotective effects. The current study was designed to review the relationship between chrysin administration and neurological complications by discussing the feasible mechanism and signaling pathways. Herein, we mentioned the sources, pharmacological properties, chemistry, and drug delivery systems associated with chrysin pharmacotherapy. The role of chrysin was discussed in depression, anxiety, neuroinflammation, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, cerebral ischemia, spinal cord injury, neuropathy, Multiple Sclerosis, and Guillain-Barré Syndrome. The findings indicate that chrysin has protective effects against neurological conditions by modulating oxidative stress, inflammation, and apoptosis in animal models. However, more studies should be done to clear the neuroprotective effects of chrysin.

Roles of Nrf2 in Gastric Cancer: Targeting for Therapeutic Strategies.

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) is a specific transcription factor with potent effects on the regulation of antioxidant gene expression that modulates cell hemostasis under various conditions in tissues. However, the effects of Nrf2 on gastric cancer (GC) are not fully elucidated and understood. Evidence suggests that uncontrolled Nrf2 expression and activation has been observed more frequently in malignant tumors, including GC cells, which is then associated with increased antioxidant capacity, chemoresistance, and poor clinical prognosis. Moreover, Nrf2 inhibitors and the associated modulation of tumor cell redox balance have shown that Nrf2 also has beneficial effects on the therapy of various cancers, including GC. Based on previous findings on the important role of Nrf2 in GC therapy, it is of great interest to scientists in basic and clinical tumor research that Nrf2 can be active as both an oncogene and a tumor suppressor depending on different background situations.

Nutraceuticals-based therapeutic approach: recent advances to combat pathogenesis of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanying memory deficits. The available pharmaceutical care has some limitations mostly entailing side effects, shelf-life, and patient's compliance. The momentous implications of nutraceuticals in AD have attracted scientists. Several preclinical studies for the investigation of nutraceuticals have been conducted.Areas covered: This review focuses on the potential use of a nutraceuticals-based therapeutic approach to treat and prevent AD. Increasing knowledge of AD pathogenesis has led to the discovery of new therapeutic targets including pathophysiological mechanisms and various cascades. Hence, the present contribution will attend to the most popular and effective nutraceuticals with proposed brief mechanisms entailing antioxidant, anti-inflammatory, autophagy regulation, mitochondrial homeostasis, and more. Therefore, even though the effectiveness of nutraceuticals cannot be dismissed, it is essential to do further high-quality randomized clinical trials.Expert opinion: According to the potential of nutraceuticals to combat AD as multi-target directed drugs, there is critical importance to assess them as feasible lead compounds for drug discovery and development. To the best of the authors' knowledge, modification of blood-brain barrier permeability, bioavailability, and features of randomized clinical trials should be considered in prospective studies.

Impact of Metformin on Cancer Biomarkers in Non-Diabetic Cancer Patients: A Systematic Review and Meta-Analysis of Clinical Trials.

INTRODUCTION: Our aim was to investigate and evaluate the influence of metformin on cancer-related biomarkers in clinical trials. METHODS: This systematic study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Major databases, including Scopus, Web of Sciences, PubMed, Ovid-Medline, and Cochrane, were systematically reviewed by February 2020. Clinical trials investigating metformin effects on the evaluation of homeostatic models of insulin resistance (HOMA-IR), Ki-67, body mass index (BMI), fasting blood sugar (FBS), and insulin were selected for further analysis. Quality assessment was performed with version 2 of the Cochrane tool for determining the bias risk for randomized trials (RoB 2). Heterogeneity among the included studies was assessed using the Chi-square test. After quality assessment, a random effects model was performed to summarize the data related to insulin, HOMA-IR, Ki-67, and a fixed-effect model for FBS and BMI in a meta-analysis. RESULTS: Nine clinical trials with 716 patients with operable breast and endometrial cancer and 331 with primary breast cancer were involved in the current systematic and meta-analysis study. Systematic findings on the nine publications indicated metformin decreased insulin levels in four studies, FBS in one, BMI in two, Ki-67 in three studies, and HOMA-IR in two study. The pooled analysis indicated that metformin had no significant effect on the following values: insulin (standardized mean differences (SMD) = -0.87, 95% confidence intervals (CI) (-1.93, 0.19), p = 0.11), FBS (SMD = -0.18, 95% CI (-0.30, -0.05), p = 0.004), HOMA-IR (SMD = -0.17, 95% CI (-0.52, 0.19), p = 0.36), and BMI (SMD = -0.13, 95% CI (-0.28, 0.02), p = 0.09). Metformin could decrease Ki-67 in patients with operable endometrial cancer versus healthy subjects (SMD = 0.47, 95% CI (-1.82, 2.75), p = 30.1). According to Egger's test, no publication bias was observed for insulin, FBS, BMI, HOMA-IR, and Ki-67. CONCLUSIONS: Patients with operable breast and endometrial cancer under metformin therapy showed no significant changes in the investigated metabolic biomarkers in the most of included study. It was also found that metformin could decrease Ki-67 in patients with operable endometrial cancer. In comparison to the results obtained of our meta-analysis, due to the high heterogeneity and bias of the included clinical trials, the present findings could not confirm or reject the efficacy of metformin for patients with breast cancer and endometrial cancer.

Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin.

Chrysin has been shown to exert several beneficial pharmacological activities. Chrysin has anti-cancer, anti-viral, anti-diabetic, neuroprotective, cardioprotective, hepatoprotective, and renoprotective as well as gastrointestinal, respiratory, reproductive, ocular, and skin protective effects through modulating signaling pathway involved in apoptosis, oxidative stress, and inflammation. In the current review, we discussed the emerging cellular and molecular mechanisms underlying therapeutic indications of chrysin in various cancers. Online databases comprising Scopus, PubMed, Embase, ProQuest, Science Direct, Web of Science, and the search engine Google Scholar were searched for available and eligible research articles. The search was conducted by using MeSH terms and keywords in title, abstract, and keywords. In conclusion, experimental studies indicated that chrysin could ameliorate cancers of the breast, gastrointestinal tract, liver and hepatocytes, bladder, male and female reproductive systems, choroid, respiratory tract, thyroid, skin, eye, brain, blood cells, leukemia, osteoblast, and lymph. However, more studies are needed to enhance the bioavailability of chrysin and evaluate this agent in clinical trial studies.

New insights into the role of the Nrf2 signaling pathway in green tea catechin applications.

Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcriptional signaling pathway that plays a crucial role in numerous clinical complications. Pivotal roles of Nrf2 have been proved in cancer, autoimmune diseases, neurodegeneration, cardiovascular diseases, diabetes mellitus, renal injuries, respiratory conditions, gastrointestinal disturbances, and general disorders related to oxidative stress, inflammation, apoptosis, gelatinolysis, autophagy, and fibrogenesis processes. Green tea catechins as a rich source of phenolic compounds can deal with various clinical problems and manifestations. In this review, we attempted to focus on intervention between green tea catechins and Nrf2. Green tea catechins especially epigallocatechin gallate (EGCG) elucidated the protective role of Nrf2 and its downstream molecules in various disorders through Keap-1, HO-1, NQO-1, GPx, GCLc, GCLm, NF-kB cross-link, kinases, and apoptotic proteins. Subsequently, we compiled an updated expansions of the Nrf2 role as a gate to manage and protect different disorders and feasible indications of green tea catechins through this signaling pathway. The present review highlighted recent evidence-based data in silico, in vitro, and in vivo studies on an outline for future clinical trials.

Tantalizing role of p53 molecular pathways and its coherent medications in neurodegenerative diseases.

Neurodegenerative diseases are incongruous, commonly age-related disorders characterized by progressive neuronal loss, comprising the most prevalent being Alzheimer's disease, Parkinson's disease, and Huntington's disease. Perilous health states are anticipated following the neurodegeneration. Their etiology remains largely ambiguous, while various mechanisms are ascribed to their pathogenesis. A recommended conception is regarding the role of p53, as a transcription factor regulating numerous cellular pathways comprising apoptosis. Neuronal fates are a feasible occurrence that contributes to all neurodegenerative diseases. In this work, we review the research investigated the potential role of p53 in the pathogenesis of these diseases. We put special emphasis on intricate We not only describe aberrant changes in p53 level/activity observed in CNS regions affected by particular diseases but, most importantly, put special attention to the complicated reciprocal tuning connections prevailing between p53 and molecules considered in pathological hallmarks of these disorders. Natural and synthetic medications regulating p53 expression are regarded as well.

Curcumin and cardiovascular diseases: Focus on cellular targets and cascades.

Cardiovascular diseases (CVDs) are one of the leading causes of the most considerable mortality globally, and it has been tried to find the molecular mechanisms and design new drugs that triggered the molecular target. Curcumin is the main ingredient of Curcuma longa (turmeric) that has been used in traditional medicine for treating several diseases for years. Numerous investigations have indicated the beneficial effect of Curcumin in modulating multiple signaling pathways involved in oxidative stress, inflammation, apoptosis, and proliferation. The cardiovascular protective effects of Curcumin against CVDs have been indicated in several studies. In the current review study, we provided novel information on Curcumin's protective effects against various CVDs and potential molecular signaling targets of Curcumin. Nonetheless, more studies should be performed to discover the exact molecular target of Curcumin against CVDs.

Biological and therapeutic activities of thymoquinone: Focus on the Nrf2 signaling pathway.

Thymoquinone is a monoterpenoid compound, which is derived from volatile and fixed oil of Nigella sativa (Ranunculaceae). This phytochemical compound has several biological effects, including antioxidant, antibacterial, antineoplastic, nephroprotective, hepatoprotective, gastroprotective, neuroprotective, anti-nociceptive, and anti-inflammatory activities. Thymoquinone shows pharmacological activities, including anti-hepatocellular carcinoma, nephroprotection, neuroprotection, retina protection, gastroprotection, cardioprotection, anti-allergy, reproductive system protection, bladder protection, and respiratory protection. It was found that these beneficial effects are mostly related to modulation of the Nrf2 signaling pathway by blockage of Keap1, stimulating the expression of the Nrf2 gene, and inducing the nuclear translocation of Nrf2. In the present review, the therapeutic effects of thymoquinone are overviewed through the Nrf2 signaling pathway.

Preparation and Evaluation of Possible Antioxidant Activities of Rose Traditional Tablet"(Qurs-e-Vard)" A Selected Traditional Persian Medicine (TPM) Formulation via Various Procedures.

BACKGROUND: Free radicals can lead to liver dysfunction. Quality control of traditional formulations ensures their safe, pure, and pharmaceutical efficacy. "Qurs-e-Vard", containing petals of Rosa damascena Mill., fruits of Rhus coriaria L. and roots of Glycyrrhiza glabra L. has been suggested as a hepatoprotective preparation in Traditional Persian Medicine (TPM). OBJECTIVE: This study was directed at the evaluation of the phytochemical characterization, standardization, and in vitro antioxidant activity determination of a solid formulation and its components. METHODS: Some qualitative and quantitative controls were performed like ash value, heavy metals investigation, and microbial contamination. The phytochemical assays were used for obtaining total phenolic and flavonoid contents with spectrophotometric methods. 2, 2-Diphenyl-1-c (DPPH) and Nitric Oxide (NO) assays were run for determining Radical scavenging activities of the formulation and its components. Ferric reducing antioxidant power assay (FRAP) was determined as well. RESULTS: Total phenolic contents of hydroalcoholic and aqueous extracts of the polyherbal formulation measured respectively, (376±0.93) and (297.6±0.96) mg of gallic acid/g of dry matter. Total flavonoid contents of the formulation were also measured (36.27±0.98) for hydroalcoholic extract and (17.79±0.86) mg of quercetin/g of dry matter for aqueous extract. The IC50 of hydroalcoholic and aqueous extract was obtained (88.14±1.15) and (140.78±2.98) µg/ml, respectively. NO scavenging percentages (200µg/ml) of hydroalcoholic and aqueous extracts were measured (59.11±2.15) and (65.08±2.35). FRAP values of hydroalcoholic and aqueous extracts were achieved (255.24±3.45) and (134.57±3.45) µg/ml as well. CONCLUSION: Our findings indicated that this polyherbal formulation and its components have justifiable antioxidant effects.

Zingiber officinale ameliorates Alzheimer's disease and Cognitive Impairments: Lessons from preclinical studies.

Alzheimer's disease (AD) is a neurodegenerative condition mostly communal in people of advanced years accompanying various dysfunctionalities especially cognitive impairments. A number of cellular damages, such as amyloid-beta aggregation, tau protein hyperphosphorylation, some neurotransmitter imbalances, apoptosis, oxidative stress, and inflammatory responses are responsible for AD incidence. As a reason for inadequate efficacy, side effects, and pharmacokinetic problems of conventional drugs used for AD, the discovery of novel therapeutic agents with multi-targeted potential is desirable. Protective properties of phytochemicals combat numerous diseases and their vast acceptance and demand in human beings encouraged scientists to assess their effective activities. Zingiber officinale, gingerol, shogaol, and borneol were evaluated against memory impairments. Online databases including; Web of Science, Scopus, Embase, Pubmed, ProQuest, ScienceDirect, and Cochrane Library were searched until 3th February 2020. In vitro, in vivo, and clinical studies are included after screening their eligibility. Mostly interventive mechanisms such as; oxidative stress, neuroinflammation, and apoptosis are described. Correlation between the pathogenesis of AD and signaling pathways is explicated. Results and scores of cognition measurements are clarified due to in vivo studies and clinical trials. Some traditional aspects of consuming ginger in AD are also mentioned in the present review. In accumulation ginger and its components possess great potency for improving and abrogating memory dysfunctions but conducting further studies to evaluate their pharmacological and pharmaceutical aspects is required.

An Overview of the Role of Adipokines in Cardiometabolic Diseases.

Obesity as an independent risk factor for cardiovascular diseases (CVDs) leads to an increase in morbidity, mortality, and a shortening of life span. The changes in heart structure and function as well as metabolic profile are caused by obese people, including those free of metabolic disorders. Obesity alters heart function structure and affects lipid and glucose metabolism, blood pressure, and increase inflammatory cytokines. Adipokines, specific cytokines of adipocytes, are involved in the progression of obesity and the associated co-morbidities. In the current study, we review the scientific evidence on the effects of obesity on CVDs, focusing on the changes in adipokines. Several adipokines have anti-inflammatory and cardioprotective effects comprising omentin, apelin, adiponectin, and secreted frizzled-related protein (Sfrp-5). Other adipokines have pro-inflammatory impacts on the cardiovascular system and obesity including leptin, tumor necrosis factor (TNF), retinol-binding protein4 (RBP-4), visfatin, resistin, and osteopontin. We found that obesity is associated with multiple CVDs, but can only occur in unhealthy metabolic patients. However, more studies should be designed to clarify the association between obesity, adipokine changes, and the occurrence of CVDs.

Molecular mechanism-based therapeutic properties of honey.

Honey and its phenolic compounds specifically chrysin are focused as nutritional supplements and likewise as valued phytochemicals, nutraceuticals, and phytopharmaceuticals alone, or adjuvant with some conventional medications to cause synergistic therapeutic or cytotoxic effects. Through the verified beneficial strategies combat several disturbances, phenolic compounds play fundamental functions in the avoidance and treatment of disorders. Oxidative stress, inflammation, and apoptosis are the three most imperative physiological reactions in the prevalence of numerous ailments. Honey, chrysin, and other phenolic compounds detected in honey can modify clinical conditions via modulation of these contrivances and correlated signaling pathways. The current study desires to review the therapeutic effects of honey and its allied molecular mechanisms. Evidenced-base studies show that honey would represent therapeutic potential against various types of cancer and tumor proliferation (colorectal cancer, breast cancer, bladder cancer, leukemia, glioma, hepatocellular cancer, pancreatic cancer, and melanoma), wounds, diabetes mellitus, neurological (depression, Parkinson disease, and Alzheimer's disease), respiratory, gastrointestinal (peptic ulcer and ulcerative colitis), cardiovascular disorders, renal injuries, liver diseases and many other kinds of physiological dysfunctionalities through various molecular mechanisms contributed with oxidative stress, inflammatory process, and apoptosis.