Targeting Hippo signaling pathway by phytochemicals in cancer therapy.

The current era of cancer research has been continuously advancing upon identifying novel aspects of tumorigenesis and the principal mechanisms behind the unleashed proliferation, invasion, drug resistance and immortality of cancer cells in hopes of exploiting these findings to achieve a more effective treatment for cancer. In pursuit of this goal, the identification of the first components of an extremely important regulatory pathway in Drosophila melanogaster that largely determines cell fate during the developmental stages, ended up in the discovery of the highly sophisticated Hippo signaling cascade. Soon after, it was revealed that deregulation of the components of this pathway either via mutations or through epigenetic alterations can be observed in a vast variety of tumors and these alterations greatly contribute to the neoplastic transformation of cells, their survival, growth and resistance to therapy. As more hidden aspects of this pathway such as its widespread entanglement with other major cellular signaling pathways are continuously being uncovered, many researchers have sought over the past decade to find ways of therapeutic interventions targeting the major components of the Hippo cascade. To date, various approaches such as the use of exogenous targeting miRNAs and different molecular inhibitors have been recruited herein, among which naturally occurring compounds have shown a great promise. On such a basis, in the present work we review the current understanding of Hippo pathway and the most recent evidence on targeting its components using natural plant-derived phytochemicals.

New perspective on DNA response pathway (DDR) in glioblastoma, focus on classic biomarkers and emerging roles of ncRNAs.

BACKGROUND: Glioblastoma (GBM) is the most frequent type of primary brain cancer, having a median survival of only 15 months. The current standard of care includes a combination of surgery, radiotherapy (RT) and chemotherapy with temozolomide, but with limited results. Moreover, multiple studies have shown that tumour relapse and resistance to classic therapeutic approaches are common events that occur in the majority of patients, and eventually leading to death. New approaches to better understand the intricated tumour biology involved in GBM are needed in order to develop personalised treatment approaches. Advances in cancer biology have widen our understanding over the GBM genome and allowing a better classification of these tumours based on their molecular profile. METHODS: A new targeted therapeutic approach that is currently investigated in multiple clinical trials in GBM is represented by molecules that target various defects in the DNA damage repair (DDR) pathway, a mechanism activated by endogenous and exogenous factors that induce alteration of DNA, and is involved for the development of chemotherapy and RT resistance. This intricate pathway is regulated by p53, two important kinases ATR and ATM and non-coding RNAs including microRNAs, long-non-coding RNAs and circular RNAs that regulate the expression of all the proteins involved in the pathway. RESULTS: Currently, the most studied DDR inhibitors are represented by PARP inhibitors (PARPi) with important results in ovarian and breast cancer. PARPi are a class of tumour agnostic drugs that showed their efficacy also in other localisations such as colon and prostate tumours that have a molecular signature associated with genomic instability. These inhibitors induce the accumulation of intracellular DNA damage, cell cycle arrest, mitotic catastrophe and apoptosis. CONCLUSIONS: This study aims to provide an integrated image of the DDR pathway in glioblastoma under physiological and treatment pressure with a focus of the regulatory roles of ncRNAs. The DDR inhibitors are emerging as an important new therapeutic approach for tumours with genomic instability and alterations in DDR pathways. The first clinical trials with PARPi in GBM are currently ongoing and will be presented in the article. Moreover, we consider that by incorporating the regulatory network in the DDR pathway in GBM we can fill the missing gaps that limited previous attempts to effectively target it in brain tumours. An overview of the importance of ncRNAs in GBM and DDR physiology and how they are interconnected is presented.

Harnessing polyphenol power by targeting eNOS for vascular diseases.

Vascular diseases arise due to vascular endothelium dysfunction in response to several pro-inflammatory stimuli and invading pathogens. Thickening of the vessel wall, formation of atherosclerotic plaques consisting of proliferating smooth muscle cells, macrophages and lymphocytes are the major consequences of impaired endothelium resulting in atherosclerosis, hypercholesterolemia, hypertension, type 2 diabetes mellitus, chronic renal failure and many others. Decreased nitric oxide (NO) bioavailability was found to be associated with anomalous endothelial function because of either its reduced production level by endothelial NO synthase (eNOS) which synthesize this potent endogenous vasodilator from L-arginine or its enhanced breakdown due to severe oxidative stress and eNOS uncoupling. Polyphenols are a group of bioactive compounds having more than 7000 chemical entities present in different cereals, fruits and vegetables. These natural compounds possess many OH groups which are largely responsible for their strong antioxidative, anti-inflammatory antithrombotic and anti-hypersensitive properties. Several flavonoid-derived polyphenols like flavones, isoflavones, flavanones, flavonols and anthocyanidins and non-flavonoid polyphenols like tannins, curcumins and resveratrol have attracted scientific interest for their beneficial effects in preventing endothelial dysfunction. This article will focus on in vitro as well as in vivo and clinical studies evidences of the polyphenols with eNOS modulating activity against vascular disease condition while their molecular mechanism will also be discussed.

Oral microbiota in cancer: could the bad guy turn good with application of polyphenols?

The human oral cavity is comprised of dynamic and polynomial microbes which uniquely reside in the microenvironments of oral cavities. The cumulative functions of the symbiotic microbial communities maintain normal homeostasis; however, a shifted microbiota yields a dysbiosis state, which produces local and systemic diseases including dental caries, periodontitis, cancer, obesity and diabetes. Recent research reports claim that an association occurs between oral dysbiosis and the progression of different types of cancers including oral, gastric and pancreatic ones. Different mechanisms are proposed for the development of cancer, such as induction of inflammatory reactions, production of carcinogenic materials and alteration of the immune system. Medications are available to treat these associated diseases; however, the current strategies may further worsen the disease by unwanted side effects. Natural-derived polyphenol molecules significantly inhibit a wide range of systemic diseases with fewer side effects. In this review, we have displayed the functions of the oral microbes and we have extended the report regarding the role of polyphenols in oral microbiota to maintain healthy conditions and prevention of diseases with emphasis on the treatment of oral microbiota-associated cancer.

Plant based food bioactives: A boon or bane for neurological disorders.

Neurological disorders are the foremost occurring diseases across the globe resulting in progressive dysfunction, loss of neuronal structure ultimately cell death. Therefore, attention has been drawn toward the natural resources for the search of neuroprotective agents. Plant-based food bioactives have emerged as potential neuroprotective agents for the treatment of neurodegenerative disorders. This comprehensive review primarily focuses on various plant food bioactive, mechanisms, therapeutic targets, in vitro and in vivo studies in the treatment of neurological disorders to explore whether they are boon or bane for neurological disorders. In addition, the clinical perspective of plant food bioactives in neurological disorders are also highlighted. Scientific evidences point toward the enormous therapeutic efficacy of plant food bioactives in the prevention or treatment of neurological disorders. Nevertheless, identification of food bioactive components accountable for the neuroprotective effects, mechanism, clinical trials, and consolidation of information flow are warranted. Plant food bioactives primarily act by mediating through various pathways including oxidative stress, neuroinflammation, apoptosis, excitotoxicity, specific proteins, mitochondrial dysfunction, and reversing neurodegeneration and can be used for the prevention and therapy of neurodegenerative disorders. In conclusion, the plant based food bioactives are boon for neurological disorders.

Multiple potential targets of opioids in the treatment of acute respiratory distress syndrome from COVID-19.

COVID-19 can present with a variety of clinical features, ranging from asymptomatic or mild respiratory symptoms to fulminant acute respiratory distress syndrome (ARDS) depending on the host's immune responses and the extent of the associated pathologies. This implies that several measures need to be taken to limit severely impairing symptoms caused by viral-induced pathology in vital organs. Opioids are most exploited for their analgesic effects but their usage in the palliation of dyspnoea, immunomodulation and lysosomotropism may represent potential usages of opioids in COVID-19. Here, we describe the mechanisms involved in each of these potential usages, highlighting the benefits of using opioids in the treatment of ARDS from SARS-CoV-2 infection.

Phytostilbenes as agrochemicals: biosynthesis, bioactivity, metabolic engineering and biotechnology.

Covering: 1976 to 2020. Although constituting a limited chemical family, phytostilbenes represent an emblematic group of molecules among natural compounds. Ever since their discovery as antifungal compounds in plants and their ascribed role in human health and disease, phytostilbenes have never ceased to arouse interest for researchers, leading to a huge development of the literature in this field. Owing to this, the number of references to this class of compounds has reached the tens of thousands. The objective of this article is thus to offer an overview of the different aspects of these compounds through a large bibliography analysis of more than 500 articles. All the aspects regarding phytostilbenes will be covered including their chemistry and biochemistry, regulation of their biosynthesis, biological activities in plants, molecular engineering of stilbene pathways in plants and microbes as well as their biotechnological production by plant cell systems.

Targeting epigenetics in cancer: therapeutic potential of flavonoids.

Irrespective of sex and age, cancer is the leading cause of mortality around the globe. Therapeutic incompliance, unwanted effects, and economic burdens imparted by cancer treatments, are primary health challenges. The heritable features in gene expression that are propagated through cell division and contribute to cellular identity without a change in DNA sequence are considered epigenetic characteristics and agents that could interfere with these features and are regarded as potential therapeutic targets. The genetic modification accounts for the recurrence and uncontrolled changes in the physiology of cancer cells. This review focuses on plant-derived flavonoids as a therapeutic tool for cancer, attributed to their ability for epigenetic regulation of cancer pathogenesis. The epigenetic mechanisms of various classes of flavonoids including flavonols, flavones, isoflavones, flavanones, flavan-3-ols, and anthocyanidins, such as cyanidin, delphinidin, and pelargonidin, are discussed. The outstanding results of preclinical studies encourage researchers to design several clinical trials on various flavonoids to ascertain their clinical strength in the treatment of different cancers. The results of such studies will define the clinical fate of these agents in future.

Map kinase signaling as therapeutic target for neurodegeneration.

Aging is known to be one of the major risk factors in many neurodegenerative diseases (ND) whose prevalence is estimated to rise in the coming years due to the increase in life expectancy. Examples of neurodegenerative diseases include Huntington's, Parkinson's, and Alzheimer's diseases, along with Amyotrophic Lateral Sclerosis, Spinocerebellar ataxias and Frontotemporal Dementia. Given that so far these ND do not have effective pharmacological therapies, a better understanding of the molecular and cellular mechanisms can contribute to development of effective treatments. During the previous decade, the data indicated that dysregulation of MAP kinases [which included c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and p38] are associated with several stages of the inflammatory process which in turn contributes to age-related neurodegenerative diseases. This evidence suggests that control of inflammation through regulation of MAP kinase could be a worthwhile approach against neurodegenerative diseases. In this review we summarize the pathways of MAP kinase signal transduction and different pharmacological inhibitors that can be used in its modulation against ND.

Therapeutic potential of polyphenols in cardiovascular diseases: Regulation of mTOR signaling pathway.

Cardiovascular diseases comprise of non-communicable disorders that involve the heart and/or blood vessels and have become the leading cause of death worldwide with increased prevalence by age. mTOR is a serine/threonine-specific protein kinase which plays a central role in many physiological processes including cardiovascular diseases, and also integrates various proliferative signals, nutrient and energy abundance and stressful situations. mTOR also acts as central regulator during chronic stress, mitochondrial dysfunction and deregulated autophagy which are associated with senescence. Under oxidative stress, mTOR has been reported to exert protective effects regulating apoptosis and autophagy processes and favoring tissue repair. On the other hand, inhibition of mTOR has been suggested to have beneficial effects against atherosclerosis, cardiac hypertrophy and heart failure, and also in extending the lifespan. In this aspect, the use of drugs or natural compounds, which can target mTOR is an interesting approach in order to reduce the number of deaths caused by cardiovascular disease. In the present review, we intend to shed light on the possible effects and molecular mechanism of natural agents like polyphenols via regulating mTOR.

Toll-like receptors as novel therapeutic targets for herpes simplex virus infection.

Seropositivity for HSV reaches more than 70% within the world population, and yet no approved vaccine exists. While HSV1 is responsible for keratitis, encephalitis, and labialis, HSV2 carriers have a high susceptibility to other STD infections, such as HIV. Induction of antiviral innate immune responses upon infection depends on a family of pattern recognition receptors called Toll-like receptors (TLR). TLRs bridge innate and adaptive immunity by sensing virus infection and activating antiviral immune responses. HSV adopts smart tricks to evade innate immunity and can also manipulate TLR signaling to evade the immune system or even confer destructive effects in favor of virus replication. Here, we review mechanisms by which HSV can trick TLR signaling to impair innate immunity. Then, we analyze the role of HSV-mediated molecular cues, in particular, NF-κB signaling, in promoting protective versus destructive effects of TLRs. Finally, TLR-based therapeutic opportunities with the goal of preventing or treating HSV infection will be discussed.

Evaluation of the status quo of polyphenols analysis: Part II-Analysis methods and food processing effects.

Nowadays due to the concern with the environmental impact of analytical techniques and in order to reduce the ecological footprint there is a tendency to use more efficient and faster procedures that use a smaller amount of organic solvents. Polyphenols have been widely studied in plant-based matrices due to their wide and potent biological properties; however there are no standardized procedures both for sample preparation and analysis of these compounds. The second of a two-part review will carry out a critical review of the extraction procedures and analytical methods applied to polyphenols and their selection criteria over a wide range of factors in relation to commerce-associated, environmental, and economic factors. It is foreseen that in the future the analysis of polyphenols in plant-based matrices includes the use of techniques that allow the simultaneous determination of different subclasses of polyphenols using fast, sophisticated, and automated techniques that allow the minimal consumption of solvents.

Evaluation of the status quo of polyphenols analysis: Part I-phytochemistry, bioactivity, interactions, and industrial uses.

Phytochemicals, especially polyphenols, are gaining more attention from both the scientific community and food, pharmaceutical, and cosmetics industries due to their implications in human health. In this line, lately new applications have emerged, and of great importance is the selection of accurate and reliable analytical methods for better evaluation of the quality of the end-products, which depends on diverse process variables as well as on the matrices and on the physicochemical properties of different polyphenols. The first of a two-part review on polyphenols will address the phytochemistry and biological activities of different classes of polyphenols including flavonoids, lignans and flavanolignans, stilbenoids, tannins, curcuminoids, and coumarins. Moreover, the possible interactions of polyphenols and current and potential industrial applications of polyphenols are discussed.

Novel therapeutic strategies for stroke: The role of autophagy.

Autophagy is an important biological mechanism involved in the regulation of numerous fundamental cellular processes that are mainly associated with cellular growth and differentiation. Autophagic pathways are vital for maintaining cellular homeostasis by enhancing the turnover of nonfunctional proteins and organelles. Neuronal cells, like other eukaryotic cells, are dependent on autophagy for neuroprotection in response to stress, but can also induce cell death in cerebral ischemia. Recent studies have demonstrated that autophagy may induce neuroprotection following acute brain injury, including ischemic stroke. However in some special circumstances, activation of autophagy can induce cell death, playing a deleterious role in the etiology and progression of ischemic stroke. Currently, there are no therapeutic options against stroke that demonstrate efficient neuroprotective abilities. In the present work, we will review the significance of autophagy in the context of ischemic stroke by first outlining its role in ischemic neuronal death. We will also highlight the potential therapeutic applications of pharmacological modulators of autophagy, including some naturally occurring polyphenolic compounds that can target this catabolic process. Our findings provide renewed insight on the mechanism of action of autophagy in stroke together with potential neuroprotective compounds, which may partially exert their function through enhancing mitochondrial function and attenuating damaging autophagic processes.

Targeting BDNF signaling by natural products: Novel synaptic repair therapeutics for neurodegeneration and behavior disorders.

Neurodegenerative disorders like Alzheimer's disease, Huntington's disease, Parkinson's disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, frontotemporal dementia to prion diseases, Friedreich's ataxia, hereditary spastic paraplegia and optic atrophy type 1, and behavior disorders like neuropsychiatric, hyperactivity and autism spectrum disorders are closely associated with neurobiological deficits. Brain derived neurotrophic factor (BDNF) is an extensively studied neurotrophin. BDNF is essential for neuronal genesis, differentiation, survival, growth, plasticity, synaptic viability and transmission. BDNF has emerged as a promising target for regulating synaptic activity and plasticity. An overview of effects and mechanisms of the natural products targeting BDNF is described. This review is an attempt to enumerate the effects of various natural products on BDNF as a novel therapeutic approach for neurodegenerative and neuropsychiatric disorders.

Targeting Hedgehog signaling pathway: Paving the road for cancer therapy.

The Hedgehog pathway is essential for embryonic development but also for tissue and organ homeostasis in adult organisms. Activation of this pathway leads to the expression of target genes involved in proliferation, angiogenesis and stem cell self-renewal. Moreover, abnormal persistence of Hedgehog signaling is directly involved in a wide range of human cancers. Development of novel strategies targeting the Hedgehog pathway has become a subject of increased interest in anticancer therapy. These data are sustained by pre-clinical studies demonstrating that Hedgehog pathway inhibitors could represent an effective strategy against a heterogeneous panel of malignancies. Limited activity in other tumor types could be explained by the existence of crosstalk between the Hedgehog pathway and other signaling pathways that can compensate for its function. This review describes the Hedgehog pathway in detail, with its physiological roles during embryogenesis and adult tissues, and summarizing the preclinical evidence on its inhibition, the crosstalk between Hedgehog and other cancer-related pathways and finally the potential therapeutic effects of emerging compounds.

Targeting STATs in neuroinflammation: The road less traveled!

JAK/STAT transduction pathway is a highly conserved pathway implicated in regulating cellular proliferation, differentiation, survival and apoptosis. Dysregulation of this pathway is involved in the onset of autoimmune, haematological, oncological, metabolic and neurological diseases. Over the last few years, the research of anti-neuroinflammatory agents has gained considerable attention. The ability to diminish the STAT-induced transcription of inflammatory genes is documented for both natural compounds (such as polyphenols) and chemical drugs. Among polyphenols, quercetin and curcumin directly inhibit STAT, while Berberis vulgaris L. and Sophora alopecuroides L extracts act indirectly. Also, the Food and Drug Administration has approved several JAK/STAT inhibitors (direct or indirect) for treating inflammatory diseases, indicating STAT can be considered as a therapeutic target for neuroinflammatory pathologies. Considering the encouraging data obtained so far, clinical trials are warranted to demonstrate the effectiveness and potential use in the clinical practice of STAT inhibitors to treat inflammation-associated neurodegenerative pathologies.

Anti-inflammatory effects of Melatonin: A mechanistic review.

N-acetyl-5-methoxy-tryptamine (melatonin) is a natural substance produced both by plants, as a secondary metabolite, and animals, by the pineal gland and other tissues. In humans, melatonin participates in numerous functions including the regulation of mood, sleep, reproduction, promotion of immunomodulation, antioxidant defense and as an anti-inflammatory agent. The anti-inflammatory activity of melatonin could yield beneficial effects on intake, particularly against the chronic inflammation which underlies many chronic diseases. This review aims to provide an assessment of the literature data on the anti-inflammatory activity of melatonin, with a particular focus on the mechanisms responsible for this behavior. We can conclude that many in vitro studies and in vivo studies in experimental animal model systems show that melatonin exerts anti-inflammatory activity in a number of chronic diseases which affect different organs in different circumstances. Clinical trials, however, often fail to reach positive results and are thus far inconclusive. Thus, in the future, long-term well-designed investigations on melatonin-rich foods or melatonin food supplements could provide valuable information towards public health recommendations on melatonin, taking into account both the nature of the compound and the optimal dose, for protection from long-term inflammation linked to chronic diseases.

Targeting miRNAs by polyphenols: Novel therapeutic strategy for cancer.

In the recent years, polyphenols have gained significant attention in scientific community owing to their potential anticancer effects against a wide range of human malignancies. Epidemiological, clinical and preclinical studies have supported that daily intake of polyphenol-rich dietary fruits have a strong co-relationship in the prevention of different types of cancer. In addition to direct antioxidant mechanisms, they also regulate several therapeutically important oncogenic signaling and transcription factors. However, after the discovery of microRNA (miRNA), numerous studies have identified that polyphenols, including epigallocatechin-3-gallate, genistein, resveratrol and curcumin exert their anticancer effects by regulating different miRNAs which are implicated in all the stages of cancer. MiRNAs are short, non-coding endogenous RNA, which silence the gene functions by targeting messenger RNA (mRNA) through degradation or translation repression. However, cancer associated miRNAs has emerged only in recent years to support its applications in cancer therapy. Preclinical experiments have suggested that deregulation of single miRNA is sufficient for neoplastic transformation of cells. Indeed, the widespread deregulation of several miRNA profiles of tumor and healthy tissue samples revealed the involvement of many types of miRNA in the development of numerous cancers. Hence, targeting the miRNAs using polyphenols will be a novel and promising strategy in anticancer chemotherapy. Herein, we have critically reviewed the potential applications of polyphenols on various human miRNAs, especially which are involved in oncogenic and tumor suppressor pathways.

Two likely targets for the anti-cancer effect of indole derivatives from cruciferous vegetables: PI3K/Akt/mTOR signalling pathway and the aryl hydrocarbon receptor.

Diets containing high quantities of plant foods are linked with a decreased likelihood of incidence of cancer. Several common plant-based dietary components exert effects on DNA methylation levels, and can positively influence genome stability and the transcription of tumor suppressors and oncogenes. Indole-3-carbinol (I3C) is a substance present in vegetables of the Brassicaeae family, especially broccoli, white cabbage, Brussels sprouts and cauliflower. The in vivo biological effects of I3C are ascribed to a series of oligomeric products (including 3,3'-diindolylmethane), developed under acidic conditions. I3C is one of the many natural products and bioactive compounds found in foods which have recently received much attention for its potential effects in cancer prevention and treatment. In vitro studies report that I3C suppresses the proliferation of different tumor cells, including those isolated from breast, prostate, endometrium, and colon cancers. I3C resulted to be a potent in vivo chemopreventive agent for certain hormone-dependent cancers, including breast and cervical cancer. However, the mechanisms underlying these effects are not well defined. In this review, we have analysed recent literature on the use of indole derivatives against various forms of cancer, and have identified the main signalling pathways involved in their anti-cancer effect as PI3K/Akt/mTOR and the aryl hydrocarbon receptor.