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.

Natural compounds modulate the crosstalk between apoptosis- and autophagy-regulated signaling pathways: Controlling the uncontrolled expansion of tumor cells.

Due to the high number of annual cancer-related deaths, and the economic burden that this malignancy affects today's society, the study of compounds isolated from natural sources should be encouraged. Most cancers are the result of a combined effect of lifestyle, environmental factors, and genetic and hereditary components. Recent literature reveals an increase in the interest for the study of phytochemicals from traditional medicine, this being a valuable resource for modern medicine to identify novel bioactive agents with potential medicinal applications. Phytochemicals are components of traditional medicine that are showing promising application in modern medicine due to their antitumor activities. Recent studies regarding two major mechanisms underlying cancer development and regulation, apoptosis and autophagy, have shown that the signaling pathways of both these processes are significantly interconnected through various mechanisms of crosstalk. Phytochemicals are able to activate pro-autophagic and pro-apoptosis mechanisms. Understanding the molecular mechanism involved in apoptosis-autophagy relationship modulated by phytochemicals plays a key role in development of a new therapeutic strategy for cancer treatment. The purpose of this review is to outline the bioactive properties of the natural phytochemicals with validated antitumor activity, focusing particularly on their role in the regulation of apoptosis and autophagy crosstalk that triggers the uncontrolled expansion of tumor cells. Furthermore, we have also critically discussed the limitations and challenges of existing research strategies and the prospective research directions in this field.

Production of high molecular-ordered stilbene oligomers for the study of their biological activity: total synthesis, bio-catalyzed synthesis and production by plant systems.

Though the iconic stilbene resveratrol and its related dimers constitute a top storyline in the field of natural product research, resveratrol oligomers (condensation >2) have been left aside despite their higher biological activity compared to that of the monomers. This situation largely results from the difficulty of getting them in sufficient quantities to enable evaluation of their biological properties in vivo. We present here a synthetic and critical analysis of the methods used for the production of high molecular-ordered stilbene oligomers of potential biomedical interest, gathering the most salient data regarding the approaches employed to prepare them by total synthesis, use of biomimetic approaches or through plant systems.

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.

A close-up view of dynamic biomarkers in the setting of COVID-19: Striking focus on cardiovascular system.

Based on the recent reports, cardiovascular events encompass a large portion of the mortality caused by the COVID-19 pandemic, which drawn cardiologists into the management of the admitted ill patients. Given that common laboratory values may provide key insights into the illness caused by the life-threatening SARS-CoV-2 virus, it would be more helpful for screening, clinical management and on-time therapeutic strategies. Commensurate with these issues, this review article aimed to discuss the dynamic changes of the common laboratory parameters during COVID-19 and their association with cardiovascular diseases. Besides, the values that changed in the early stage of the disease were considered and monitored during the recovery process. The time required for returning biomarkers to basal levels was also discussed. Finally, of particular interest, we tended to abridge the latest updates regarding the cardiovascular biomarkers as prognostic and diagnostic criteria to determine the severity of COVID-19.

Synthesis, surface modifications, and biomedical applications of carbon nanofibers: Electrospun vs vapor-grown carbon nanofibers.

Engineered nanostructures are materials with promising properties, enabled by precise design and fabrication, as well as size-dependent effects. Biomedical applications of nanomaterials in disease-specific prevention, diagnosis, treatment, and recovery monitoring require precise, specific, and sophisticated approaches to yield effective and long-lasting favorable outcomes for patients. In this regard, carbon nanofibers (CNFs) have been indentified due to their interesting properties, such as good mechanical strength, high electrical conductivity, and desirable morphological features. Broadly speaking, CNFs can be categorized as vapor-grown carbon nanofibers (VGCNFs) and carbonized CNFs (e.g., electrospun CNFs), which have distinct microstructure, morphologies, and physicochemical properties. In addition to their physicochemical properties, VGCNFs and electrospun CNFs have distinct performances in biomedicine and have their own pros and cons. Indeed, several review papers in the literature have summarized and discussed the different types of CNFs and their performances in the industrial, energy, and composites areas. Crucially however, there is room for a comprehensive review paper dealing with CNFs from a biomedical point of view. The present work therefore, explored various types of CNFs, their fabrication and surface modification methods, and their applications in the different branches of biomedical engineering.

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.

Phytochemical and toxicological evaluation of Tamarix stricta Boiss.

The genus Tamarix includes several plant species well-known for their medicinal properties since ancient times. Tamarix stricta Boiss is a plant native to Iran which has not been previously investigated regarding its phytochemical and biological properties. This study assessed phytochemical and toxicological aspects of T. stricta. The plant was collected from Kerman province of Iran and after authentication by botanist, it was extracted with 70% ethanol. Total phenolic compounds, total flavonoids, and antioxidant properties were measured using spectrophometric methods. Quercetin content of the extract was measured after complete acid hydrolysis with high-performance liquid chromatography. The phytochemical profile of the extract was provided using liquid chromatography-mass spectrometry method. Acute toxicity study with a single intragastric dose of 5000 mg/kg of the extract and sub-chronic toxicity using 50, 100, and 250 mg/kg of the extract was assessed in Wistar rats. Phytochemical analysis showed that polyphenols constitute the major components of the extract. Also, the extract contained 1.552 ± 0.35 mg/g of quercetin. Biochemical, hematological, and histological evaluations showed no sign of toxicity in animals. Our experiment showed that T. stricta is a rich source of polyphenols and can be a safe medicinal plant. Further pharmacological evaluations are recommended to assess the therapeutic properties of this plant.

The potential of pumpkin seed oil as a functional food-A comprehensive review of chemical composition, health benefits, and safety.

The growing interest in foods that can be beneficial to human health is bringing into focus some products that have been used locally for centuries but have recently gained worldwide attention. One of these foods is pumpkin seed oil, which has been used in culinary and traditional medicine, but recent data also show its use in the pharmaceutical and cosmetic industries. In addition, some sources refer to it as a potential functional food, mainly because it is obtained from pumpkin seeds, which contain many functional components. However, the production process of the oil may affect the content of these components and consequently the biological activity of the oil. In this review, we have focused on summarizing scientific data that explore the potential of pumpkin seed oil as a functional food ingredient. We provide a comprehensive overview of pumpkin seed oil chemical composition, phytochemical content, biological activity, and safety, as well as the overview of production processes and contemporary use. The main phytochemicals in pumpkin seed oil with health-related properties are polyphenols, phytoestrogens, and fatty acids, but carotenoids, squalene, tocopherols, and minerals may also contribute to health benefits. Most studies have been conducted in vitro and support the claim that pumpkin seed oil has antioxidant and antimicrobial activities. Clinical studies have shown that pumpkin seed oil may be beneficial in the treatment of cardiovascular problems of menopausal women and ailments associated with imbalance of sex hormones.

Transdermal Delivery of Curcumin-Loaded Solid Lipid Nanoparticles as Microneedle Patch: an In Vitro and In Vivo Study.

Curcumin is well known for its neuroprotective effect, and also able to alleviate Parkinsonian features. Clinical application of curcumin is limited due to its low bioavailability. Hence, we hypothesized that the microneedles (MN) containing drug-loaded solid lipid nanoparticles (SLNs) may be able to improve its bioavailability and efficacy. The SLNs were prepared with microemulsion technique using glyceryl monostearate as a lipid and tween 80 as a stabilizer. The particle size, polydispersity index, zeta potential, and entrapment efficiency of prepared SLNs were determined. The optimized formulation was incorporated into microneedle arrays using micromolding technique and fabricated microneedle patch were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, optical microscopy, ex vivo permeation studies, histology studies, and fluorescent microscopy. The fabricated microneedle patch was also evaluated for neuroprotective activity and skin irritation potential. Fourier transform infrared spectroscopy studies of SLNs and microneedles confirmed the chemical compatibility of excipients with curcumin. The developed microneedles were also found to be non-irritant with decreased degree of bradykinesia, high motor coordination, and balance ability. The study provided a theoretical basis for the use of novel microneedle containing curcumin-loaded solid lipid nanoparticles as a useful tool for the treatment of Parkinson's disease.

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.

Arglabin could target inflammasome-induced ARDS and cytokine storm associated with COVID-19.

Arglabin (l(R),10(S)-epoxy-5(S),5(S),7(S)-guaia-3(4),ll(13)-dien-6,12-olide), is a natural sesquiterpene γ-lactone which was first isolated from Artemisia glabella. The compound has been shown to possess anti-inflammatory activity through inhibition of the NLR Family pyrin domain-containing 3 (NLRP3) inflammasome and production of proinflammatory cytokines including interleukin (IL)-1ß and IL-18. A more hydrophilic derivative of the compound also exhibited antitumor activity in the breast, colon, ovarian, and lung cancer. Some other synthetic derivatives of the compound have also been synthesized with antitumor, cytotoxic, antibacterial, and antifungal activities. Since both NLRP3 inflammasome and cytokine storm are associated with the pathogenesis of COVID-19 and its lethality, compounds like arglabin might have therapeutic potential to attenuate the inflammasome-induced acute respiratory distress syndrome and/or the cytokine storm associated with COVID-19.

Epigenetic targeting of cancer stem cells by polyphenols (cancer stem cells targeting).

Epigenetic alterations are one of the main factors that disrupt the expression of genes and consequently, they have an important role in the carcinogenicity and the progression of different cancers. Cancer stem cells (CSCs) are accountable for the recurrence, metastasis, and therapeutic failure of cancer. The noticeable and specific pathways in CSCs can be organized by epigenetic mechanisms such as DNA methylation, chromatin remodeling, regulatory RNAs, among others. Since epigenetics modifications can be changed and reversed, it is a possible tool for cancer control and treatment. Epigenetic therapies against CSCs are emerging as a very new strategy with a good future expectation to treat cancer patients. Phenolic compounds are a vast group of substances with anticarcinogenic functions, antiinflammatory, and antioxidative activities. It seems these characteristics are related to neutralizing CSCs development, their microenvironment, and metabolism through epigenetic mechanisms. In the current work, the types of epigenetic changes known in these cells are introduced. In addition, some studies about the use of polyphenols acting through a variety of epigenetic mechanisms to counteract these cells will be reviewed. The reported results seem to indicate that the use of these phenolic compounds may be useful for CSCs defeat.

Systematic review: Effectiveness of herbal oral care products on ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) resulting from bacterial infection is a prevalent medical problem in intensive care units (ICUs). The purpose of this study was to systematically review available studies on oral products employed to control and reduce VAP in patients undergoing tracheal intubation. This study was based on a systematic review of clinical trial data from science databases such as PubMed, Cochrane, Scopus, and Web of science. Articles were reviewed and selected according to defined criteria and assessed by the primary evaluation checklist. After a critical review of 3,143 search hits, only 18 relevant articles were finally selected for discussion. Our assessment revealed that chlorhexidine and some other oral herbal medications are beneficial in preventing VAP. Chlorhexidine oral dosage forms provide a remarkable role in oral health and prevention of VAP by decreasing the microbial flora in the mouth. Because of similar benefits and comparable effects, some herbal medicines can be suggested as a practical alternative to chlorhexidine.

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.

Brief recommendations on the management of adult patients with familial hypercholesterolemia during the COVID-19 pandemic.

Individuals with Familial Hypercholesterolaemia (FH) are at very high risk of cardiovascular disease, which is associated with poor outcomes from coronavirus infections. COVID-19 puts strain on healthcare systems and may impair access to routine FH services. On behalf of the International Lipid Expert Panel (ILEP) and the European FH Patient Network (FH Europe), we present brief recommendations on the management of adult patients with FH during the COVID-19 pandemic. We discuss the implications of COVID-19 infections for FH patients, the importance of continuing lipid-lowering therapy where possible, issues relating to safety monitoring and service delivery. We summarise the evidence for additional benefits of statins and other lipid-lowering drugs during viral infections. The recommendations do not override in any way the individual responsibility of physicians to make appropriate and accurate decisions taking into account the condition of a given patient and the doses, rules, and regulations applicable to drugs and devices at the time of their prescription/use.