Flavonoids, a group of natural substances with variable phenolic structures, are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. These natural products are well known for their beneficial effects on health and efforts are being made to isolate the ingredients so called flavonoids. Flavonoids are now considered as an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications. This is attributed to their anti-oxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme function. Research on flavonoids received an added impulse with the discovery of the low cardiovascular mortality rate and also prevention of CHD. Information on the working mechanisms of flavonoids is still not understood properly. However, it has widely been known for centuries that derivatives of plant origin possess a broad spectrum of biological activity. Current trends of research and development activities on flavonoids relate to isolation, identification, characterisation and functions of flavonoids and finally their applications on health benefits. Molecular docking and knowledge of bioinformatics are also being used to predict potential applications and manufacturing by industry. In the present review, attempts have been made to discuss the current trends of research and development on flavonoids, working mechanisms of flavonoids, flavonoid functions and applications, prediction of flavonoids as potential drugs in preventing chronic diseases and future research directions.

/pdf/flavonoids-an-overview-5gkev1wgy2.pdf

Flavonoids: an overview

Nanostructures of different sizes, shapes and material properties have many applications in biomedical imaging, clinical diagnostics and therapeutics1,2,3,4,5,6. In spite of what has been achieved so far, a complete understanding of how cells interact with nanostructures of well-defined sizes, at the molecular level, remains poorly understood. Here we show that gold and silver nanoparticles coated with antibodies can regulate the process of membrane receptor internalization. The binding and activation of membrane receptors and subsequent protein expression strongly depend on nanoparticle size. Although all nanoparticles within the 2–100 nm size range were found to alter signalling processes essential for basic cell functions (including cell death)7, 40- and 50-nm nanoparticles demonstrated the greatest effect. These results show that nanoparticles should no longer be viewed as simple carriers for biomedical applications, but can also play an active role in mediating biological effects. The findings presented here may assist in the design of nanoscale delivery and therapeutic systems and provide insights into nanotoxicity.

http://basicmed.med.ncku.edu.tw/admin/up_img/980407-3.pdf

Nanoparticle-mediated cellular response is size-dependent

The metastatic process, i.e. the dissemination of cancer cells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave the primary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization. Notably, direct experimental evidence linking the formation of migratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In this review, we have summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.

/pdf/emt-the-cytoskeleton-and-cancer-cell-invasion-1tg17auqq5.pdf

EMT, the cytoskeleton, and cancer cell invasion

There are numerous ways that endocytic cargo molecules may be internalized from the surface of eukaryotic cells. In addition to the classical clathrin-dependent mechanism of endocytosis, several pathways that do not use a clathrin coat are emerging. These pathways transport a diverse array of cargoes and are sometimes hijacked by bacteria and viruses to gain access to the host cell. Here, we review our current understanding of various clathrin-independent mechanisms of endocytosis and propose a classification scheme to help organize the data in this complex and evolving field.

Pathways of clathrin-independent endocytosis.

The Ras-dependent activation of mitogen-activated protein (MAP) kinase pathways by many receptors coupled to heterotrimeric guanine nucleotide binding proteins (G proteins) requires the activation of Src family tyrosine kinases. Stimulation of beta2 adrenergic receptors resulted in the assembly of a protein complex containing activated c-Src and the receptor. Src recruitment was mediated by beta-arrestin, which functions as an adapter protein, binding both c-Src and the agonist-occupied receptor. beta-Arrestin 1 mutants, impaired either in c-Src binding or in the ability to target receptors to clathrin-coated pits, acted as dominant negative inhibitors of beta2 adrenergic receptor-mediated activation of the MAP kinases Erk1 and Erk2. These data suggest that beta-arrestin binding, which terminates receptor-G protein coupling, also initiates a second wave of signal transduction in which the "desensitized" receptor functions as a critical structural component of a mitogenic signaling complex.

https://science.sciencemag.org/content/sci/283/5402/655.full.pdf

Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.

Epidermal growth factor receptor (EGFR) signaling was analyzed in mammalian cells conditionally defective for receptor-mediated endocytosis. EGF-dependent cell proliferation was enhanced in endocytosis-defective cells. However, early EGF-dependent signaling events were not uniformly up-regulated. A subset of signal transducers required the normal endocytic trafficking of EGFR for full activation. Thus, endocytic trafficking of activated EGFR plays a critical role not only in attenuating EGFR signaling but also in establishing and controlling specific signaling pathways.

https://science.sciencemag.org/content/sci/274/5295/2086.full.pdf

Control of EGF receptor signaling by clathrin-mediated endocytosis.

Objective: Dietary flavonoids and their metabolites may have neuroprotective effects against age-associated neurodegenerative disorders such as Alzheimer’s and related dementias (dementia). There is a lack of population studies, however, on correlations between flavonoid intake and dementia. The main objective of the present study was to analyse such a relationship at a large-scale population level. Design: Based on global data (FAO, WHO), databases were generated for: (i) flavonoid content of foods; (ii) per capita national dietary intakes of flavonoids and other dietary factors; and (iii) disability-adjusted life years ‐ a measure of burden and death ‐ due to dementia. Five major flavonoid subclasses were examined. To minimize influences due to accuracy and reliability of the disease source data, twenty-three developed countries were selected after statistical evaluation. Results: Flavonols and combined flavonoids (all five combined) intakes were the only two parameters with significant (P ,0?05) negative dementia correlations. Multiple linear regression models confirmed this relationship, and excluded confounding from some other dietary and non-dietary factors. Similar analyses with non-dementia, neurological/psychiatric diseases did not yield significant correlations. Conclusions: At a global level, and in the context of different genetic backgrounds, our results suggest that higher consumption of dietary flavonoids, especially flavonols, is associated with lower population rates of dementia in these countries.

/pdf/flavonoid-intake-and-disability-adjusted-life-years-due-to-4c772r66co.pdf

Flavonoid intake and disability-adjusted life years due to Alzheimer’s and related dementias: a population-based study involving twenty-three developed countries

Both the neurotransmitter dopamine (DA) and a neurotoxic metabolite, 6-hydroxy DA, can be oxidized to generate hydrogen peroxide and other reactive species (ROS). ROS promote oxidative stress and have been implicated in dopaminergic neurodegeneration, e.g., Parkinson's disease (PD). There is also evidence for a relation between catecholamine-mediated oxidative damage in dopaminergic neurons and the effects of these neurotransmitters on the redox state of cytochrome c (Cytc). In neurons and other cells, oxidative stress may be enhanced by abnormal release of Cytc and other mitochondrial proteins into the cytoplasm. Cytc release can result in apoptosis; but sub-apoptogenic-threshold release can also occur, and may be highly damaging in the presence of DA metabolites. Loss of mitochondrial membrane integrity, a pathological situation of relevance to several aging-related neurodegenerative disorders including PD, contributes to release of Cytc; and the level of such release is known to be indicative of the extent of mitochondrial dysfunction. In this context, we have used a Cytc-enhanced 6-hydroxy DA oxidation reaction to gauge dietary antioxidant activities. Anthocyanin-rich preparations of Vaccinium species ( Vaccinium myrtillus , Vaccinium corymbosum , and Vaccinium oxycoccus ) as well as a purified glycosylated anthocyanidin were compared. The most potent inhibition of oxidation was observed with V. myrtillus preparation: 50% inhibition with 7 μM of total anthocyanins. This activity was 1.5–4 times higher than that for the other preparations or for the purified anthocyanin. Ascorbate (Vitamin C), at up to 4-fold higher concentrations, did not result in significant inhibition in this assay. Antioxidant activity in the assay correlated strongly ( r 2  > 0.91, P Vaccinium content of anthocyanins and total cyanidins, but not quercetin or myricetin. The results provide evidence for the high potency of anthocyanins towards a potentially neurotoxic reaction, and provide a basis for in vivo testing of these flavonoids and their physiological metabolites in the context of neuro- and mitochondrio-protective effects.

Protective activities of Vaccinium antioxidants with potential relevance to mitochondrial dysfunction and neurotoxicity.

Accurate estimates of flavonoid intake are important for public health studies and potential policies related to these phytochemicals. As an alternative to studies involving population samples and individual food consumption surveys, the international FAO Food Balance Sheets (FBS) were used in the current study to estimate flavonoid consumption among the populations of the UK and Republic of Ireland. A supplemented USDA database was prepared for flavonoid analyses of the foods reported in the FBS. Twenty-three flavonoids from five groups (anthocyanidins, flavonols, flavanols, flavanones, and flavones) were analyzed. Estimated per-capita daily flavonoid intake (all five groups) was 182 mg and 177 mg for the UK and Ireland, respectively. In both cases, anthocyanidins and flavanols accounted for about 65% of total consumption. Combined intake of flavones, flavanones, and flavonols was 60 mg/day in the UK and 69 mg/day in Ireland. These flavonoid intake values are compared with those previously reported for t...

Amandio Vieira

Papers

Control of EGF receptor signaling by clathrin-mediated endocytosis.

Flavonoid intake and disability-adjusted life years due to Alzheimer’s and related dementias: a population-based study involving twenty-three developed countries

Protective activities of Vaccinium antioxidants with potential relevance to mitochondrial dysfunction and neurotoxicity.

An assessment of dietary flavonoid intake in the UK and Ireland

Transport of Serum Transthyretin into Chicken Oocytes: A RECEPTOR-MEDIATED MECHANISM (∗)