FLAVONOIDS: BIOCHEMISTRY, BIOPHYSICS, MEDICINE - Tarakhovsky Yu. S. - 2013

Conclusion

Flavonoids are polyphenolic compounds that protect plants against adverse environmental factors. They perform similar functions in animals, whose bodies do not synthesize these compounds but obtain them through diet. Although the concentration of flavonoids in animal Tissues is significantly lower than in plants, these substances retain their protective functions and are normally present in Blood, Lymph, and intercellular fluids, interacting with cellular signaling receptors. Flavonoids can also enter the Cytoplasm, exerting a direct effect on The activity of certain Enzymes. Currently, there is substantial evidence of altered expression and function of various cytoplasmic and Nuclear Proteins, although the molecular mechanisms underlying the Effects of Flavonoids on protein function remain poorly understood. Furthermore, in the animal body, flavonoids undergo various chemical modifications, and their metabolic products also exhibit biological activity. However, flavonoid pharmacokinetics is still in its infancy, and research in this field remains relatively scarce.

Studies on the action of flavonoids demonstrate their ability to modulate various physiological processes in both individual Cells and the Organism as a whole. Although epidemiological studies investigating the correlation between the consumption of flavonoids and the incidence of various pathologies (cardiovascular, oncological, and neurological disorders) have yielded ambiguous results, animal experiments and clinical trials involving human volunteers provide compelling evidence regarding the therapeutic potential of certain flavonoids in the Prevention and even Treatment of various diseases.

Among plant polyphenols, flavonoids constitute a rather specialized group of compounds with a highly conserved Structure, although even within these constraints, nature has generated an immense variety of structural modifications. Owing to dimensions comparable to those of certain biologically active regulators, flavonoids can influence the function of enzymes and cellular signaling components modulated by Steroids, adenosine derivatives, and other small molecules. Variations in the positioning of hydroxyl groups within the flavonoid molecule presumably create specific surface charge distributions that facilitate their specific interaction with protein regulatory sites.

Flavonoids are also capable of penetrating the hydrophobic and interfacial regions of Introduction/36.html">Biological Membranes, thereby exerting profound effects on numerous cellular processes. This efficacy may stem from the ability of flavonoids to interact with specialized Cell/33.html">Plasma Membrane domains known as lipid rafts, which concentrate numerous receptors and cellular signaling components. By altering the PHYSICOCHEMICAL PROPERTIES OF The Lipid Bilayer within raft domains, flavonoids can modulate the function of individual Membrane Proteins as well as their propensity to interact with one another and form functional macromolecular assemblies.

Flavonoids are potent antioxidants that prevent oxidative stress in cells where METABOLISM is impaired by toxic prooxidants, UV radiation, and other damaging factors. The Antioxidant Properties of flavonoids are determined both by their ability to scavenge free radicals and by their capacity to chelate transition metal cations involved in oxidation processes. Notably, metal complexation enhances the antioxidant properties of flavonoids. For instance, flavonoid-metal complexes exhibit superoxide dismutase activity, which is absent in uncomplexed flavonoids. Furthermore, interaction with metals alters the lipophilicity of flavonoids. In the presence of trace amounts of metals, these complexes are lipophilic and can partition into the lipid bilayer, thereby helping to protect biological membranes. Conversely, under conditions of metal excess, the resulting complexes exhibit increased Water solubility and can interact with soluble oxidation products.

The antioxidant action of flavonoids is not limited to their direct effect on Lipid Peroxidation processes. More importantly, flavonoids can activate innate cellular defense mechanisms against oxidative stress. Treatment with flavonoids upregulates the expression of enzymes such as catalase, superoxide dismutase, and Glutathione peroxidase. Conversely, in Cancer cells, certain flavonoids suppress the activity of antioxidant enzymes, triggering oxidative stress and promoting apoptosis. Thus, one of the most remarkable properties of flavonoids is their ability to normalize the metabolism of normal cells when impaired, while selectively inducing apoptosis in cancer cells by disrupting their metabolic pathways. This dual action is likely achieved through the activation of evolutionary conserved natural defense mechanisms of the organism.

Animals and humans have consumed flavonoids throughout their evolutionary history, and these substances have consistently remained Components of the body's internal environment. Although they are not essential micronutrients in the strict sense of Vitamins—whose absence leads to distinct deficiency syndromes and specific diseases—flavonoids are nonetheless required for normal physiological function. Upon entering the body, they become integrated into numerous pathways of cellular signaling, Gene Expression, and Metabolic Regulation, while also protecting the organism against parasitic and infectious agents. Flavonoids represent a subtle yet essential link in protein assembly and function, biological membrane Organization, and Intracellular Signaling. Being readily available, they act as versatile helpers in numerous cellular processes, serving as a biological 'lubricant' within The Cell's complex machinery. It is hoped that further research into flavonoids will yield numerous exciting discoveries, and that the synthesis of novel artificial derivatives will provide effective therapeutic agents.

Class="center">Accepted Abbreviations

AA - arachidonic acid. A polyunsaturated C20:4, omega-6 fatty acid, acting as a secondary messenger, key inflammatory intermediate, and vasodilator.

AhR - aryl hydrocarbon receptor. Mediates the aryl hydrocarbon signaling pathway to induce the expression of detoxification enzymes (such as Cytochromes P450, NQO1, etc.).

Akt - alternative name: protein kinase B (PKB). A Serine/Threonine-specific protein kinase involved in glucose metabolism, apoptosis, and cell proliferation.

AMPA - aminomethylphosphonic acid. A blocker of AMPA receptors, which constitute a subclass of ionotropic glutamate receptors.

AP1 - activator protein. A Transcription factor that regulates GENE EXPRESSION IN response to cytokines, growth factors, stress, and infection.

Bak - a kinase associated with BRI (brassinosteroid receptor, a plant hormone). In animals, it participates in The regulation of apoptosis.

Bcl-2-associated X protein (Bax). An apoptotic protein that inserts into the outer mitochondrial membrane, triggering the release of cytochrome c and leading to apoptosis.

BBB - blood-Brain barrier. A diffusion barrier formed by endothelial cells of Central Nervous system capillaries that prevents the penetration of pathogens and toxins into the brain.

B-cell lymphoma 2 (Bcl-2). A family of proteins regulating outer mitochondrial membrane permeability and controlling apoptosis in numerous cell types, including lymphocytes and Neurons.

BCRP - breast cancer resistance protein.

Bid - a pro-apoptotic protein of the Bcl-2 family (BH3 interacting-domain death agonist).

bZIP - basic leucine zipper domain, present in various eukaryotic DNA-binding proteins.

c-FLIP - apoptosis regulator (alternative names: CASP8- and FADD-like apoptosis regulator).

COX - cyclooxygenase. An enzyme involved in the synthesis of Prostanoids, including Prostaglandins, prostacyclins, and thromboxanes, which mediate inflammatory responses.

DISC - death-inducing signaling complex. A multiprotein plasma membrane complex formed by death receptors.

DMPC - dimyristoylphosphatidylcholine. A synthetic glycerophospholipid. Its hydrocarbon chains are formed by two myristic acid residues.

DR - death receptor, also known as TNFR (Tumor necrosis factor receptor). A cell surface receptor that binds tumor necrosis factors, such as TNF-alpha.

EGCG - epigallocatechin-3-gallate. An ester of epigallocatechin and gallic acid. The most characteristic green tea catechin, which holds significant therapeutic value.

EPA - eicosapentaenoic acid. A polyunsaturated fatty acid (С20:5, omega-3). A precursor in the synthesis of Eicosanoids: prostaglandins, thromboxanes, and Leukotrienes.

ERK - extracellular signal-regulated Kinases. Involved in the regulation of mitosis, Meiosis, cell growth, and differentiation.

FasL - FAS-Ligand. A transmembrane protein and ligand for the death receptor located on the cell surface. A component of immune anticancer defense.

GABA - gamma-aminobutyric acid. A crucial inhibitory neurotransmitter of the central nervous system. Interacts with GABA receptors at synapses.

GPCR - G protein-coupled receptors. Widespread transmembrane receptors for Hormones, Neurotransmitters, pheromones, and many other agents.

GRB2 - growth factor receptor-bound protein 2. A protein complex that interacts with regulatory proteins on the cell surface, regulating cell growth and proliferation.

HDAC - histone deacetylase. Affects The structure of histone proteins and regulates gene expression.

HPETE - 5-hydroperoxyeicosatetraenoic acid. Also known as arachidonic acid 5-hydroperoxide. An intermediate in The production of leukotriene A4.

HRE - hormone response element. A short DNA sequence within the promoter region that binds Hormone Receptors and regulates gene expression.

IAP - inhibitors of apoptosis. A family of proteins that enhance cell survival.

ICAM1 - intercellular adhesion molecule 1, also known as cluster of differentiation 54. A glycoprotein found On the surface of endothelial and immune system cells.

IGF-1 - Insulin-like growth factor. A protein hormone structurally similar to insulin. Acts as an apoptosis inhibitor.

IKK - inhibitor of nuclear factor kappa-B kinase. A component of the signaling pathway involved in the Immune Response, which suppresses the expression of inflammatory proteins.

IL - interleukin. A protein cytokine and signaling molecule produced by epithelial cells and macrophages. Acts as an immune response regulator.

iNOS - inducible nitric oxide synthase. An enzyme that produces nitric oxide and participates in the immune response.

IkB - inhibitor of kappa-B. A protein kinase and enzymatic complex involved in the cellular response of B-lymphocytes to inflammation.

JAK - janus kinase. Belongs to Tyrosine kinases. Transmits cytokine signals via the JAK-STAT pathway from the cell surface through the cytoplasm to The Nucleus, where it regulates gene expression.

JNK - c-Jun N-terminal kinase. Belongs to the mitogen-activated protein kinase family. Involved in stress responses (such as heat Shock and osmotic shock).

LOX - lipoxygenases. Enzymes involved in the synthesis of eicosanoids (prostaglandins and leukotrienes)—signaling molecules and inflammation regulators derived from C20 Fatty acids (omega-3 or omega-6).

LT - leukotrienes. Lipid mediators of inflammation present in leukocytes and other immune system cells.

MAPK - mitogen-activated protein kinases. Serine/threonine protein kinases involved in cellular responses to heat and osmotic shock, as well as the presence of pro-inflammatory cytokines.

Mcl-1 - induced myeloid leukemia Cell Differentiation protein. A member of the Bcl-2 protein family. Involved in the regulation of apoptosis.

MCP-1 - monocyte chemotactic protein 1, also known as chemokine (C-C motif) ligand 2.

MEK - a protein kinase that phosphorylates mitogen-activated protein kinase (MAPK). Better known as MAPKK or MAP2K (mitogen-activated protein kinase kinase).

MMP-9 - matrix metallopeptidase 9. An enzyme that degrades the Extracellular matrix during normal physiological processes of tissue growth and differentiation.

MRP2 - multidrug resistance-associated protein 2.

mTRP - mitochondrial permeability transition pore. A protein pore formed in The inner mitochondrial membrane, involved in cell apoptosis.

NF-kB - nuclear factor kappa-B. A protein complex that regulates DNA Transcription in response to external signals.

NMDA - N-methyl-D-aspartate. A blocker of NMDA receptors, which are a subtype of glutamate receptors.

NQO1 - NAD(P)H:quinone oxidoreductase. Also known as NAD(P)H dehydrogenase, quinone 1. An enzyme that prevents quinone reduction and free radical generation.

NRF1 - nuclear respiratory factor 1. A protein regulator of mitochondrial respiratory protein gene transcription.

OH-1 - heme oxygenase. An enzyme that catalyzes heme degradation to form biliverdin and iron.

p21 - cyclin-dependent kinase inhibitor 1. Inhibits the activity of the protein complex on chromosome 6, arresting Cell Division at the G1 phase.

p38 - mitogen-activated protein kinases. Protein kinases that regulate cell differentiation and apoptosis in response to external stimuli.

PAF - platelet-activating factor. A phospholipid activator and mediator of various platelet functions, including aggregation and degranulation. Involved in inflammatory and anaphylactic reactions.

PG - prostaglandins. Lipid messengers derived from C20 polyunsaturated fatty acids.

P-gp - P-glycoprotein. A multidrug resistance protein belonging to the ABCB1 transporter family.

PI3K - phosphatidylinositol 3-kinases. A family of enzymes that phosphorylate phosphatidylinositol, involved in the propagation of cell growth and differentiation signals.

PKA - protein kinase A. A cAMP-activated protein kinase involved in the REGULATION OF CARBOHYDRATE and Lipid Metabolism.

PLA - phospholipase A1 or A2. Enzymes involved in the Cleavage of fatty acids from glycerolipid molecules at the sn-1 or sn-2 position.

POPC - 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. A synthetic phospholipid containing palmitic and oleic fatty acids.

PP2A - protein phosphatase 2A. A serine/threonine phosphatase involved in the oncogenic signaling cascade alongside Raf, MEK, and AKT.

PPAR - peroxisome proliferator-activated receptor. Nuclear receptors for certain hormones and vitamins that act as transcription factors.

PTK2 - protein tyrosine kinase 2. Also known as focal adhesion kinase (FAK). A protein involved in Cell Adhesion and tumor metastasis.

QSAR - quantitative structure-activity relationship. The evaluation of the biological activity of substances based on computational modeling.

Raf - proto-oncogene serine/threonine-protein kinase. Controls genes responsible for cell division, apoptosis, differentiation, and migration.

Ras - small GTPases. Proteins involved in intracellular signal Transduction, belonging to the proto-oncogene family.

RhoA - Ras homolog gene family, member A. A small GTPase protein. A key regulator of the Actin Cytoskeleton.

ROS - reactive oxygen species. They include oxygen ions and peroxides. Involved in The Development of oxidative stress and cellular signaling.

RTK - receptor tyrosine kinases. Cell surface receptors specific for growth factors, cytokines, and hormones. Involved in carcinogenesis.

RXR - retinoid X receptor. A nuclear receptor for 9-cis-retinoic acid. A transcription regulator.

SMAC - second Mitochondria-derived activator of caspases. A mitochondrial protein involved in cytochrome c-dependent apoptosis.

SOS1 - son of sevenless 1, a membrane-associated guanine nucleotide exchange factor. Transduces signals for cell growth and differentiation.

SP1 - Specificity Protein 1. A transcription factor responsible for gene expression during the Cytology/cytology/16.html">Early stages of organism development.

Src - proto-oncogene tyrosine-protein kinase Src. A protein involved in embryonic development. Its mutant form is implicated in carcinogenesis.

STAT - signal transducer and activator of transcription. A protein that regulates cell growth and differentiation.

TGF-α - transforming growth factor alpha. A protein that induces epithelial cell growth. Overproduction of this protein is observed in certain types of cancer cells.

TNF-α - tumor necrosis factor alpha. A protein cytokine involved in systemic inflammatory responses. Produced mainly by macrophages.

TRAIL - TNF-related apoptosis-inducing ligand. A protein cytokine that induces apoptosis upon binding to death receptors on the cell surface.

TX - thromboxanes. Regulatory Lipids belonging to eicosanoids. Vasoconstrictors that increase blood pressure and participate in platelet aggregation.

VCAM1 - vascular cell adhesion protein 1. Also known as cluster of differentiation 106 (CD106). Involved in cell adhesion.

XIAP - X-linked inhibitor of apoptosis protein. A mammalian protein that prevents apoptosis.

АФл - flavonoid aglycones. The polyphenolic moiety of a flavonoid molecule, lacking the saccharide residue.

ГлК - glucuronic acid.

ГФл - flavonoid Glycosides. Flavonoid molecules with attached saccharide residues.

МКИ - minimal inhibitory concentration. The lowest concentration of an antimicrobial agent that inhibits visible growth of a microorganism after 12 hours of incubation.