See also Probiotics
Introduction:
Polyphenols: are a group of phytochemical compounds with potential health-promoting effects. They are classified into favonoids, stilbenes and phenolic acids. In the case of favonoics, the literature generally classifed them into flavonols, flavanones, isoflanones, flavones, flavan-3-ols (flavanols) and anthocyanins.
Phenolic compounds are a diverse group of plant-derived molecules with an aromatic ring and at least one hydroxyl group, classified into several major classes including flavonoids, phenolic acids, tannins, ligands, and stilbenes. This classification is based on their number of phenol rings and the structural elements that link them.
Flavonoids: are a specific type of polyphenol.
Flavonoids:
Flavonoids represent a group of naturally occurring phenolic compounds that are characterized by a structure consisting of two benzene rings (A and B) linked thorugh a pyran ring. Some flavonoids of interest due to their medicinal properties include the following:
Diosmin (DIS (diosmetin 7-O-rutinoside): is a flavone glycoside of dismetin (see below). It is a precursor to diosmetin; its primary pharmacological effect is to become diosmetin in the gut. It is manufactured form citrus fruit peels as a phlebotonic non-prescription dietary supplment used to aid treatment of hemorrhoids or chronic venous diseases, mainly of the legs.
Diosmin is a flavonoid glycoside (a sugar molecule attached to a flavonoid) that is converted into its aglycone (the non-sugar part) form, diosmetin, within the human body, primarily by intestinal bacteria. The aglycone (the non-sugar portion) of diosmin. Therefore, diosmetin is the active metabolite of diosmin; diosmin is not directly active, but when the sugar is removed, the resulting diosmetin exhibits various biological activities like antioxidant, anti-inflammatory, and anti-tumor effects, according to PubChem and National Institutes of Health (NIH) data.
Diosmetin (DSMT) (3′,5,7-trihydroxy-4’methoxy-flavonine): is an O-methylated flavone, the aglycone part of the flavonoid glycosides diosmin occurs naturally in citrus fruit. Diosmetin, a citrus flavanoid, has a variety of therapeutic properties such as antibacterial, anti-inflammatory and antioxidant effects.
Flavonoids with amino acids: Dominguez Chavez (US 2024/0285534) discloses co-amorphous solids of flavonoids such as diosmin and amino acids.
Red wines contain a large array of polyphenolic constituents that have been shown to block carcinogenesis and to inhibit the growth of tumors in whole animals, or in cell culture by altering the activity of certain enzymes or the expression of specific genes.
Naringenin (NRG): belongs to the flavanone calss. It is extracted from teh peel of some citrus fruits and is mainly responsible for their bitter taste. It is also located in the pulp of fruits, in leaves, flowers and seeds. It is found in food supplements, promoted as an enhancer of other supplements, which increases physical capacity and acts as a fat burner for weight loss, among other effects.
Genistein (GTN): is an aglycone of the plant isoflavone family. It is found naturally in soybeans. Isoflavones have chemical structures similar to human estrogens. Some publications mention that genistein could be useful in bone and brain health, to prevent heart disease, to reduce the occurrence of breast and prostate cancer, and to prevent hypertension. One of the mechanisms of action is the reduciton of oxidative stress, the promotion of growth factor signaling and immune suppression in endothelial, glial and neuronal cells.
Genistein is an aglycone phytoestrogen found in soy and soy products. It has been assocaited with a number of beneficial health effects including reduced risk of fracture and breast cancer and lowered risk of CD. It is classified as an isoflavone and it structurally resembles 17-beta estradiol, although its pharmacological profile is somewhat different from that of endogenous estrogens. Highly purified genistein alycone from soy has undergone testing in clinical trils to ascertain its effects on bone health, monopausal symptoms and cardiovascular function. (Burnett, US 2009/0258845, US 2015,0190365; US Patent Nos: 8,338,393, 9,066,921, 9,486,438; Primus Pharmaceuticals, Inc.,)
–Genivda® is a pure, synthetic form of genistein, a plant compound (isoflavone) used in dietary supplements, primarily to help relieve menopause symptoms like hot flashes and night sweats, and support long-term bone health by mimicking estrogen’s effects in the body. Developed by DSM, it’s soy-free, hormone-free, and clinically studied for safety and effectiveness in women’s health products, found in brands like Centrum and Doctor’s Best.
Genistin: is the above genistein bound to a sugar (e.g., 7-O-glucoside). These are different chemical species (different molecular mass, formula). Genistein aglycone is the non-sugar fomr which is commonly referred to as genistein (see above).
Red wine is considered a source of flavonoids because it contains various flavonoid compounds, such as flavanols (like catechin), flavonols (like quercetin), and anthocyanins, which are primarily derived from the skins and seeds of grapes. Flavonoids are beneficial plant compounds that act as antioxidants and are also found in other foods like berries, tea, and dark chocolate.
Research in the Massachusetts Institute of Technology laboratory of Leonard Guarente has shown that increasing the activity of a single gene, called SIR2, can extend the life span of yeast and that without the gene, calorie restriction does not prolong life. The Sir2 enzyme belongs to a large family of evolutionarily conserved molecules termed sirtuins. In lower organisms, such as yeast and worms, these enzymes regulate a wide range of cellular activities that affect lifespan, including modulating how tightly DNA is packaged inside cells. In mammalian cells, sirtuins act as regulators of programmed cell death and differentiation.
Certain molecules also activate SIR2 in yeast, as well an an analogous gene, SIRT1, in human cells. These compounds include the following:
- quercetin a polyphenol found in apples and tea
- piceatannol a polyphenol
- resveratrol is a phytoalexin, one of a group of compounds that are produced in plants during times of environmental stress or pathogenic attack. Resveratol has been found in at least 72 plant species, a number of which are components of the human diet, including mulberries, peanuts, and grapes. Resveratrol found in grapes and red wine has been shown to increase SIRT1 activity 13-fold (24 August, Nature). Many studies report that resveratrol exerts its anti-cancer effects by causing cell cycle arrest and inducing apoptosis in many different human cancers. In non-Hodgkin’s lymphoma and multiple myeloma, resveratrol not only induced apoptosis but also potentiated the effects of paclitaxel-induced apoptosis. Resveratrol was also shown to sensitize tumor cells, but not normal human fibroblasts, to TRAIL-induced apoptosis. In 2003, David sinclar of Harvard medical School in Boston and his colleagues reported that yeast dosed with resveratrol lived 60% longer than yeast that did not receive the compound.
are a type of polyphenol found in natural substances like .
Capsaicin: is a major phenolic compound from chili peper. It has been shown to induce cell apoptosis in vitro.
Curcumin (1.7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione): See curcuminoids
Ginger: ginger is a source of flavonoids; research has identified various flavonoid components in ginger, including in its young varieties and leaves, which contribute to its pharmacological properties. The presence and concentration of these flavonoids can vary depending on the ginger variety, growth stage, and processing methods used.
Ginger has been used in China for over 2500 years for colds, nausea and headaches. Ginger and its constituents have been shown to inhibit tumor promotion in mouse skin.
–Treatment of Erectile Dysfunction (See also signal transduction):
—–PDE5 inhibitors + Ginger: Milchteim (US 2018/0078602) discloses the the treatment of erectile dysfunction (“ED”) can be extended by concomitant administration of compositions that include ginger, a compound that produces L-arginine in vivo. with phosphodiesterase inhibitors. ED is associated with the aging process and chacracterized histologically within the cavernosa by a progressive apoptosis or loss of the corporal smooth muscle cells (CSM) and replacement of these cells with collagen. Drugs like VIAGRA and CIALIS are often prescirbed after a patient has presented with symptoms of ED. These drugs belong to a class of drugs called type 5 phosphodiesterase (PDE5) inhibitors. PDE5 is an enzyme that breaks down cGMP once it is formed. PDE35 inhibiotrs such as VIAGRA prevent the cGMP from breaking down, so the effect of cGMP on the tissues is enhanced. With regards to erectile funciton, cGMP is formed within the CSM from a reaction that is initiated by the NO that is released form the cavernosal nerve following sexual stimulation. The NO that begins the erectile response comes from teh enzyme nNOS that is located in the nerve endings. NO goes into the CSM cells and casues reaction to occur in these CSM cells. NO activates the enzyem soluble guanylyl cyclase (sGC) in the cytoplasms of the CSM and this enzyme in turn coverts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). An increase in cGMP stimualtes protein kinase G to phosphorylate potassium and calcium channels cuasing a decrease in cytosolic calcium, dilation of the helicine arterioles, and the relaxation of the trebecular smooth muslce withere all the CSM cells are loacted. The relaxation of the smooth muslce leads to an increase in the intracavernosal volume, initiating the erectile process. Normally, endogenous PDE5 enzyme degrades cGMP which reverses the relaxation of the smooth muscle cells and leads to loss of erection wehreas the ingestion of PDE5 inhibitors (PDE5-a) prior to sexual simulation prevents the degradation of the cGMP thereby prolonging any CSM relaxation and ehnacing an erectile resposne.
Gingko biloba is known to be enriched with falvonoids and has demonstrated benefits for Alzheimer’s disease. These findings are supported by in vitro studies, where the catechin EGCG or the Ginkgo biloba extract were shown to prevent amylooid B peptide (Ab)-induced neurotoxicity in cultured hippocampal neurons.
Polycyclic-phenolic compounds:
Hypericin belongs to the chemical class of naphthodianthrones and, more broadly, is considered a phenanthoperylene quinone or polycyclic-phenolic compound. It is a natural product found in plants, particularly those of the Hypericum genus, such as St. John’s wort (Hypericum perforatum).
Hypericin from St. John’s Wort is best known in the treatment of depression. It is also known to induce apoptosis in different enoplastic cell lines. There are also some reports of anti-inflammatory potential such as inhibition of phorbol ester-induced NF-kB activation.
Curcumin (diferuloylmethane)/Curcuminoid (see outline)
Curcumin (diferuloylmethane)/Curcuminoid
Introduction Definitions:
–Curcuminoids: may be obtained form or found in a turmeric extract or may be syntehsized. Curcuminoids include curcumin (see below), tetrahydrocurcuminoids (see below), hexahydrocurcuminoids and octahydrocurcuminoids, .
–Curcumin (diferuloylmethane) is a golden pigment from turmeric which has been linked with antioxidant, anti-inflammatory, anticancer, antiiral, antibacterial, and antidiabetic properties. Most of these activities have been assigned to methoxy, hydroxyl, alpha,beta-unsaturated carbonyl moiety or to diketone groups present in curcumin. (Prasad, “Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular resposnes” Molcules 2015, 20, 185-205).
–Tetrahydrocurcumin (THC): One of the major metabolites of curcumin is tetrahydrocurcumin (THC), which lacks alpha, beta-unsaturated carbonyl moiety and is white in color. The yellow component of turmeric, is metabolized to white THC and these two compound exhibit distinct activities. Studies have shown that curcumin given intraperitoneally is first biottransformed to dihydrocurcumin and then to THC. THC, one of the major metabolites of curcumin, was very stable in 0.1 M phospahte buffers at various pH values and was more stable than curcumin in 0.1 M phosphate buffer at pH 7.2 (37C). (Prasad, “Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular resposnes” Molcules 2015, 20, 185-205).
Use in Treatment of Neurological Disorders:
–in combination Probiotic bacterium:
Van de Wiel (US 2023/0190835) discloses probiotic bacteria in particular combination with herbal active agents such as a curcuminoid and/or a cannabinoid to treat or prevent Alzheimer’s disease. In one embodiment the probiotic bacterium is selected form the genus of Lactobacillus bacteria.