Targeting beta-catenin signaling for prevention of colorectal cancer - Nutraceutical, drug, and dietary options.

Progressive up-regulation of ß-catenin signaling is very common in the transformation of colorectal epithelium to colorectal cancer (CRC). Practical measures for opposing such signaling hence have potential for preventing or slowing such transformation. cAMP/PKA activity in colon epithelium, as stimulated by COX-2-generated prostaglandins and ß2-adrenergic signaling, boosts ß-catenin activity, whereas cGMP/PKG signaling has the opposite effect. Bacterial generation of short-chain fatty acids (as supported by unrefined high-carbohydrate diets, berberine, and probiotics), dietary calcium, daily aspirin, antioxidants opposing cox-2 induction, and nicotine avoidance, can suppress cAMP production in colonic epithelium, whereas cGMP can be boosted via linaclotides, PDE5 inhibitors such as sildenafil or icariin, and likely high-dose biotin. Selective activation of estrogen receptor-ß by soy isoflavones, support of adequate vitamin D receptor activity with UV exposure or supplemental vitamin D, and inhibition of CK2 activity with flavanols such as quercetin, can also oppose ß-catenin signaling in colorectal epithelium. Secondary bile acids, the colonic production of which can be diminished by low-fat diets and berberine, can up-regulate ß-catenin activity by down-regulating farnesoid X receptor expression. Stimulation of PI3K/Akt via insulin, IGF-I, TLR4, and EGFR receptors boosts ß-catenin levels via inhibition of glycogen synthase-3ß; plant-based diets can down-regulate insulin and IGF-I levels, exercise training and leanness can keep insulin low, anthocyanins and their key metabolite ferulic acid have potential for opposing TLR4 signaling, and silibinin is a direct antagonist for EGFR. Partially hydrolyzed phytate can oppose growth factor-mediated down-regulation of ß-catenin by inhibiting Akt activation. Multifactorial strategies for safely opposing ß-catenin signaling can be complemented with measures that diminish colonic mutagenesis and DNA hypomethylation - such as avoidance of heme-rich meat and charred or processed meats, consumption of phase II-inductive foods and nutraceuticals (e.g., Crucifera), and assurance of adequate folate status.

Properties of Cephalopod Skin Ommochromes to Inhibit Free Radicals, and the Maillard Reaction and Retino-Protective Mechanisms in Cellular Models Concerning Oxidative Stress, Angiogenesis, and Inflammation.

Ommochromes are pigments of invertebrates that exhibit oxidative stress protection. The aim of this study was to investigate ommochromes extracted from cephalopod's skin for their ability to inhibit age-related-macular degeneration (AMD)-related factors such as H2O2-induced and iron-dependent oxidative stress (ferroptosis and erastin), accumulation of advanced glycation end-products (AGEs), as well as vascular endothelial growth factor (VEGF), and inflammatory cytokines (interleukin 6 and interleukin 8) secretion. As cell systems, we used primary porcine retinal pigment epithelium (RPE), human retinal pigment epithelium cell line ARPE-19 and uveal melanoma cell line OMM-1. In vitro, ommochromes produced an antiglycation effect by the inhibition of fructosylation reaction. The ommochromes showed protective effects against erastin- induced cell death in ARPE-19. In addition, in long-term stimulation (7 days) ommochromes decreased constitutively secreted VEGF, as well as interleukin 6 and interleukin 8 induced by Poly I:C in primary RPE. No relevant effects were detected in OMM-1 cells. The effects are dependent on the cell system, time of exposition, and concentration. This substance is of interest for further research concerning age-related macular degeneration.

Inhibition of Pathogenic Bacteria and Fungi by Natural Phenoxazinone from Octopus Ommochrome Pigments.

Cephalopods, in particular octopus (Octopus vulgaris), have the ability to alter their appearance or body pattern by showing a wide range of camouflage by virtue of their chromatophores, which contain nanostructured granules of ommochrome pigments. Recently, the antioxidant and antimicrobial activities of ommochromes have become of great interest; therefore, in this study, the pH-dependent redox effect of the extraction solvent on the antioxidant potential and the structural characterization of the pigments were evaluated. Cell viability was determined by the microdilution method in broth by turbidity, MTT, resazurin, as well as fluorescence microscopy kit assays. A Live/Dead Double Staining Kit and an ROS Kit were used to elucidate the possible inhibitory mechanisms of ommochromes against bacterial and fungal strains. The results obtained revealed that the redox state alters the color changes of the ommochromes and is dependent on the pH in the extraction solvent. Natural phenoxazinone (ommochromes) is moderately toxic to the pathogens Staphylococcus aureus, Bacillus subtilis, Salmonella Typhimurium and Candida albicans, while the species Pseudomonas aeruginosa and Pseudomonas fluorescens, and the filamentous fungi Aspergillus parasiticus, Alternaria spp. and Fusarium verticillioides, were tolerant to these pigments. UV/visible spectral scanning and Fourier- transform infrared spectroscopy (FTIR) suggest the presence of reduced ommatin in methanol/ HCl extract with high intrinsic fluorescence.

Nutraceuticals/Drugs Promoting Mitophagy and Mitochondrial Biogenesis May Combat the Mitochondrial Dysfunction Driving Progression of Dry Age-Related Macular Degeneration.

In patients with age-related macular degeneration (AMD), the crucial retinal pigment epithelial (RPE) cells are characterized by mitochondria that are structurally and functionally defective. Moreover, deficient expression of the mRNA-editing enzyme Dicer is noted specifically in these cells. This Dicer deficit up-regulates expression of Alu RNA, which in turn damages mitochondria-inducing the loss of membrane potential, boosting oxidant generation, and causing mitochondrial DNA to translocate to the cytoplasmic region. The cytoplasmic mtDNA, in conjunction with induced oxidative stress, triggers a non-canonical pathway of NLRP3 inflammasome activation, leading to the production of interleukin-18 that acts in an autocrine manner to induce apoptotic death of RPE cells, thereby driving progression of dry AMD. It is proposed that measures which jointly up-regulate mitophagy and mitochondrial biogenesis (MB), by replacing damaged mitochondria with "healthy" new ones, may lessen the adverse impact of Alu RNA on RPE cells, enabling the prevention or control of dry AMD. An analysis of the molecular biology underlying mitophagy/MB and inflammasome activation suggests that nutraceuticals or drugs that can activate Sirt1, AMPK, Nrf2, and PPARα may be useful in this regard. These include ferulic acid, melatonin urolithin A and glucosamine (Sirt1), metformin and berberine (AMPK), lipoic acid and broccoli sprout extract (Nrf2), and fibrate drugs and astaxanthin (PPARα). Hence, nutraceutical regimens providing physiologically meaningful doses of several or all of the: ferulic acid, melatonin, glucosamine, berberine, lipoic acid, and astaxanthin, may have potential for control of dry AMD.

Targeting Sirt1, AMPK, Nrf2, CK2, and Soluble Guanylate Cyclase with Nutraceuticals: A Practical Strategy for Preserving Bone Mass.

There is a vast pre-clinical literature suggesting that certain nutraceuticals have the potential to aid the preservation of bone mass in the context of estrogen withdrawal, glucocorticoid treatment, chronic inflammation, or aging. In an effort to bring some logical clarity to these findings, the signaling pathways regulating osteoblast, osteocyte, and osteoclast induction, activity, and survival are briefly reviewed in the present study. The focus is placed on the following factors: the mechanisms that induce and activate the RUNX2 transcription factor, a key driver of osteoblast differentiation and function; the promotion of autophagy and prevention of apoptosis in osteoblasts/osteoclasts; and the induction and activation of NFATc1, which promotes the expression of many proteins required for osteoclast-mediated osteolysis. This analysis suggests that the activation of sirtuin 1 (Sirt1), AMP-activated protein kinase (AMPK), the Nrf2 transcription factor, and soluble guanylate cyclase (sGC) can be expected to aid the maintenance of bone mass, whereas the inhibition of the serine kinase CK2 should also be protective in this regard. Fortuitously, nutraceuticals are available to address each of these targets. Sirt1 activation can be promoted with ferulic acid, N1-methylnicotinamide, melatonin, nicotinamide riboside, glucosamine, and thymoquinone. Berberine, such as the drug metformin, is a clinically useful activator of AMPK. Many agents, including lipoic acid, melatonin, thymoquinone, astaxanthin, and crucifera-derived sulforaphane, can promote Nrf2 activity. Pharmacological doses of biotin can directly stimulate sGC. Additionally, certain flavonols, notably quercetin, can inhibit CK2 in high nanomolar concentrations that may be clinically relevant. Many, though not all, of these agents have shown favorable effects on bone density and structure in rodent models of bone loss. Complex nutraceutical regimens providing a selection of these nutraceuticals in clinically meaningful doses may have an important potential for preserving bone health. Concurrent supplementation with taurine, N-acetylcysteine, vitamins D and K2, and minerals, including magnesium, zinc, and manganese, plus a diet naturally high in potassium, may also be helpful in this regard.

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond.

Inflammasomes are intracellular protein complexes that form in response to a variety of stress signals and that serve to catalyze the proteolytic conversion of pro-interleukin-1ß and pro-interleukin-18 to active interleukin-1ß and interleukin-18, central mediators of the inflammatory response; inflammasomes can also promote a type of cell death known as pyroptosis. The NLRP3 inflammasome has received the most study and plays an important pathogenic role in a vast range of pathologies associated with inflammation-including atherosclerosis, myocardial infarction, the complications of diabetes, neurological and autoimmune disorders, dry macular degeneration, gout, and the cytokine storm phase of COVID-19. A consideration of the molecular biology underlying inflammasome priming and activation enables the prediction that a range of nutraceuticals may have clinical potential for suppressing inflammasome activity-antioxidants including phycocyanobilin, phase 2 inducers, melatonin, and N-acetylcysteine, the AMPK activator berberine, glucosamine, zinc, and various nutraceuticals that support generation of hydrogen sulfide. Complex nutraceuticals or functional foods featuring a number of these agents may find utility in the prevention and control of a wide range of medical disorders.

Solvent effects on phytochemical constituent profiles and antioxidant activities, using four different extraction formulations for analysis of Bucida buceras L. and Phoradendron californicum.

BACKGROUND: The present investigation evaluated 4 different solvent compositions for their relative capacity to extract total phenolic and total flavonoid (TF) components of the leaves, trunks, and stems of Bucida buceras L. (Combretaceae), and the stems of Phoradendron californicum (Viscaceae), plus mesquite and oak species endemic to the Southwestern United States, northern Mexico, and tropical regions of Central and South America, as well as to profile the composition of these plant materials and to measure their antioxidant capacity. METHODS: The total phenolic content of plant material used in the present investigation was measured using the Folin-Ciocalteau assay. Total flavonoids were assayed by AlCl3 and 2,4-dinitrophenylhydrazin colorimetry. Nitroblue tetrazolium was utilized for scavenging of superoxide anion, and in vitro antioxidant activity was evaluated using the 2, 2-diphenyl-1-picrylhydrazyl and Ferric Reducing/Antioxidant Power assays. RESULTS: Phytochemical screening of each plant extract evaluated revealed the following major results: (1) No evidence of alkaloids for each of the extraction phases tested was detected in the hexanic, ethanolic, or aqueous phases of Bucida buceras and Phoradendron californicum (oak and mesquite); (2) Analysis of the hexane phase of B. buceras and P. californicum (mesquite) extracts revealed the presence of carotenes, triterpenes/steroids, and lactonic groups; (3) Analysis of the ethanol and aqueous extraction phases for both plants revealed the presence of a diverse range of compounds, including tripterpenes/steroids, lactonics groups, saponins, phenols/tannins, amines and/or amino acids, and flavonoids/anthocyanins; and (4) The highest total phenolic and flavonoid content were observed in P. californicum (oak): 523.886 ± 51.457 µg GAE/mg extract and 409.651 ± 23.091 µg/mg of extract for methanol and aqueous fractions, respectively. The highest flavonoid content was 237.273 ± 21.250 µg PNE/mg extract in the acetone extract of Bucida buceras stems; while the flavonol content (260.685 ± 23.031 µg CE/mg extract) was higher in the ethanol extract of P. californicum (oak). The acetone extract of B. buceras trunk extract showed the highest levels of DPPH radical-scavenging activity (IC50 = 4.136 ± 0.446 µg/mL) and reducing power (4928.392 ± 281.427 µM AAE/mg extract). The highest superoxide radical scavenging activity (IC50) was 55.249 ± 9.829 µg/mL, observed in acetone extracts of B. buceras leaves. CONCLUSIONS: The results of the present investigation demonstrated the effects of extraction solvent on phenolic and flavonoid content yield-and antioxidant activities by Bucida buceras and Phoradendron californicum. The present investigation further revealed that Bucida buceras exhibited optimal antioxidant capacity when acetone was used as extraction solvent; and the highest yield of phenols and flavonoids were obtained from the P. californicum oak, using methanol and aqueous solvents, respectively.

Retino-protective effect of Bucida buceras against oxidative stress induced by H2O2 in human retinal pigment epithelial cells line.

BACKGROUND: Reactive Oxygen Species (ROS) impair the physiological functions of Retinal Pigment Epithelial (RPE) cells, which are known as one major cause of age-related macular degeneration and retinopathy diseases. The purpose of this study is to explore the cytoprotective effects of the antioxidant Bucida buceras extract in co-treatment with hydrogen peroxide (H2O2) delivery as a single addition or with continuous generation using glucose oxidase (GOx) in ARPE-19 cell cultures. The mechanism of Bucida buceras extract is believed to be associated with their antioxidant capacity to protect cells against oxidative stress. METHODS: A comparative oxidative stress H2O2-induced was performed by addition and enzymatic generation using glucose oxidase on human retinal pigment epithelial cells line. H2O2-induced injury was measured by toxic effects (cell death and apoptotic pathway) and intracellular redox status: glutathione (GSH), antioxidant enzymes (catalase and glutathione peroxidase) and reducing power (FRAP). The retino-protective effect of co-treatment with Bucida buceras extract on H2O2-induced human RPE cell injury was investigated by cell death (MTT assay) and oxidative stress biomarkers (H2O2, GSH, CAT, GPx and FRAP). RESULTS: Bucida buceras L. extract is believed to be associated with the ability to prevent cellular oxidative stress. When added as a pulse, H2O2 is rapidly depleted and the cytotoxicity analyses show that cells can tolerate short exposure to high peroxide doses delivered as a pulse but are susceptible to lower chronic doses. Co-treatment with Bucida buceras was able to protect the cells against H2O2-induced injury. In addition to preventing cell death treatment with antioxidant plant could also reverse the significant decrease in GSH level, catalase activity and reducing power caused by H2O2. CONCLUSION: These findings suggest that Bucida buceras could protect RPE against ocular pathogenesis associated with oxidative stress induced by H2O2-delivered by addition and enzymatic generation.

Hábitos alimentarios en el consumo de vegetales en un grupo poblacional / Food habits in the consumption of vegetables in a population group

El presente trabajo está dirigido a estudiar los hábitos alimentarios en el consumo de vegetales en un grupo poblacional, su relación con el hábito de fumar y la posibilidad de sufrir riesgo de estrés oxidativo. Se realizó un trabajo descriptivo, y se aplicó una encuesta sobre hábitos alimentarios y estilo de vida a 84 pacientes con edades comprendidas entre los 15 y los 73 años, pertenecientes al Consultorio Médico no. 23, del área de salud de Calabazar (58 del sexo femenino y 26 del masculino), y los resultados se procesaron a través del programa estadístico para Windows. Los vegetales de mayor preferencia para la población fueron: el tomate, la lechuga, la col y el pepino; y los de menor aceptación, la espinaca, la berenjena y el rábano. Se apreció que para todos los grupos de edades, específicamente para la población fumadora, las frecuencias de consumo son de 1 a 2 veces a la semana, por lo que no se cumplen las recomendaciones de agencias internacionales en este sentido. Las bajas frecuencias de consumo pueden estar asociadas con las enfermedades cardiovasculares, que resultaron ser las que más afectaron a nuestra población, por lo que se evidencia la posibilidad de que esta se encuentre bajo riesgo de estrés oxidativo(AU)

Hábitos alimentarios en el consumo de vegetales en un grupo poblacional / Food habits in the consumption of vegetables in a population group

El presente trabajo está dirigido a estudiar los hábitos alimentarios en el consumo de vegetales en un grupo poblacional, su relación con el hábito de fumar y la posibilidad de sufrir riesgo de estrés oxidativo. Se realizó un trabajo descriptivo, y se aplicó una encuesta sobre hábitos alimentarios y estilo de vida a 84 pacientes con edades comprendidas entre los 15 y los 73 años, pertenecientes al Consultorio Médico no. 23, del área de salud de Calabazar (58 del sexo femenino y 26 del masculino), y los resultados se procesaron a través del programa estadístico para Windows. Los vegetales de mayor preferencia para la población fueron: el tomate, la lechuga, la col y el pepino; y los de menor aceptación, la espinaca, la berenjena y el rábano. Se apreció que para todos los grupos de edades, específicamente para la población fumadora, las frecuencias de consumo son de 1 a 2 veces a la semana, por lo que no se cumplen las recomendaciones de agencias internacionales en este sentido. Las bajas frecuencias de consumo pueden estar asociadas con las enfermedades cardiovasculares, que resultaron ser las que más afectaron a nuestra población, por lo que se evidencia la posibilidad de que esta se encuentre bajo riesgo de estrés oxidativo.