On pourrait dire la même chose de l'Haritaki qui à lui seul représente une bonne partie de la formule et qui à lui seul a des effets considérables, c'est une plante ayruvédique majeure, utilisée un peu partout et qui a en plus la particularité de casser les biofilms. Plante du célèbre mélange intestinal Triphala. Ce produit est vraiment énorme de par sa composition, moi je m'étais aussi posé la question de savoir si je ne serai pas mieux à me faire moi même mon mélange, car les Vitamines B en quantité stratosphériques ne me rassuraient pas trop, je n'ai pas de problème de méthylation mais ça m'inquiète un peu...
Néanmoins, je sens que ce produit commence à être efficace, ça n'a pas été immédiat, mais progressivement je sens que ça travaille et que ça actionne des trucs. Je suis passé à la dose maximale 3 gellules, et je pense prendre des grosses doses ponctuellement pour induire un état de stress.
Il y a aussi de la nattokinase pour les biofilms, bref c'est un produit puissant.
titox a écrit:L'apport en antioxydants semble indispensable d'après le Dr Shade.Jibouille l'a rappelé sur la première page du topic.
En fait, toutes ces composés que l'on qualifie d'antioxydants sont en fait des oxydants au niveau cellulaire, qui viennent créer une cascade de réactions radicalaires, qui viennent stresser la cellule qui par réaction d'adaptation va adopter de nouvelles mesures anti-oxydantes et refaire basculer la vapeur (nrf2 protein). Le terme d'antioxydants qu'on utilise à tour de bras est donc un peu galvaudé. C'est très intéréssant, un peu complexe mais c'est un éclairage nouveau sur nos capacités anti-oxydantes et sur les antioxydants qu'on nous vend à tous les coins de rue.
https://www.caymanchem.com/app/template ... ticle/2168Nrf2 Antioxidant Stress Response: Managing its 'Dark Side'
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Olivia L. May, Ph.D.
There is a longstanding principle that antioxidants reduce risk of certain pathological conditions, such as cancer, diabetes, atherosclerosis, aging, and neurodegeneration. Antioxidant supplements are popularly consumed and certain dietary choices are made with the belief that externally ramping up antioxidant capacity improves the ability to ward off potential oxidative damage caused by reactive oxygen species (ROS). Recent advances made in understanding redox homeostasis maintained via the Keap1/Nrf2 signaling pathway may challenge this concept of artificially supplying the body with antioxidants. The feedback nature of the redox system must be considered fully, as chronic ingestion of antioxidants may actually diminish the body’s endogenous, defensive antioxidant capability and could provide a favorable environment for pathological conditions to propagate.
Keap1-Nrf2 Stress Response Pathway
When confronted with oxidative stressors, cells must quickly augment their antioxidant capacity to counteract increased ROS production and maintain homeostasis. The nuclear factor erythroid 2-related factor (Nrf2) is a transcription factor that functions as the key controller of the redox homeostatic gene regulatory network (Figure 1). Under oxidative and electrophilic stresses, the Nrf2 signaling pathway is activated to enhance the expression of a multitude of antioxidant and phase II enzymes that restore redox homeostasis. Kelch-like ECH-associated protein 1 (Keap1), a cysteine-rich protein that is anchored to actin in the cytosol, interacts with Nrf2, acting as an adaptor protein for the Cul3-dependent E3 (Cul3) ubiquitin ligase complex. Under normal conditions, Keap1 promotes ubiquitination and eventual degradation of Nrf2. This is a relatively rapid event, with Nrf2 exhibiting a short half-life of 13-21 minutes.1,2 Such rapid turnover maintains a low, basal level of Nrf2. The many cysteine residues in the amino acid sequence of Keap1 enable it to act as a sensor, detecting changes in cellular redox state. An increase in intracellular ROS or electrophiles yields an increase in the oxidation or conjugation of key Keap1 cysteines (C151, C273, C288, C613), which weakens its activity as an E3 ligase adaptor. Thus, during cellular stress, Keap1 is less effective at promoting Nrf2 degradation. As Nrf2 is stabilized (half-life is extended 100-200 minutes under high levels of oxidative stress)1,3 it enters the nucleus where it activates transcription of a host of cytoprotective genes, including the components of an antioxidant system that can balance high ROS levels.4
The nuclear export signal (NES), located in the transactivation domain of Nrf2 and which functions to shuffle Nrf2 out of the nucleus, is also redox sensitive. It contains a cysteine residue at position 183 that is modified under oxidative stress, which weakens the NES activity, leading to increased retention of Nrf2 in the nucleus.5 Accumulating Nrf2 in the nucleus associates with its transcriptional partner, Maf proteins, forming a heterodimer that binds to antioxidant response elements (ARE) on the DNA of target cytoprotective genes.
The Keap1-Nrf2 pathway regulates over 600 cytoprotective genes (see table for a brief list of examples) that confer upon the cell multiple layers of protection. In short this includes: antioxidant enzymes, conjugating enzymes, proteins that enhance the export of xenobiotics and their metabolites, enzymes that participate in the synthesis and regeneration of glutathione, enzymes that promote the synthesis of reducing equivalents, enzymes that inhibit inflammation, proteins that protect against heavy metal toxicity, proteins that function to repair and remove damaged proteins, and proteins that regulate the expression of other transcription factors and growth factors.
Redox Regulation in Cancer
High levels of ROS are harmful to normal cells and lead to tumor development by inducing DNA damage, increasing cancer-causing mutations, and activating inflammatory pathways. Because of these cancer promoting activities of ROS, antioxidants are thought to reduce cancer risk. Malignant transformation further increases cellular stress, leading to even more enhanced levels of ROS. Because the Keap1-Nrf2 system protects cells from the harmful effects of oxidants and electrophiles by regulating the expression of cytoprotective proteins, it has been considered useful to exploit this pathway as a cancer therapeutic. Nrf2 has been demonstrated to be protective against tumor formation in mouse models of stomach, bladder, and skin cancer6-10 and has been shown to be down-regulated in skin tumors in mice and in prostate cancer in humans.10,11 The mechanism through which Nrf2 is protective against tumorigenesis has been attributed to its ability to reduce the amount of ROS and DNA damage in cells. Conversely, it has also been suggested that constitutive Nrf2 activity can be beneficial for tumor survival. Recent work indicates Nrf2 overexpression in head and neck squamous cell carcinomas12 and there is a correlation of aggressive, chemoresistant endometrial tumors with high Nrf2 expression.13
This suggests that the beneficial activity of Nrf2, which protects normal cells from basal levels of ROS, can be subverted by cancer cells to protect themselves from the cellular stress-inducing conditions of the tumor microenvironment. In order to survive, even cancer cells must adapt to this toxic environment, moderating ROS levels below a certain threshold and within a range that permits their growth and survival. In such a situation, an active Nrf2 pathway could maintain a favorable redox balance and upregulate ARE-dependent genes to generate antioxidants in cancer cells to promote their survival. This tumor-protective role of Nrf2 has been referred to as its “dark side”.14
In mice, several oncogenes have been shown to actively induce transcription of Nrf2, promoting a ROS detoxification program that creates a permissive environment for tumor formation. DeNicola et al., 2011 have shown that a stress-response program is triggered early in tumor development and that the K-Ras, B-Raf, and Myc oncogenes can increase Nrf2 transcription, creating a reducing environment that enables tumor formation.15 Furthermore they demonstrated that genetic deletion of Nrf2 in early stage cancer cells results in high ROS levels and senescence-like growth arrest. However, treatment of these Nrf2-lacking cells with antioxidants resumed tumor proliferation. Thus it seems the Nrf2 antioxidant/detoxification program can potentially be hijacked to the advantage of cancer cell survival.
Feedback, Antioxidants, and Potential Therapy
While supplementation with antioxidants is not altogether a bad idea, it’s interesting to consider the broader significance of “tweaking” the stress response pathway in the context of cancer. Increased antioxidant levels lower ROS and free radical levels in cells, eventually creating a reducing intracellular environment, keeping Keap 1 in a reduced configuration. With less oxidized Keap1 present, ubiquitination and degradation of Nrf2 increases, leading to a lower basal steady-state Nrf2 level and, subsequently, lower basal levels of endogenous antioxidant and phase II enzymes. If cancer cells have adapted this ROS stress-response pathway to their advantage, then disrupting redox and ROS homeostasis is a promising strategy to treat cancer with careful, targeted selection. Raj et al., 2011 have identified the small molecule, piperlongumine, a natural product isolated from the Long pepper (Piper longum), a plant indigenous to southern India and southeast Asia, which selectively blocks the Nrf2 program in cancer cells, sparing normal cells from toxicity.16 These investigators hypothesize that compared to basal conditions for normal cells, malignantly transformed cells have a higher capacity to generate ROS, creating a greater dependence on the Keap1-Nrf2 antioxidant pathway to maintain a permissive growth environment. This dependency of cancer cells on ROS homeostasis seems to underlie the selectivity of piperlongumine. As such, with the rapid progress made in understanding the Keap1-Nrf2 antioxidant pathway, targeted approaches such as this provide novel strategies for cancer treatment. Piperlongumine is available from Cayman to aid in this research.
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Quicksilver Scientific Clear Way Cofactors Proprietary blend of phytoextracted polyphenolics, sodium buffered R-Alpha Lipoic Acid, targeted vitamins, selenium, standardized kelp extract and Lumbrokinase designed to maximize metal detoxification pathways.
EpicatechinThe Clear Way Cleanse Cofactors is a is a proprietary blend of phytoextracted polyphenolics, sodium buffered R-Alpha Lipoic Acid (Na-RALA), targeted vitamins (B1, B5, B6), selenium, standardized kelp extract and high-potency Nattokinase designed to maximize metal detoxification pathways. The polyphenolics and Na-RALA have demonstrated the ability to upregulate the detoxification systems of the body, especially the glutathione system, through stimulation of the Nrf2/antioxidant response element pathway. Furthermore many of the highest-content ingredients (Haritaki, Pine Bark Extract, R-lipoic acid, and Gotu Kola) have been shown to have radioprotective effects.
The glutathione system contains multiple molecules and enzymes that function to quench oxidative stress, repair damaged proteins and detoxify/remove endogenous (internally created) and exogenous (externally acquired) toxins. The only way to truly optimize the function of the glutathione system is to stimulate the production of the system componnets from within the cells. Polyphenolic antixoidants such as Epicatechin (found in pine bark and green tea extracts), have demonstrated tremendous efficacy in doing this by "turning on" a cellular master switch called the Nrf2 protein. This protein turns on the cellular production of several antioxidants and detoxification molecules. Polyphenols have the added benefits of high anti-inflammatory properties, anticarcinogenic activity and passage through the blood-brain barrier.
Clear Way Cofactors features highly concentrated extracts of:
Haritaki is the polyphenolic-rich fruit of the Terminalia Chebula tree. Haritaki is widely used in Ayurvedic medicine where it is held sacred to Shiva. It is pictured as the quintessential healing plant by the Medicine Buddha in Tibet, where Haritaki is called "The King of Herbs." Haritaki was recently shown to have extraordinary effects on the antioxidant and detoxification systems.
Pine Bark Extract is the richest source of epicatechins (the building block of Of'C's - oligomeric proanthocyanidins) and powerful anti-inflammatory, cardioprotective glutathione bullders. Also used for GSH system support and protection and repair from solar radiation.
Pomegranate Extract, a rich source of ellagic acid, which has shown impressive activity on glutathione synthesis and glutathione S-transferase octivity.
Gotu Kola Extract is added for nerve protection and has been shown to protect against gamma-radiation induced damage to both DNA and membranes.
Dandelion Extract is added for liver protection and to stimulate adequate bile and urinary flow.Kelp Extract is added for iodine/other trace minerals and polyphenolic content.
R-Lipoic Acid - this potent antioxidant confers both water-based (cytoplasm) and lipid-based (cell membrane) protection that is essential to full protection from radiation damage. Additionally it has tremendous impact on mitochondrial integrity.
Nattokinase and Biofilms:
In addition to the comprehensive cellular protection delivered by the antioxidant components of the formula, high-potency Lumbrokinase is included to help break down biofilms in the gut. These biofilms prevent detoxification and absorption of nutrients as well as lock in dysbiotic intestinal flora. Additionally, Lumbrokinase has well documented circulation benefits in patients with ischemic conditions. It has the unique quality of possessing strong anti-coagulative properties without the risk of uncontrolled bleeding. The fibrinolytic activity of Nattokinase (the strongest of all fibrolytic enzymes) will provide a significant edge in the fight against toxin accumulation and subsequent bodily degeneration. For safety, DO NOT give this supplement to patients with hemolytic conditions.
ClearWay Cofactors is a proprietary mixture of high-potency polyphenolic antioxidant phytonutrients, R-Lipoid Acid, Kelp, and B Vitamins designed to support the body’s natural antioxidant and detoxification systems. Dr. Chris Shade specifically created this formula to help reduce any side effects from detoxification. This product can also be used for immune support.
Haritaki is the powerhouse polyphenolic-rich fruit of the Terminalia Chebufa tree. Haritaki is widely used in Ayurvedic medicine where it is held sacred to Shiva. It is pictured as the quintessential healing plant in depictions of the Medicine Buddha in Tibet, where Haritaki is called 'The King of Herbs." Haritaki has been shown to have extraordinary effects on the antioxidant5 and detoxification systems", especially glutathione pathways, through an Nrf2-like pathway and to confer protection against radiation-induced DNA strand breaks.
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