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A Case For High ROS, Antioxidants Are Useless And Potentially Harmful!

Inaut

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Turning P53 on in cancer cells
Posted on 26. July 2010 by Vince Giuliano
The P53 protein provides a first line of defense against cancers, causing cancer cells to commit apoptosis. “p53 (also known as protein 53 or tumor protein 53), is a tumor suppressor protein that in humans is encoded by the TP53 gene.[1][2][3] p53 is important in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer. As such, p53 has been described as “the guardian of the genome“, the “guardian angel gene”, and the “master watchman”, referring to its role in conserving stability by preventing genome mutation[4](ref). ” However, the guardian angel can’t do its job if is mutated in the cancer or if the cancer has evolved a method to turn it off – which is the case in about 50% of cancer types, those having “wild type” P-53. Therefore, in recent years there has been considerable research on how to get the P53 going again in those cancers. This blog entry reviews that and other research relevant to P53 and where it appears to be heading as a promising new anti-cancer approach.

The introduction to a 2010 review article Targeting p53 for Novel Anticancer Therapy sets the stage. “Carcinogenesis is a multistage process, involving oncogene activation and tumor suppressor gene inactivation as well as complex interactions between tumor and host tissues, leading ultimately to an aggressive metastatic phenotype. Among many genetic lesions, mutational inactivation of p53 tumor suppressor, the “guardian of the genome,” is the most frequent event found in 50% of human cancers. p53 plays a critical role in tumor suppression mainly by inducing growth arrest, apoptosis, and senescence, as well as by blocking angiogenesis. In addition, p53 generally confers the cancer cell sensitivity to chemoradiation. Thus, p53 becomes the most appealing target for mechanism-driven anticancer drug discovery. This review will focus on the approaches currently undertaken to target p53 and its regulators with an overall goal either to activate p53 in cancer cells for killing or to inactivate p53 temporarily in normal cells for chemoradiation protection.”

The amazing P53 and cell metabolism

P53 plays other roles besides regulating cell cycle arrest and apoptosis in the presence of strong stress. The 2009 publication Homeostatic functions of the p53 tumor suppressor: regulation of energy metabolism and antioxidant defense describes an additional role. “The p53 tumor suppressor plays pivotal role in the organism by supervising strict compliance of individual cells to needs of the whole organisms. It has been widely accepted that p53 acts in response to stresses and abnormalities in cell physiology by mobilizing the repair processes or by removing the diseased cells through initiating the cell death programs. Recent studies, however, indicate that even under normal physiological conditions certain activities of p53 participate in homeostatic regulation of metabolic processes and that these activities are important for prevention of cancer. These novel functions of p53 help to align metabolic processes with the proliferation and energy status, to maintain optimal mode of glucose metabolism and to boost the energy efficient mitochondrial respiration in response to ATP deficiency. Additional activities of p53 in non-stressed cells tune up the antioxidant defense mechanisms reducing the probability of mutations caused by DNA oxidation under conditions of daily stresses. The deficiency in the p53-mediated regulation of glycolysis and mitochondrial respiration greatly accounts for the deficient respiration of the predominance of aerobic glycolysis in cancer cells (the Warburg effect), while the deficiency in the p53-modulated antioxidant defense mechanisms contributes to mutagenesis and additionally boosts the carcinogenesis process.” The suggestion is therefore that maintaining strong P53 activity is an important aspect of maintaining health.

The role of P53 in cell respiration was described in the 2006 publication p53 aerobics: the major tumor suppressor fuels your workout. “In addition to its role as the central regulator of the cellular stress response, p53 can regulate aerobic respiration via the novel transcriptional target SCO2, a critical regulator of the cytochrome c oxidase complex (Matoba et al., 2006). Loss of p53 results in decreased oxygen consumption and aerobic respiration and promotes a switch to glycolysis, thereby reducing endurance during physical exercise.”

The glycolysis provides an ideal environment for carcinogenesis. As stated in the 2006 paper p53 regulates mitochondrial respiration, “The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.”

Recapitulating in simple terms, deficiency or mutation of P53 switches the respiratory environment in cells to glycolysis favoring cancer development. This is in addition to inactivated or mutated P53 being unable to kill off cancer cells by apoptosis. The research literature of cancer metabolism and its relationship to mitochondrial signaling is very rich and interesting and I was tempted to cite more publications in that area. However, I choose to focus on P53 here.

Mutations of P53 in cancers

The 2007 paper Restoration of wild-type p53 function in human tumors: strategies for efficient cancer therapy points out “The p53 tumor suppressor gene is mutated in around 50% of all human tumors. Most mutations inactivate p53’s specific DNA binding, resulting in failure to activate transcription of p53 target genes. As a consequence, mutant p53 is unable to trigger a p53-dependent biological response, that is cell cycle arrest and apoptosis. Many tumors express high levels of nonfunctional mutant p53. Several strategies for restoration of wild-type p53 function in tumors have been designed. Wild-type p53 reconstitution by adenovirus-mediated gene transfer has shown antitumor efficacy in clinical trials. Screening of chemical libraries has allowed identification of small molecules that reactivate mutant p53 and trigger mutant p53-dependent apoptosis. These novel strategies raise hopes for more efficient cancer therapy.” As will be explained, not only is there the issue of mutant P53 in some cancers, but there is also an issue of wild-type (normal) P53 in other cancers being inactivated by the cancer.

MDM2 and MDMX

Two key proteins are known to play roles in both normal and cancer P53 homeostasis MDM2 and MDMX. Regulation of these proteins may offer an important cancer therapy approach, not only in cells with mutated P53 but also in cancer cells with wild-type P53. The 2010 review paper The regulation of MDM2 by multisite phosphorylation–opportunities for molecular-based intervention to target tumours? explains: “The p53 tumour suppressor is a tightly controlled transcription factor that coordinates a broad programme of gene expression in response to various cellular stresses leading to the outcomes of growth arrest, senescence, or apoptosis. MDM2 is an E3 ubiquitin ligase that plays a key role in maintaining p53 at critical physiological levels by targeting it for proteasome-mediated degradation. Expression of the MDM2 gene is p53-dependent and thus p53 and MDM2 operate within a negative feedback loop in which p53 controls the levels of its own regulator. Induction and activation of p53 involves mainly the uncoupling of p53 from its negative regulators, principally MDM2 and MDMX, an MDM2-related and -interacting protein that inhibits p53 transactivation function. MDM2 is tightly regulated through various mechanisms including gene expression, protein turnover (mediated by auto-ubiquitylation), protein-protein interaction with key regulators, and post-translational modification, mainly, but not exclusively, by multisite phosphorylation.–. This analysis also provides an opportunity to consider the signalling pathways regulating MDM2 as potential targets for non-genotoxic therapies aimed at restoring p53 function in tumour cells.”


Many cancers have in the course of evolution developed a strategy for inactivating P53 using MDM2. Reactivating MDM2 has therefore been considered as an anti-cancer strategy. The 2008 publication Reactivation of p53 by a specific MDM2 antagonist (MI-43) leads to p21-mediated cell cycle arrest and selective cell death in colon cancer states “MDM2 oncoprotein binds directly to the p53 tumor suppressor and inhibits its function in cancers retaining wild-type p53. Blocking this interaction using small molecules is a promising approach to reactivate p53 function and is being pursued as a new anticancer strategy.– This study suggests that p53 activation by a potent and specific spiro-oxindole MDM2 antagonist may represent a promising therapeutic strategy for the treatment of colon cancer and should be further evaluated in vivo and in the clinic.”

A somewhat broader view of the same situation is offered in the previously-mentioned 2007 paper Restoration of wild-type p53 function in human cancer: relevance for tumor therapy. “BACKGROUND: In the majority of human cancers, the tumor suppressor activity of p53 is impaired because of mutational events or interactions with other proteins (i.e., MDM2). The loss of p53 function is responsible for increased aggressiveness of cancers, while tumor chemoresistance and radioresistance are dependent upon the expression of mutant p53 proteins. METHODS: Review of the literature indicates that p53 acts primarily as a transcription factor whose function is subject to a complex and diverse array of covalent post-translational modifications that markedly influence the expression of p53 target genes responsible for cellular responses such as growth arrest, senescence, or apoptosis. The ability of p53 to induce apoptosis in cancer cells is believed essential for cancer therapy. RESULTS: Numerous data indicate that p53 dependent apoptosis is a relevant factor in determining the efficacy of anticancer treatments. Thus, the development of new strategies for restoration of p53 function in human tumors is considered an important issue. Two main approaches for restoration of p53 function have been pursued that impact anticancer treatments: (a) de novo expression of wild-type p53 (wt-p53) through gene therapy and (b) identification of small molecules reactivating wt-p53 function. CONCLUSIONS: The extensive body of knowledge acquired has identified manipulations of p53 signaling as a relevant issue for successful therapies. In this context, the recognition of p53 status in cancer cells is significant and would help considerably in the selection of an appropriate therapeutic approach. p53 manipulations for cancer therapy have revealed the need for specificity of p53 activation and ability to spare body tissues. Furthermore, the promising results obtained by using molecules competent to reactivate wt-p53 functions in cancer cells provide the basis for the design of new molecules with lower side effects and higher anti-tumor efficiency. The reexpression and reactivation of p53 protein in human cancer cells would increase tumor susceptibility to radiation or chemotherapy enhancing the efficacy of standard therapeutic protocols.”

Numerous other publications have been concerned with reactivation of the P53 pathway in cancers including the 2005 publication Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma. “Mutation of p53 is a rare event in multiple myeloma, but it is unknown if p53 signaling is functional in myeloma cells, and if targeted nongenotoxic activation of the p53 pathway is sufficient to kill tumor cells. Here, we demonstrate that treatment of primary tumor samples with a small-molecule inhibitor of the p53-murine double minute 2 (MDM2) interaction increases the level of p53 and induces p53 targets and apoptotic cell death.”

The 2010 publication Controlling the Mdm2-Mdmx-p53 Circuit offers a note of caution “Two human family members, Mdm2 and Mdmx, are primarily responsible for inactivating p53 transcription and targeting p53 protein for ubiquitin-mediated degradation. — In tumors that harbor wild-type p53, reactivation of p53 by modulating both Mdm2 and Mdmx signaling is well suited as a therapeutic strategy. However, the rationale for development of kinase inhibitors that target the Mdm2-Mdmx-p53 axis must be carefully considered since modulation of certain kinase signaling pathways has the potential to destabilize and inactivate p53.” The interactions are quite complex.

Enter Nutlins

There is great interest in a new class of MDM2 inhibitors called Nutlins. “Nutlins are cisimidazoline analogs which inhibit the interaction between MDM2 and p53, and were discovered by screening a chemical library by Vassiliev et al. Nutlin-1, Nutlin-2 and Nutlin-3 were all identified in the same screen,[1] however Nutlin-3 is the compound most commonly used in anti-cancer studies.[2] Inhibiting the interaction between MDM2 and p53 stabilizes p53 and is thought to selectively kill cancer cells. These compounds are therefore thought to work best on tumors that contain normal or wild type p53(ref).”

The 2008 publication The MDM2 inhibitor Nutlins as an innovative therapeutic tool for the treatment of haematological malignancies tells the story. “At variance to solid tumors, which show percentage of p53 deletions and/or mutations close to 50%, more than 80% of haematological malignancies express wild-type p53 at diagnosis. Therefore, activation of the p53 pathway by antagonizing its negative regulator murine double minute 2 (MDM2) might offer a new therapeutic strategy for the great majority of haematological malignancies. Recently, potent and selective small-molecule MDM2 inhibitors, the Nutlins, have been identified. Studies with these compounds have strengthened the concept that selective, non-genotoxic p53 activation might represent an alternative to the current cytotoxic chemotherapy. Interestingly, Nutlins not only are able to induce apoptotic cell death when added to primary leukemic cell cultures, but also show a synergistic effect when used in combination with the chemotherapeutic drugs commonly used for the treatment of haematological malignancies. Of interest, Nutlins also display non-cell autonomous biological activities, such as inhibition of vascular endothelial growth factor, stromal derived factor-1/CXCL12 and osteprotegerin expression and/or release by primary fibroblasts and endothelial cells. Moreover, Nutlins have a direct anti-angiogenic and anti-osteoclastic activity. Thus, Nutlins might have therapeutic effects by two distinct mechanisms: a direct cytotoxic effect on leukemic cells and an indirect non-cell autonomous effect on tumor stromal and vascular cells, and this latter effect might be therapeutically relevant also for treatment of haematological malignancies carrying p53 mutations.”

A number of other 2010 papers are also concerned with the use of Nutlins as P-53 activating cancer therapies, including Nutlin-3 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through up-regulation of death receptor 5 (DR5) in human sarcoma HOS cells and human colon cancer HCT116 cells and Pharmacological activation of the p53 pathway in haematological malignancies. “p53 gene mutations are rarely detected at diagnosis in common haematological cancers such as multiple myeloma (MM), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and Hodgkin’s disease (HD), although their prevalence may increase with progression to more aggressive or advanced stages. Therapeutic induction of p53 might therefore be particularly suitable for the treatment of haematological malignancies. Some of the anti-tumour activity of current chemotherapeutics has been derived from activation of p53. However, until recently it was unknown whether p53 signalling is functional in certain haematological cancers including MM and if p53 activity is sufficient to trigger an apoptotic response. With the recent discovery of nutlins, which represent the first highly selective small molecule inhibitors of the p53-MDM2 interaction, pharmacological tools are now available to induce p53 irrespective of upstream signalling defects, and to functionally analyse the downstream p53 pathway in primary leukaemia and lymphoma cells. Combination therapy is emerging as a key factor, and development of non-genotoxic combinations seems very promising for tackling the problems of toxicity and resistance. This review will highlight recent findings in the research into molecules capable of modulating p53 protein activities and mechanisms that activate the p53 pathway, restoring response to therapy in haematological malignancies.”

Nutlins and Vitamin D.

What about supplements in the anti-aging firewalls regimen and activation of P-53 and the other pro-apoptotic channels in cancers? There is much to say about that subject and it has to be the focus of a separate blog entry. However, I stumbled across one paper relevant to the present discussion 1,25-dihydroxyvitamin D3 enhances the apoptotic activity of MDM2 antagonist nutlin-3a in acute myeloid leukemia cells expressing wild-type p53. in leukemia cells expressing wild-type P-53 “Combination of nutlin-3a with 1,25D accelerated programmed cell death, likely because of enhanced nutlin-induced upregulation of the proapoptotic PIG-6 protein and downregulation of antiapoptotic BCL-2, MDMX, human kinase suppressor of Ras 2, and phosphorylated extracellular signal-regulated kinase 2.”

The scope of the relevant research literature is overwhelming. A search in Pubmed on Nutlin produces 220 references! What I have included here should be enough to convey the general picture, however. A search in clinicaltrials.gov on “nutlin and cancer” failed to reveal any trials, suggesting that nutlin-based cancer therapies are not yet in the clinical trials phase. I expect such clinical trials will be launched soon.

The bottom line

Turning on a strong P53 defense is emerging as an important anticancer strategy in the advanced research stage. A central approach for cancers with wild-type P53 is to inhibit the P53-controlling proteins MDM2 and MDMX using a new class of substances called Nutlins. This approach is not yet in clinical trials but probably soon will be. A separate blog entry will deal with the anti-cancer capabilities of supplements in the anti-aging firewalls regimen.

Turning P53 on in cancer cells - AGINGSCIENCES™ - Anti-Aging Firewalls™
 

Inaut

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P53 Supporters:
• Cruciferous vegetables, especially watercress
IP6
Resveratrol
• Herbs such as sage, rosemary, ginger, curcumin, and ashwaganda
• EFA’s from omega 3 fatty acids (please use caution with fish oil supplements as they can be toxic). For a plant based formula, you could take BodyBio Balance Oil.
• Licorice
• Mistletoe
Vitamin D
Selenium
• Vitamin C
Zinc
Black Seed
Clinoptilolite (a special form of Zeolite)
On the other hand, processed foods, refined flours, and sugars will impair P53. Smokey flavoring and smoked foods can also damage DNA. Chemicals such as benzene and perchloroethylene, two volatile organic compounds, negatively affect p53, possibly causing them to stimulate rather than suppress cell proliferation.


Somethings anti-peat on that list and should be avoided but a couple ie. zinc,vitamin d, selenium, vitaminc c, ginger and turmeric are welcomed. I love ginger :)
 

Obi-wan

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Obi-wan

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P53 Supporters:
• Cruciferous vegetables, especially watercress
IP6
Resveratrol
• Herbs such as sage, rosemary, ginger, curcumin, and ashwaganda
• EFA’s from omega 3 fatty acids (please use caution with fish oil supplements as they can be toxic). For a plant based formula, you could take BodyBio Balance Oil.
• Licorice
• Mistletoe
Vitamin D
Selenium
• Vitamin C
Zinc
Black Seed
Clinoptilolite (a special form of Zeolite)
On the other hand, processed foods, refined flours, and sugars will impair P53. Smokey flavoring and smoked foods can also damage DNA. Chemicals such as benzene and perchloroethylene, two volatile organic compounds, negatively affect p53, possibly causing them to stimulate rather than suppress cell proliferati


Somethings anti-peat on that list and should be avoided but a couple ie. zinc,vitamin d, selenium, vitaminc c, ginger and turmeric are welcomed. I love ginger :)

There is a lot of antioxidants on this list
 

TreasureVibe

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why dont we like ozone as an effective oxidant again? I had my mom drink 2 cups of ozonated water every morning after chemo for her breast cancer ---in addition to pau d'arco tea (as she would not take supplements --discouraged by the oncologist..) Not sure if it helped but my hopes (prayer) was that it made the chemo slightly more effective while stimulating her immune system to step up and deal with some of the toxic chemicals.....It took her a while to lose her hair but it has grown back and she looks great. Hoping she can live cancer/care free from here on out :) Easier said then done for somebody with the monkey on the back but it's about mindstate, intention and prayer (also a form of intention)... JMO
I would like to mention that I've found out ozone might be very dangerous! Drinking hydrogen peroxide can cause gas embolism due to bubbles developing in your stomach and those being absorbed. Hydrogen peroxide is a product from ozone.

According to a case study, cleaning a wound with hydrogen peroxide caused gas embolism. Also other studies show hydrogen peroxide can cause deadly levels of oxygen in the blood which can cause deadly heart arrythmias and is cardiotoxic. Hydrogen peroxide by itself was also shown in a study to be damaging to the heart.

The studies show these adverse effects from hydrogen peroxide and not directly from ozone, so it needs further study as to how the relation between and ozone and hydrogen peroxide exactly works.

Here's an article on ozone being bad too:
https://www.webmd.com/heart/news/20120626/ozone-hurts-heart-doesnt-take-a-lot

For cancer, modified citrus pectin is high on my list for what I've seen what's available thus far. Inhibiting the galectin-3 molecule simply stops cancer in its tracks, science suggests. The chelation of cancer causing and cancer growth promoting heavy metals that comes with it is a great bonus too.

The xanthones from mangosteen rind (juice) are also interesting for cancer.
 

mimmo123

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Matt cook talked about healing someone who had pancreatic cancer that spread to the bone on an interview I was listening too

He is a regenerative medicine guy.
Meet Dr. Matthew Cook - BioReset Medical

Also this DC device with silver Ions worked on melanoma, tongue cancers,tuberculosis etc
you can contact them and give it a shot.

Silver is extremely oxidative

https://siselectromed.com/wp-content/uploads/2018/10/SaoPauloV10.1.pdf
https://electromedicine.org.au/wp-content/uploads/2019/03/MelanomaReversal.pdf
 

Inaut

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You got me doing more research Obi :)

Have you tried making some liposomal pau d’arco tea? Could make a difference in terms of getting the naptho/anthraquinones into the cell?

Halfway through the video, the speaker mentioned effectiveness of peptides increasing when incorporating lipids into formulations. It’s way out of my league but maybe others can digest it better
 

Obi-wan

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You got me doing more research Obi :)

Have you tried making some liposomal pau d’arco tea? Could make a difference in terms of getting the naptho/anthraquinones into the cell?

Halfway through the video, the speaker mentioned effectiveness of peptides increasing when incorporating lipids into formulations. It’s way out of my league but maybe others can digest it better


Maybe mixing milk with the pau d'arco tea
 

Inaut

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Maybe mixing milk with the pau d'arco tea

I think i read once that milk should not be taken with pau d'arco....something to do with calcium...can't remember the study though....I've been mixing it with mct or coconut oil in a blender. it's kind of tasty in a weird way. pretty sure it makes it further along the digestive tract too.
 

Obi-wan

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I think i read once that milk should not be taken with pau d'arco....something to do with calcium...can't remember the study though....I've been mixing it with mct or coconut oil in a blender. it's kind of tasty in a weird way. pretty sure it makes it further along the digestive tract too.

coconut oil should just melt in the hot tea
 

Obi-wan

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I would like to mention that I've found out ozone might be very dangerous! Drinking hydrogen peroxide can cause gas embolism due to bubbles developing in your stomach and those being absorbed. Hydrogen peroxide is a product from ozone.

According to a case study, cleaning a wound with hydrogen peroxide caused gas embolism. Also other studies show hydrogen peroxide can cause deadly levels of oxygen in the blood which can cause deadly heart arrythmias and is cardiotoxic. Hydrogen peroxide by itself was also shown in a study to be damaging to the heart.

The studies show these adverse effects from hydrogen peroxide and not directly from ozone, so it needs further study as to how the relation between and ozone and hydrogen peroxide exactly works.

Here's an article on ozone being bad too:
https://www.webmd.com/heart/news/20120626/ozone-hurts-heart-doesnt-take-a-lot

For cancer, modified citrus pectin is high on my list for what I've seen what's available thus far. Inhibiting the galectin-3 molecule simply stops cancer in its tracks, science suggests. The chelation of cancer causing and cancer growth promoting heavy metals that comes with it is a great bonus too.

The xanthones from mangosteen rind (juice) are also interesting for cancer.

Hydrogen Peroxide makes a great teeth whitener...
 

Obi-wan

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coconut oil should just melt in the hot tea

Tried the coconut oil in the Pau d' Arco tea. Nice energy result...will continue
 

Douglas Ek

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Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)

Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)

Increasing evidence indicates that reactive oxygen species (ROS), consisting of superoxide, hydrogen peroxide, and multiple others, do not only cause oxidative stress, but rather may function as signaling molecules that promote health by preventing or delaying a number of chronic diseases, and ultimately extend lifespan. While high levels of ROS are generally accepted to cause cellular damage and to promote aging, low levels of these may rather improve systemic defense mechanisms by inducing an adaptive response. This concept has been named mitochondrial hormesis or mitohormesis. We here evaluate and summarize more than 500 publications from current literature regarding such ROS-mediated low-dose signaling events, including calorie restriction, hypoxia, temperature stress, and physical activity, as well as signaling events downstream of insulin/IGF-1 receptors, AMP-dependent kinase (AMPK), target-of-rapamycin (TOR), and lastly sirtuins to culminate in control of proteostasis, unfolded protein response (UPR), stem cell maintenance and stress resistance. Additionally, consequences of interfering with such ROS signals by pharmacological or natural compounds are being discussed, concluding that particularly antioxidants are useless or even harmful.

Physical inactivity promotes the onset of a variety of diseases like obesity, cardiovascular disease, DM type 2, and cancer. Consistently, regular physical activity unquestionably exerts beneficial or preventive effects on the above mentioned diseases, and additionally delays depressive symptoms, neurodegeneration (including Alzheimer’s disease), and general aging (Warburton et al. 2006, James et al. 1984, Hu et al. 2001, Brown et al. 2012, Lanza et al. 2008, Manini et al. 2006, Powers et al. 2011). Exercise is not only linked to enhanced mitochondrial biogenesis and oxidative metabolism, but also to increased generation of mtROS (Powers and Jackson 2008, Chevion et al. 2003, Davies et al. 1982, Alessio and Goldfarb 1988, Alessio et al. 1988). Thus, and because of its obvious beneficial effects in regards to health and aging, make it a paradigm of adaptive response processes and finally mitohormesis (Radak et al. 2008, Radak et al. 2005, Ji et al. 2006, Watson 2013). However, similar to physical inactivity, overtraining or excessive exercise represents the other end of the hormesis curve as the adaption process is inhibited, leading to incomplete recovery (Chevion et al. 2003) and resulting in maladaptation and possibly increased risk of diseases (Alessio et al. 1988).

To our knowledge, the first direct evidence that increased ROS production following exercise may act as stimulus to activate mitochondria biogenesis and mediates potential health-beneficial effects dates back to 1982 (Davies et al. 1982). An indirect clue was already given in 1971 with an antioxidant, namely vitamin E, causing unfavorable effects on the endurance performance of swimmers (Sharman et al. 1971). Since then, a bulk of studies (in most cases inadvertently) proved the hypothesis that ROS are required for the health-promoting effects of physical activity, causing an increase in antioxidant defense mechanisms and with this, prolong health span and mean lifespan (Crawford and Davies 1994, Davies 1986, Kim et al. 1996, Marzatico et al. 1997, Balakrishnan and Anuradha 1998, Ji et al. 2006, Powers and Lennon 1999, Niess et al. 1999, Hollander et al. 2001, Higuchi et al. 1985, Gomez-Cabrera et al. 2008b, Quintanilha 1984, Vincent et al. 1999, Boveris and Navarro 2008).

One of the main changes due to regular physical activity is the increase in mitochondria energy metabolism. Exercise activates PGC-1α, which is capable of controlling mitochondrial gene expression via NRF1 and the mitochondrial transcription factor A (TFAM). This mediates enhanced replication of mitochondrial DNA, leading to increased mitochondrial biogenesis and efficient muscle contraction (Nikolaidis and Jamurtas 2009, Akimoto et al. 2005, Baar 2004, Arbogast and Reid 2004). Furthermore, PGC-1 promotes the response to oxidative stress through activation of NRF2 and induction of antioxidant enzyme expression (St. Pierre et al. 2006). Another important point is the massive consumption of ATP followed by an increase in AMP, which activates AMPK, leading again to induction of PGC-1 and enhanced mitochondrial biogenesis (Bergeron et al. 2001, Atherton et al. 2005). This increase in mitochon -drial metabolism leads to enhanced oxygen consumption in muscle fibers followed by lower intracellular oxygen tension during exercise, promoting ROS generation (Franco et al. 1999, Puntschart et al. 1996). There are also other so-called contraction-induced changes that stimulate ROS production in muscle, for instance increased CO2 tension, decreased cellular pH, and rise in muscle temperature (Arbogast and Reid 2004). The main source of ROS during exercise is probably skeletal muscle (Davies et al. 1982, Powers and Jackson 2008), but other tissues such as heart, lungs, and blood are also likely to be important contributors (Powers and Jackson 2008, Nikolaidis and Jamurtas 2009). On cellular level, mtROS were considered to be the predominant fraction of ROS produced during physical activity over decades (Koren et al. 1983, Davies et al. 1982), whereas recent research pointed out also important roles for nicotin-amide adenine dinucleotide phosphate (NADPH) oxidase, phospholipase A2, and xanthine oxidase (Powers et al. 2011).

ROS signals caused by a single bout of exercise only already activate antioxidant defense enzymes like mitochondrial SOD and inducible nitric oxide synthase (iNOS) (Hemmrich et al. 2003, Hollander et al. 2001). Regular exercise leads to proper adaptation to oxidative stress due to upregulation of diverse SODs, catalase, HSPs, and glutathione peroxidase (Powers and Lennon 1999, Leeuwenburgh and Heinecke 2001, Franco et al. 1999, Puntschart et al. 1996). The second line of antioxidant response which includes repair systems is important to minimize the damaging effects of ROS and is also activated through regular physical activity (Crawford and Davies 1994, Davies 1986), assigning important roles for proteasomal degradation and DNA repair enzymes (Radak et al. 2000, Radak et al. 1999, Radak et al. 2003).

Correspondingly, there is convincing evidence that supplementation of antioxidants is useless (Gey et al. 1970, Keren and Epstein 1980, Maughan 1999, Theodorou et al. 2011, Yfanti et al. 2010) or even harmful for athletes, potentially abolishing the beneficial effects on endurance performance, immune status, muscle development, and prevention of diseases (Gomez-Cabrera et al. 2008a, Strobel et al. 2011, Ristow et al. 2009, Marshall et al. 2002, Khassaf et al. 2003). For instance, athletes supplementing vitamin C and E did not display an induction of insulin sensitivity and endogenous antioxidant defense regulators due to exercise as seen in the control group (Ristow et al. 2009). It was shown that enhanced mitochondrial biogenesis and with this, increased respiration and ROS generation according to physical activity is prevented by co-treatment with antioxidants, leading to the inhibition of the beneficial mitohormetic response (Gomez-Cabrera et al. 2008a, Strobel et al. 2011, Kang et al. 2009, Fischer et al. 2006, Ristow et al. 2009). Furthermore, studies proved the harmful effect of antioxidants in regards to performance as it has shown to delay the recovery process (Close et al. 2006, Jackson 2008). Hence, supplementation of antioxidants should not be recommended to healthy athletes due to evidence that antioxidants have counter-productive effects on performance, health, and the onset of diseases.

Very interesting. I always reacted badly to higher doses of vitamin E and vitamin C. Vitamin E gives me fatigue. Vitamin C sorta combination of fatigue and a headache. And have reacted with increased energy from things like iron. Maybe it’s involved in the homeostasis?
 

Douglas Ek

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Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)

Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)

Increasing evidence indicates that reactive oxygen species (ROS), consisting of superoxide, hydrogen peroxide, and multiple others, do not only cause oxidative stress, but rather may function as signaling molecules that promote health by preventing or delaying a number of chronic diseases, and ultimately extend lifespan. While high levels of ROS are generally accepted to cause cellular damage and to promote aging, low levels of these may rather improve systemic defense mechanisms by inducing an adaptive response. This concept has been named mitochondrial hormesis or mitohormesis. We here evaluate and summarize more than 500 publications from current literature regarding such ROS-mediated low-dose signaling events, including calorie restriction, hypoxia, temperature stress, and physical activity, as well as signaling events downstream of insulin/IGF-1 receptors, AMP-dependent kinase (AMPK), target-of-rapamycin (TOR), and lastly sirtuins to culminate in control of proteostasis, unfolded protein response (UPR), stem cell maintenance and stress resistance. Additionally, consequences of interfering with such ROS signals by pharmacological or natural compounds are being discussed, concluding that particularly antioxidants are useless or even harmful.

Physical inactivity promotes the onset of a variety of diseases like obesity, cardiovascular disease, DM type 2, and cancer. Consistently, regular physical activity unquestionably exerts beneficial or preventive effects on the above mentioned diseases, and additionally delays depressive symptoms, neurodegeneration (including Alzheimer’s disease), and general aging (Warburton et al. 2006, James et al. 1984, Hu et al. 2001, Brown et al. 2012, Lanza et al. 2008, Manini et al. 2006, Powers et al. 2011). Exercise is not only linked to enhanced mitochondrial biogenesis and oxidative metabolism, but also to increased generation of mtROS (Powers and Jackson 2008, Chevion et al. 2003, Davies et al. 1982, Alessio and Goldfarb 1988, Alessio et al. 1988). Thus, and because of its obvious beneficial effects in regards to health and aging, make it a paradigm of adaptive response processes and finally mitohormesis (Radak et al. 2008, Radak et al. 2005, Ji et al. 2006, Watson 2013). However, similar to physical inactivity, overtraining or excessive exercise represents the other end of the hormesis curve as the adaption process is inhibited, leading to incomplete recovery (Chevion et al. 2003) and resulting in maladaptation and possibly increased risk of diseases (Alessio et al. 1988).

To our knowledge, the first direct evidence that increased ROS production following exercise may act as stimulus to activate mitochondria biogenesis and mediates potential health-beneficial effects dates back to 1982 (Davies et al. 1982). An indirect clue was already given in 1971 with an antioxidant, namely vitamin E, causing unfavorable effects on the endurance performance of swimmers (Sharman et al. 1971). Since then, a bulk of studies (in most cases inadvertently) proved the hypothesis that ROS are required for the health-promoting effects of physical activity, causing an increase in antioxidant defense mechanisms and with this, prolong health span and mean lifespan (Crawford and Davies 1994, Davies 1986, Kim et al. 1996, Marzatico et al. 1997, Balakrishnan and Anuradha 1998, Ji et al. 2006, Powers and Lennon 1999, Niess et al. 1999, Hollander et al. 2001, Higuchi et al. 1985, Gomez-Cabrera et al. 2008b, Quintanilha 1984, Vincent et al. 1999, Boveris and Navarro 2008).

One of the main changes due to regular physical activity is the increase in mitochondria energy metabolism. Exercise activates PGC-1α, which is capable of controlling mitochondrial gene expression via NRF1 and the mitochondrial transcription factor A (TFAM). This mediates enhanced replication of mitochondrial DNA, leading to increased mitochondrial biogenesis and efficient muscle contraction (Nikolaidis and Jamurtas 2009, Akimoto et al. 2005, Baar 2004, Arbogast and Reid 2004). Furthermore, PGC-1 promotes the response to oxidative stress through activation of NRF2 and induction of antioxidant enzyme expression (St. Pierre et al. 2006). Another important point is the massive consumption of ATP followed by an increase in AMP, which activates AMPK, leading again to induction of PGC-1 and enhanced mitochondrial biogenesis (Bergeron et al. 2001, Atherton et al. 2005). This increase in mitochon -drial metabolism leads to enhanced oxygen consumption in muscle fibers followed by lower intracellular oxygen tension during exercise, promoting ROS generation (Franco et al. 1999, Puntschart et al. 1996). There are also other so-called contraction-induced changes that stimulate ROS production in muscle, for instance increased CO2 tension, decreased cellular pH, and rise in muscle temperature (Arbogast and Reid 2004). The main source of ROS during exercise is probably skeletal muscle (Davies et al. 1982, Powers and Jackson 2008), but other tissues such as heart, lungs, and blood are also likely to be important contributors (Powers and Jackson 2008, Nikolaidis and Jamurtas 2009). On cellular level, mtROS were considered to be the predominant fraction of ROS produced during physical activity over decades (Koren et al. 1983, Davies et al. 1982), whereas recent research pointed out also important roles for nicotin-amide adenine dinucleotide phosphate (NADPH) oxidase, phospholipase A2, and xanthine oxidase (Powers et al. 2011).

ROS signals caused by a single bout of exercise only already activate antioxidant defense enzymes like mitochondrial SOD and inducible nitric oxide synthase (iNOS) (Hemmrich et al. 2003, Hollander et al. 2001). Regular exercise leads to proper adaptation to oxidative stress due to upregulation of diverse SODs, catalase, HSPs, and glutathione peroxidase (Powers and Lennon 1999, Leeuwenburgh and Heinecke 2001, Franco et al. 1999, Puntschart et al. 1996). The second line of antioxidant response which includes repair systems is important to minimize the damaging effects of ROS and is also activated through regular physical activity (Crawford and Davies 1994, Davies 1986), assigning important roles for proteasomal degradation and DNA repair enzymes (Radak et al. 2000, Radak et al. 1999, Radak et al. 2003).

Correspondingly, there is convincing evidence that supplementation of antioxidants is useless (Gey et al. 1970, Keren and Epstein 1980, Maughan 1999, Theodorou et al. 2011, Yfanti et al. 2010) or even harmful for athletes, potentially abolishing the beneficial effects on endurance performance, immune status, muscle development, and prevention of diseases (Gomez-Cabrera et al. 2008a, Strobel et al. 2011, Ristow et al. 2009, Marshall et al. 2002, Khassaf et al. 2003). For instance, athletes supplementing vitamin C and E did not display an induction of insulin sensitivity and endogenous antioxidant defense regulators due to exercise as seen in the control group (Ristow et al. 2009). It was shown that enhanced mitochondrial biogenesis and with this, increased respiration and ROS generation according to physical activity is prevented by co-treatment with antioxidants, leading to the inhibition of the beneficial mitohormetic response (Gomez-Cabrera et al. 2008a, Strobel et al. 2011, Kang et al. 2009, Fischer et al. 2006, Ristow et al. 2009). Furthermore, studies proved the harmful effect of antioxidants in regards to performance as it has shown to delay the recovery process (Close et al. 2006, Jackson 2008). Hence, supplementation of antioxidants should not be recommended to healthy athletes due to evidence that antioxidants have counter-productive effects on performance, health, and the onset of diseases.

Very interesting. I always reacted badly to higher doses of vitamin E and vitamin C. Vitamin E gives me fatigue. Vitamin C sorta combination of fatigue and a headache. And have reacted with increased energy from things like iron. Maybe it’s involved in the homeostasis?
 

Obi-wan

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Tried the coconut oil in the Pau d' Arco tea. Nice energy result...will continue

Careful the tea stays HOT for a long time
 

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Thanks to @bzmazu lots of discussion about the anti malaria drug Artemisinin athttps://raypeatforum.com/community/threads/alleged-cancer-cure.27459/page-2#post-417669 and a great article at Artemisinin our Ultimate Cancer Weapon a Gift from China - Jeffrey Dach MD

"Dr Tu Youyou ultimately isolated the active molecule in the tea, called artemisinin (figure 1 above), an effective anti-malaria drug, for which she received the 2015 Nobel prize in Medicine."

BUT

Antimalarial Drugs are Also Anti-Cancer Drugs

Dr. Das reports in a 2015 article that Artemisinin (or derivatives) are effective against 55 cancer cell lines with inhibitory effects against pancreatic cancer, osteosarcoma, lung cancer, colon, melanoma, breast, ovarian, prostate, central nervous system, lymphoma, leukemia and renal cancer cells. (1)

The molecular mechanism by which artemisinin compounds serve as effective anti-cancer agents can be found in its molecular structure, the endo-peroxide bridge which reacts with the iron molecule.



Active portion of molecule is the endo-peroxide bridge (red arrows) highly reactive oxygen bridge which reacts with the iron in malaria organisms, and the iron in cancer cells.

Lysosomes are the cell organelles which contain acid used for digestion and degradation of unwanted intracellular debris and endocytosed bacteria and proteins. For example, our white cells, called neutrophils, kill bacteria in our blood stream by eating them. Once eaten, these unwanted proteins are digested in lysosomes, The acid in the lysosome is produced by a molecular machine called the “V-ATPase”, a molecular pump for acid production. Lysosomes often accumulate large amounts of iron, especially in cancer cells, which may then react with oxygen, called Fenton reaction, causing release of hydroxyl radicals. This compromises the lysosomal membrane with release of acid contents freely into the cell cytosol initiating a form of cell death is called “ferroptosis” Artemisinin enters the cancer cell lysosomes, which already contain iron as a degradation product from ferritin. The endoperoxide oxygen bridge in artemisinin reacts with iron , the Fenton Reaction, and hydroxyl radicals are produced.

“We believe that this perinuclear clustering of lysosomes is, in fact, an indication of autophagy induction. We observed increase of mitochondrial ROS implicating lysosomal iron as a critical mediator in ART-induced mitochondrial ROS production and cell death. It is possible that enhanced lysosomal degradation of ferritin induced by ART leads to the transient increase of cytosolic ferrous iron, which then affects the mitochondria, leading to enhanced mitochondrial ROS production.”

ALSO

FeverFew – Targeting Cancer Stem Cells – Depleting Glutathione

Feverfew (Parthenolide) is a widely used botanical which exerts potent anti-cancer effects by blocking nuclear activation of Nuclear Factor Kappa Beta (NFKB), and depleting the cancer cell of glutathione, rendering it sensitive to ROS (reactive oxygen species) which triggers apoptotic pathways. (92-108) Parthenolide shares some similarities in chemical structure with Artemisinin

Another great study at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629082/pdf/2203.pdf

ArtemisininBlocksProstateCancerGrowthandCellCycle ProgressionbyDisruptingSp1Interactionswiththe Cyclin-dependentKinase-4(CDK4)PromoterandInhibiting CDK4GeneExpression
 

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It looks like Succinic acid is producing most of the ATP along with Lactic Acid producing ATP in the Cytosol. If the ETC is not working properly (Complex 1, 2,3, or 4) then more ROS should be generated but the cancer cell protects itself with GSH. Chemo will produce even more ROS. Pyrucet should lower the GSH/GSSG ratio. Pau D 'Arco should help with apoptosis. The question I have would using MB (methyl blue) to help generate more ATP from the ETC be beneficial? Through prior experimentation with Succinic acid and Malic acid supplementation I did not feel I got a good result...


From Fenbendazole acts as a moderate microtubule destabilizing agent and causes cancer cell death by modulating multiple cellular pathways

"Various benzimidazole compounds have been shown to be highly effective as inhibitors (up to 50% reduction of activity) of the helminth-specific enzyme fumarate reductase in vitro. While fumarate reductase converts fumarate to succinate in microbes and lower organisms, succinate dehydrogenase catalyzes the oxidation of succinate to fumarate in mammalian mitochondria. The two enzymes, therefore, act on the reverse directions of the same enzymatic interconversion. Succinate dehydrogenase (SDH) is a mitochondrial tricarboxylic acid (TCA) cycle enzyme and a known tumour suppressor gene42. Succinate, a TCA cycle metabolite, is accumulated due to SDH downregulation and provides cancer cells with a growth advantage leading to tumour progression42. Spectrophotometric assay as well as histochemical staining43 showed enhanced SDH activity in cells following FZ treatment (Fig. 8e i and ii).
 

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