Marshall Protocol Knowledge Base - home:protocol

Science behind immunopathology

anonymous@undisclosed.example.com (Anonymous) — Wed, 14 Sep 2022 20:53:47 +0000

Science behind Marshall Protocol antibiotics

anonymous@undisclosed.example.com (Anonymous) — Wed, 14 Sep 2022 20:53:47 +0000

Science behind olmesartan (Benicar)

anonymous@undisclosed.example.com (Anonymous) — Wed, 14 Sep 2022 20:53:47 +0000

02.12.2014		current
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	====== Science behind Marshall Protocol antibiotics ======		====== Science behind Marshall Protocol antibiotics ======

-	NOTE: Antibiotics are no longer considered a necessary part of the Marshall protocol.	+	NOTE: Antibiotics are no longer considered a part of the Marshall Protocol.

		+	<html><!--

	===== Safety of Marshall Protocol antibiotics =====		===== Safety of Marshall Protocol antibiotics =====
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	^Name ^Action(s) ^		^Name ^Action(s) ^
	\|Minocycline \|interferes with bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome; may bind the PXR Nuclear Receptor; inhibits activity of caspase-3 \|		\|Minocycline \|interferes with bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome; may bind the PXR Nuclear Receptor; inhibits activity of caspase-3 \|
-	\|Azithromycin (Zithromax) //no longer recommended// \|interferes with bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome; significantly inhibited expression of co-stimulatory molecules (CD40 and CD86) and major histocompatibility complex (MHC) class II by dendritic cells; reduces toll-like receptor 4 expression, interleukin-12 production and the allostimulatory capacity of dendritic cells(({{pubmed>long:22059997}})) \|	+	\|Azithromycin (Zithromax) //no longer recommended// \|interferes with bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome; significantly inhibited expression of co-stimulatory molecules (CD40 and CD86) and major histocompatibility complex (MHC) class II by dendritic cells; reduces toll-like receptor 4 expression, interleukin-12 production and the allostimulatory capacity of dendritic cells(({{pmid>long:22059997}})) \|
	\|Clindamycin \|interferes with bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome \|		\|Clindamycin \|interferes with bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome \|
	\|Demeclocycline (Declomycin) \|interferes with bacterial protein synthesis by binding to the 30S and 50S subunit of the bacterial ribosome \|		\|Demeclocycline (Declomycin) \|interferes with bacterial protein synthesis by binding to the 30S and 50S subunit of the bacterial ribosome \|
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	The affinity (Kd) of minocycline for the bacteria's 30S ribosome is not as high as one might otherwise expect based on its action. For this reason, it seems likely that minocycline may affect immune function in other ways. One possibility is the Pregnane X Nuclear Receptor (PXR).		The affinity (Kd) of minocycline for the bacteria's 30S ribosome is not as high as one might otherwise expect based on its action. For this reason, it seems likely that minocycline may affect immune function in other ways. One possibility is the Pregnane X Nuclear Receptor (PXR).

-	A recent paper has suggested that various tetracycline antibiotics including clindamycin activate the PXR.(({{pubmed>long:18505790}})) Whether that conclusion is confirmed by further research remains to be seen.	+	A recent paper has suggested that various tetracycline antibiotics including clindamycin activate the PXR.(({{pmid>long:18505790}})) Whether that conclusion is confirmed by further research remains to be seen.

	The conclusion of that paper is somewhat at odds with the //in silico// model produced by Trevor Marshall, PhD, from which he has concluded that of the tetracyclines, minocycline is the only one that activates the PXR.		The conclusion of that paper is somewhat at odds with the //in silico// model produced by Trevor Marshall, PhD, from which he has concluded that of the tetracyclines, minocycline is the only one that activates the PXR.
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	==== Inhibition of caspase-3 (minocycline) ====		==== Inhibition of caspase-3 (minocycline) ====

-	Caspase-3 is a protease, which breaks apart the VDR receptor structure and thus limits the ability of VDR to do gene transcription. Minocycline is known to inhibit Caspase-3 activation.(({{pubmed>long:15990464}}))(({{pubmed>long:16638021}}))	+	Caspase-3 is a protease, which breaks apart the VDR receptor structure and thus limits the ability of VDR to do gene transcription. Minocycline is known to inhibit Caspase-3 activation.(({{pmid>long:15990464}}))(({{pmid>long:16638021}}))


	{{tag>antibiotics Science_behind_Protocol}}		{{tag>antibiotics Science_behind_Protocol}}

		+	--></html>

		+	<nodisp>
	===== Notes and comments =====		===== Notes and comments =====


-	===== References =====	+	===== References =====</nodisp>

10.13.2018		current
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-	Many MP patients who have experienced prolonged periods of immunopathology have reached stages of significant improvement or remission. This supports the conclusion that immunopathology is a necessary result of chronic bacterial death, and a precursor to disease reversal. The MP is not unique in this regard. A number of other diseases and/or therapies generate immunopathological or immunopathological-like reactions.(({{pubmed>long:11997718}})) (({{pubmed>long:18600241}})) (({{pubmed>long:12604286}}))	+	Many MP patients who have experienced prolonged periods of immunopathology have reached stages of significant improvement or remission. This supports the conclusion that immunopathology is a necessary result of chronic bacterial death, and a precursor to disease reversal. The MP is not unique in this regard. A number of other diseases and/or therapies generate immunopathological or immunopathological-like reactions.(({{pmid>long:11997718}})) (({{pmid>long:18600241}})) (({{pmid>long:12604286}}))

	Lab work and patient reports can be used to [[home:mp:immunopathology#assessing_immunopathology\|track clinical signs of immunopathology]].		Lab work and patient reports can be used to [[home:mp:immunopathology#assessing_immunopathology\|track clinical signs of immunopathology]].
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	===== Competing models for immunopathology =====		===== Competing models for immunopathology =====

-	According to a 2010 review by evolutionary biologist Paul Ewald, PhD, there are essentially three categories of explanations for immunopathology in chronic disease:(({{pubmed>long:20415848}}))	+	According to a 2010 review by evolutionary biologist Paul Ewald, PhD, there are essentially three categories of explanations for immunopathology in chronic disease:(({{pmid>long:20415848}}))
	- The immune system is exposed to environmental conditions to which the individual is not well adapted. One hypothesis within this category, often referred to as the hygiene hypothesis, proposes that new more hygienic environmental conditions have generated compositions of symbionts that differ from those to which humans have been adapted.		- The immune system is exposed to environmental conditions to which the individual is not well adapted. One hypothesis within this category, often referred to as the hygiene hypothesis, proposes that new more hygienic environmental conditions have generated compositions of symbionts that differ from those to which humans have been adapted.
	- Infectious agents act as triggers of immunopathology by shifting the immune system into a self-destructive state.		- Infectious agents act as triggers of immunopathology by shifting the immune system into a self-destructive state.
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	===== Symptoms of infection are caused by the body's response to microbes =====		===== Symptoms of infection are caused by the body's response to microbes =====

-	A 2011 study, using a novel mouse model, showed that mice that were engineered to have a reduced innate immune response to the common cold actually showed less – not more – airway inflammation and bronchoconstriction (airway spasm) following infection.(({{pubmed>long:21637773}})) According to the study's lead author:	+	A 2011 study, using a novel mouse model, showed that mice that were engineered to have a reduced innate immune response to the common cold actually showed less – not more – airway inflammation and bronchoconstriction (airway spasm) following infection.(({{pmid>long:21637773}})) According to the study's lead author:

	<blockquote>In our study, we offer the first direct evidence that limiting the immune response reduces the manifestations of rhinovirus infection. In our model, cold-induced asthma flare-ups were caused by the body's immune response to the virus, not the virus itself. Chemicals produced by the immune system inflame cells and tissues, causing asthma symptoms such as cough and wheeze.		<blockquote>In our study, we offer the first direct evidence that limiting the immune response reduces the manifestations of rhinovirus infection. In our model, cold-induced asthma flare-ups were caused by the body's immune response to the virus, not the virus itself. Chemicals produced by the immune system inflame cells and tissues, causing asthma symptoms such as cough and wheeze.

-	//Marc B. Hershenson, M.D., [[http://www.sciencedaily.com/releases/2011/06/110616081719.htm\|ScienceDaily]]// June 17, 2011</blockquote>	+	//Marc B. Hershenson, M.D., [[https://www.sciencedaily.com/releases/2011/06/110616081719.htm\|ScienceDaily]]// June 17, 2011</blockquote>

	Even though it was conducted in a murine model, this work is relevant as it strongly suggests that symptoms of infection are due not so much to the infection but the body's response to it.		Even though it was conducted in a murine model, this work is relevant as it strongly suggests that symptoms of infection are due not so much to the infection but the body's response to it.
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	During immunopathology, cytokines, are elevated. Cytokines are released by the inflammatory process.		During immunopathology, cytokines, are elevated. Cytokines are released by the inflammatory process.

-	The release of cytokines appears to be essential for recovery after an infection. One study found that the cytokine TNF-alpha was essential for the proper expression of acquired specific resistance following infection with //Mycobacterium tuberculosis//.(({{pubmed>long:18544042}})) (({{pubmed>long:12852719}})) (({{pubmed>long:15216471}})) For this reason among others, [[home:othertreatments:antitnf\|TNF-alpha inhibitors]], drugs which suppress the cytokine, are contraindicated for MP patients.	+	The release of cytokines appears to be essential for recovery after an infection. One study found that the cytokine TNF-alpha was essential for the proper expression of acquired specific resistance following infection with //Mycobacterium tuberculosis//.(({{pmid>long:18544042}})) (({{pmid>long:12852719}})) (({{pmid>long:15216471}})) For this reason among others, [[home:othertreatments:antitnf\|TNF-alpha inhibitors]], drugs which suppress the cytokine, are contraindicated for MP patients.
	==== Endotoxins ====		==== Endotoxins ====

	Endotoxins, sometimes referred to as lipopolysaccharides, are proteins associated with bacteria and bacterial communities (microbiota). When these bacteria are destroyed by the innate immune system, as will happen during the MP, endotoxins are released causing a spike in symptoms known as an immunopathological reaction.		Endotoxins, sometimes referred to as lipopolysaccharides, are proteins associated with bacteria and bacterial communities (microbiota). When these bacteria are destroyed by the innate immune system, as will happen during the MP, endotoxins are released causing a spike in symptoms known as an immunopathological reaction.

-	The body responds to the presence of endotoxins by producing cholesterol(({{pubmed>long:20377753}})) and C-reactive protein,(({{pubmed>long:15198851}})) among other defense mechanisms.	+	The body responds to the presence of endotoxins by producing cholesterol(({{pmid>long:20377753}})) and C-reactive protein,(({{pmid>long:15198851}})) among other defense mechanisms.

-	In immunology, the term "LPS challenge" refers to the process of exposing a subject to a lipopolysaccharide that may act as a toxin. Injecting mice with LPS has been used as models for preterm labor,(({{pubmed>long:19995880}})) hyperactivity,(({{pubmed>long:18814846}})) lung injury,(({{pubmed>long:16273282}})) and periodontitis,(({{pubmed>long:15218043}})) to cite just a few examples.	+	In immunology, the term "LPS challenge" refers to the process of exposing a subject to a lipopolysaccharide that may act as a toxin. Injecting mice with LPS has been used as models for preterm labor,(({{pmid>long:19995880}})) hyperactivity,(({{pmid>long:18814846}})) lung injury,(({{pmid>long:16273282}})) and periodontitis,(({{pmid>long:15218043}})) to cite just a few examples.

	<html>		<html>
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	Occasionally, patients may notice new symptoms occurring in organs not known to be infected. The MP cannot create new infection, such symptoms are due to exacerbation of previous sub-clinical microbiota.		Occasionally, patients may notice new symptoms occurring in organs not known to be infected. The MP cannot create new infection, such symptoms are due to exacerbation of previous sub-clinical microbiota.

-	The strength of an immunopathological or herx reaction is associated with the severity of disease.(({{pubmed>long:15896248}})) (({{pubmed>long:6017505}}))	+	The strength of an immunopathological or herx reaction is associated with the severity of disease.(({{pmid>long:15896248}})) (({{pmid>long:6017505}}))

04.10.2020		current
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	Ample research supports the fact that olmesartan is one of the safest and has the most gentle side effects profiles of almost any drug on the market.		Ample research supports the fact that olmesartan is one of the safest and has the most gentle side effects profiles of almost any drug on the market.

-	For those with gastric issues, it is recommended that the pill be crushed and mixed with applesauce or similar to reduce impact on gastric lining	+	For those with gastric issues, it is recommended that the pill be crushed and mixed with applesauce or similar to reduce impact on gastric lining.

	===== Potent anti-inflammatory =====		===== Potent anti-inflammatory =====
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	<blockquote>The involvement of Vitamin D/VDR in anti-inflammation and anti-infection represents a newly identified and highly significant activity for VDR.		<blockquote>The involvement of Vitamin D/VDR in anti-inflammation and anti-infection represents a newly identified and highly significant activity for VDR.

-	//Jun Sun// (({{pubmed>long:20639756}}))</blockquote>	+	//Jun Sun// (({{pmid>long:20639756}}))</blockquote>


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	<blockquote>Vitamin D receptor (VDR) agonists are well known for their capacity to control calcium metabolism and to regulate growth and differentiation of many cell types. More recently, it has become clear that VDR agonists possess immunoregulatory properties and, in particular, pronounced pro-tolerogenic activities.... These mechanisms of action can explain some of the immunoregulatory properties of VDR agonists in the treatment of Th1-mediated autoimmune diseases, but may also represent a physiologic element in the VDR-mediated regulation of innate and adaptive immune responses.		<blockquote>Vitamin D receptor (VDR) agonists are well known for their capacity to control calcium metabolism and to regulate growth and differentiation of many cell types. More recently, it has become clear that VDR agonists possess immunoregulatory properties and, in particular, pronounced pro-tolerogenic activities.... These mechanisms of action can explain some of the immunoregulatory properties of VDR agonists in the treatment of Th1-mediated autoimmune diseases, but may also represent a physiologic element in the VDR-mediated regulation of innate and adaptive immune responses.

-	//L. Adorini, from paper "Intervention in autoimmunity: the potential of vitamin D receptor agonists"// (({{pubmed>long:15936743}}))	+	//L. Adorini, from paper "Intervention in autoimmunity: the potential of vitamin D receptor agonists"// (({{pmid>long:15936743}}))
	</blockquote>		</blockquote>

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	//Trevor Marshall, PhD//</blockquote>		//Trevor Marshall, PhD//</blockquote>

-	The ribosome blockades initiated by the [[mp_antibiotics\|Marshall Protocol antibiotics]] weaken the Th1 pathogens but are unable to actually kill the pathogens. For this reasons, patients on the MP take olmesartan, which activates the innate immune response. In this respect, olmesartan is distinct from other ARBs such as telmisartan, which has been shown to be a strong VDR antagonist.(({{pubmed>long:20222053}})) Molecular modeling has revealed that olmesartan binds and activates the Vitamin D Receptor among others. This action is validated by //in silico// data.(({{pubmed>long:16403216}}))	+	The ribosome blockades initiated by the [[mp_antibiotics\|Marshall Protocol antibiotics]] weaken the Th1 pathogens but are unable to actually kill the pathogens. For this reasons, patients on the MP take olmesartan, which activates the innate immune response. In this respect, olmesartan is distinct from other ARBs such as telmisartan, which has been shown to be a strong VDR antagonist.(({{pmid>long:20222053}})) Molecular modeling has revealed that olmesartan binds and activates the Vitamin D Receptor among others. This action is validated by //in silico// data.(({{pmid>long:16403216}}))

	Because the VDR itself is in constant motion and it is affected by the forces on the VDR from adjacent molecules, olmesartan has an ability to stay in that binding pocket for only a few hours before it is either ejected, or the VDR itself is pulled apart by outside forces.		Because the VDR itself is in constant motion and it is affected by the forces on the VDR from adjacent molecules, olmesartan has an ability to stay in that binding pocket for only a few hours before it is either ejected, or the VDR itself is pulled apart by outside forces.
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	==== The unbound Vitamin D Receptor degrades quickly ====		==== The unbound Vitamin D Receptor degrades quickly ====

-	Peleg and Nguyen observed that in the absence of an agonist such as 1,25-D, the VDR suffers from polyubiquitination and proteasome-mediated degradation in relatively short course – in the sub-4 hour region, and certainly in the sub-24hour region.(({{pubmed>long:20564192}})) This study offers some support for why sick patients need more frequent dosing than their healthy counterparts.	+	Peleg and Nguyen observed that in the absence of an agonist such as 1,25-D, the VDR suffers from polyubiquitination and proteasome-mediated degradation in relatively short course – in the sub-4 hour region, and certainly in the sub-24hour region.(({{pmid>long:20564192}})) This study offers some support for why sick patients need more frequent dosing than their healthy counterparts.

	<blockquote>Recent published reports on the dynamics of VDR recruitment to promoters of target genes in cultured cells demonstrate that the time course for maximal recruitment of the 1,25D3–VDR complex to the promoter of the CYP24 gene in osteoblasts is 3 h, whereas the time course for maximal recruitment of the VDR to the promoter of this gene in IECs is only 30 min [Kim et al., 2005; Meyer et al., 2006].		<blockquote>Recent published reports on the dynamics of VDR recruitment to promoters of target genes in cultured cells demonstrate that the time course for maximal recruitment of the 1,25D3–VDR complex to the promoter of the CYP24 gene in osteoblasts is 3 h, whereas the time course for maximal recruitment of the VDR to the promoter of this gene in IECs is only 30 min [Kim et al., 2005; Meyer et al., 2006].

-	//S. Peleg and C. V. Nguyen// (({{pubmed>long:20564192}}))	+	//S. Peleg and C. V. Nguyen// (({{pmid>long:20564192}}))
	</blockquote>		</blockquote>

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	==== Infected cells have VDRs with a shorter life span ====		==== Infected cells have VDRs with a shorter life span ====

-	Some intracellular infections (notably //Shigella//), upregulate activity of the caspases, which are proteases that cleave the VDR.(({{pubmed>long:17696608}})) When the VDR is broken apart by the caspases, it is highly likely that any ligands bound to it (such as olmesartan) would stay bound to the fragments of the protein. Therefore, a VDR agonist would be effective over shorter periods of time in patients with infected cells.	+	Some intracellular infections (notably //Shigella//), upregulate activity of the caspases, which are proteases that cleave the VDR.(({{pmid>long:17696608}})) When the VDR is broken apart by the caspases, it is highly likely that any ligands bound to it (such as olmesartan) would stay bound to the fragments of the protein. Therefore, a VDR agonist would be effective over shorter periods of time in patients with infected cells.

	==== Bacterial products down-regulate the expression of the VDR ====		==== Bacterial products down-regulate the expression of the VDR ====