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dakotadoc
Health Professional
| Joined: | Fri Jan 18th, 2008 |
| Location: | South Dakota USA |
| Posts: | 12 |
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Posted: Thu Oct 16th, 2008 20:26 |
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http://www.ncbi.nlm.nih.gov/pubmed/18458989
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Psoriasis chronic sinusitis tinnitus no D-tests Ph1Jan08 no NoIRs daily exp to natural light covered up, currently taking a break from MP.
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Dr Trevor Marshall
Foundation Staff
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Posted: Thu Oct 16th, 2008 20:49 |
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Note that one of the authors is Prof. Eishi, who spoke at our 2006 LAX conference.
You know, they are awfully close to asking the correct questions, but having to rely on an observational experiment has misled these researchers. There are too many variables in their experiment, and they don't seem to understand that. You need in-silico experience to understand those variables.
So let me tell you what I think.
First, I am not happy with the conventional view of minocycline blocking the 30S ribosome as explained in this description from the Max Planck ribosome group.
http://www.riboworld.com/antib/30santib-eng.shtml
What worries me is that the Kd is not as high as I would like to see. That is why 5 alternate binding sites are suggested by the Max Planck group.
So, if minocyline does not act principally by attacking the 30S ribosomal subunit, then how does it work?
Well, I am also not impressed with the standard DMARD actions which have been published in the various neurology journals. The problem is that we ourselves don't see it acting as a DMARD. It almost universally increases the IP in the MP.
My current interest is in the the effect of Minocycline on the levels of Caspase-3. This protease breaks apart the VDR receptor structure and thus limits the ability of VDR to do gene transcription. Mino is known to inhibit Caspase-3 activation:
http://www.ncbi.nlm.nih.gov/pubmed/15990464?dopt=Abstract
http://www.ncbi.nlm.nih.gov/pubmed/16638021?dopt=Abstract
This is in line with our observation that Benicar has to administered more frequently in people who are sick, than in people who are not so sick. There has to be a more-rapid turnover of VDR, otherwise once activated by the Benicar the VDR would stay intact and viable. But they don't seem to do that.
Another protease which can degrade VDR is Ubiquitin, so the situation is not completely clear-cut, but my best guess right now is that minocyline indeed has activities beyond microbicidal, and that one of its key actions is to slow down the degradation of VDR. However, it seems the researchers you cite have not yet begun to plumb the depths of VDR activities in the disease process
..Trevor..
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Russ
Member in Phase 3
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Posted: Fri Oct 17th, 2008 00:29 |
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Dr. Marshall, you are always a step ahead of everyone.
About what you said about Benicar needing to be administered more frequently in those who are more sick...are you finding that some patients need more than q6h dosing to get adequate VDR activiation?
Last edited on Fri Oct 17th, 2008 00:32 by Russ
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Lyme, MCS, ADD, optic nerve inflammation | Phase 1: Jul '06 | Phase 3: Jul '07 | 25D: 5 ng/ml (Oct '09)
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Ruth Goold
Health Professional
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Posted: Fri Jan 2nd, 2009 03:10 |
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This paper, published in the Dec. 4 issue of PNAS, indicates other possible mechanisms for minocycline, including inhibition of phosphorylation of the p38 MAP kinase.
Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Yansheng Du* et al.
Phosphorylation of p38 MAPK is required for induction of the VDR after its down-regulation by elevated PTH levels according to this study:
Extracellular Calcium-sensing Receptor Activation Induces Vitamin D Receptor Levels in Proximal Kidney HK-2G Cells by a Mechanism That Requires Phosphorylation of p38 MAPK.
Aparna Maiti , Nitai C. Hait , and Matthew J. Beckman
J. Biol. Chem., Vol. 283, Issue 1, 175-183, January 4, 2008
Ruth
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03/02/07 Ph 1 MP; 2001: Pulmonary sarc; 01/04/07: 125 D=110pmol/L(45.8 pg/ml)| 25D=20.8 ng/ml: 04/07 19.2: 07/07 11?: 09/07 16.5: 11/07 <10.0: 01/08 <10.0: 05/08 10 ng/ml. Ca. Elocom (ears). diphenhydramine 25 mg. Adidas EE glasses outside. NoIRs
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Dr Trevor Marshall
Foundation Staff
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Posted: Fri Jan 2nd, 2009 03:31 |
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Oh, I am sorry, I should have updated this thread. There has been a recent breakthrough in our understanding of mino.
Minocycline is a strong PXR agonist. It increases transcription of CYP3A4 (which breaks down 1,25-D). It increases CYP27A1 expression too (look at my Figure 1 of the Bioessay).
"A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine"
http://www.ncbi.nlm.nih.gov/pubmed/18505790
Clindamycin was also reported to be a PXR agonist, but I was unable to confirm that in-silico. I did confirm minocycline. I suspect that their in-vitro observation was being confused by Clindamycin acting on one of the other orphan nuclear receptors. We know so little about them at this point...
So, is the phosphorylation angle important? Probably not, IMO. the VDR seems to be where it all comes together...
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wrotek
Member in Phase 3
| Joined: | Fri Dec 31st, 2004 |
| Location: | Wroclaw, Poland |
| Posts: | 1175 |
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Posted: Fri Jan 2nd, 2009 07:57 |
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Minocycline PXR agonist ? Interesting.
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Lyme reflux chronic pain fatigue depression 125D36 Ph1Sep05 Ph2Oct06 Ph3Apr07 homebound in low lux NoIRs 25D<7 Oct06
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marion villa
Member in Phase 3
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Posted: Mon Jun 8th, 2009 21:40 |
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guys:
I have a question:
How much do TH1 illnesses affect Japanese people? I ask because they have a strong D level diet with soy and fish,I´m not sure if they process diferently because generations eating this kind of food, or so.
thanks, Im curious.
marion
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Lupus, RA, erythema nosodum, skin ulcers, MP 11/07, voltaren, paracetamol , ,Tylex w/codeine, NoIRs, limited outings covered up,Ph 2 /20 april 2008, 25D<4ng, ph 3/ 22 oct 2008.
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Dr Trevor Marshall
Foundation Staff
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Posted: Tue Jun 9th, 2009 00:08 |
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Marion,
This is a really complex question to answer, due to the changes in the types of bacteria introduced to Japan by the Western influx of people and foods after the second World War.
Sarcoidosis is at least as prevalent in Japan as it is in the USA.
Cardiovascular disease really wasn't a problem up until the 1940's, but is now rising alarmingly.
There are a lot more factors other than Vit D in the diet which allow the accumulation of pathogenic Th1 microbiota. Key among them are the species themselves...
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marion villa
Member in Phase 3
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Posted: Tue Jun 9th, 2009 02:13 |
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the globalization is charging its toll, I guess.
thanks DR, I hope you did all right in china
marion
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Lupus, RA, erythema nosodum, skin ulcers, MP 11/07, voltaren, paracetamol , ,Tylex w/codeine, NoIRs, limited outings covered up,Ph 2 /20 april 2008, 25D<4ng, ph 3/ 22 oct 2008.
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