Showing posts with label TNF. Show all posts
Showing posts with label TNF. Show all posts

Thursday, October 3, 2013

Interesting aspects of Herpetic Infections

No infection is as intriguing as the Herpetic infection.  Its interest lays in several facts
1. The mere fact that a Third of the US population may be involved makes this disease one of the most prevalent ones,  but it is also feared.  Whether the fear is justified or not remains a question.
2. Certainly it has something to do with horrific stories of potential recurrence of horrific burning neuropathic pains that we have heard about. Science does not know for sure whether only specific viral serotypes lead to this or whether certain hosts genes isoforms or inflammatory reactions  may be contributing to this presentation.
3. The outbreak is accompanied with guilt and sense of guiltiness that is mostly unjustified...many questions arise after the realization that those painful skin or otherwise lesions could be herpetic...that a partner you have gave this to you and that you may give this to a new partner?  Those questions are valid but with the prominence of the prevalence of this disease in the US, who and when one got exposed to Herpes is one of the great mysteries in herpetic disease.  Herpes 1 has been linked to Over crowding, and Herpes 2 is the one with a sexual connotation.  But one should remember that the Herpetic Virus will invade teguments (particularly abrasions) when contact happens, sexual or not!  And very often this happens in our tender ages of infancy.  Remember the infection can be symptomatic, but most of the time completely without any clinical manifestations. And enters quietly a dormancy.
4. The dormancy itself is quite a puzzling event!  All we know is that the capsule to this double stranded DNA viral particule is from the host!  This may help it to be "tolerated " by the host.  We can speculate that class I MHC will not be bothered. Only the class II may note the invader most likely and provide the Antibody that we can measure!
5. The exacerbation of the herpetic infection is also puzzling in many ways
-It happens when we are under stress (menstruation and exposure to UV light), pregnancy state and post chemotherapy, the so called state of "when the immune system" is down!
-To the writer this is a state of activity of the c-JUN and Fos, the NF-kB and full epigenetic phenomena as if cyclines and TNF, TGFs are in full swing!  Epigenetic events seem to free or unleash genes (regulators or not) that will reactivate the Virus.
-How and where these events occur (Golgi, Nucleus, or cytosolic) remains to be clarified.

 (Let raise the eyelid of this dormant disease and look at it through its eyes/pupils without awakening it!)

6. The bad exacerbation could be virally induced or it could be in fact a reaction of the Host  (Neutrophilic Grazymes) or Cyclin effects.  ie. In post Brain trauma injury (TBI) we know that post synaptic nerve death is due to  Cytokins that kill post synaptic nerve, is it the same in this herpetic disease?And if it is, what would be the therapeutic implications?!

Sunday, April 21, 2013

ONE IMPORTANT MECHANISM OF NEOPLASTIC TRANSFORMATION COMING OUT OF OUR OBSERVATION:

ONE IMPORTANT MECHANISM OF NEOPLASTIC TRANSFORMATION COMING OUT
OF OUR OBSERVATION: THE FAILURE OF RECEPTORS

LET US TAKE THIS EXAMPLE!
---------------------------------------------------------------------------------------------

Tumor necrosis factor-alpha induces mucin hypersecretion and MUC-2 gene expression by human airway epithelial cells.

Source

Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892-1662.

Abstract

Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional, pro-inflammatory cytokine that is capable of activating a diverse number of target genes within multiple cell types. Little information is known regarding the role of TNF-alpha in the regulation of human airway mucin hypersecretion and MUC-2 gene expression.

------------------------------------------------------------------------------------------

LET'S ASSUME
THAT A GROWTH FACTOR HAS 2 PRINCIPAL RECEPTORS AND 2 SECONDARY RECEPTORS
(IN THIS EXAMPLE TNF- alpha IS SAID TO HAVE  A "NUMBER OF TARGET GENES")
IF FOR SOME REASONS THE GROWTH FACTOR FAILED TO ACTIVATE ITS PRINCIPAL RECEPTORS,  2 THINGS HAPPEN:

1. THE PRINCIPAL RECEPTOR
initiates a stress like response which will involve the HP90, exacerbating the NF- kB
resulting in further activation of promoter genes and formation of MORE TNF- alpha

2. MORE TNF-alpha will exacerbate the effect on SECONDARY receptors still sensitive, leading to the activation/amplification of unwanted genes,

- Amplification of MUC-1 leads to an Adenoma and eventually Adenocarcinoma.
- Amplification of MUC-2 leads to a pseudomyxoma.
- May be MUC-7 will be lung and bladder Cancer?

Neutrophil elastase induces MUC5AC gene expression in airway epithelium via a pathway involving reactive oxygen species.

Source

Division of Pediatric Pulmonary Diseases, Duke University Medical Center, Durham, North Carolina 27710, USA.

Abstract

Neutrophil-predominant airway inflammation and mucus obstruction of the airways are major pathologic features of chronic airway diseases, including cystic fibrosis and chronic bronchitis. Neutrophils release elastase, a serine protease that impairs mucociliary clearance and stimulates goblet cell metaplasia and mucin production. We previously reported that neutrophil elastase increases expression of a major respiratory mucin gene, MUC5AC, by enhancing mRNA stability. However, the molecular mechanisms of elastase-regulated MUC5AC expression are not known. We hypothesized that reactive oxygen species, generated by elastase treatment, mediate MUC5AC gene expression.

MUC4 gene polymorphisms associate with endometriosis development and endometriosis-related infertility.

Source

Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.

Abstract

BACKGROUND:

Mucin 4 (MUC4) plays an important role in protecting and lubricating the epithelial surface of reproductive tracts, but its role in the pathogenesis of endometriosis is largely unknown.

MUC3 human intestinal mucin. Analysis of gene structure, the carboxyl terminus, and a novel upstream repetitive region.

Source

Gastrointestinal Research Laboratory (151M2), Department of Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA.

Abstract

MUC3 is a large mucin glycoprotein expressed by the human intestine and gall bladder.

MUC6 - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/MUC6
Reid CJ, Harris A (1999). "Expression of the MUC 6 mucin gene in development of the human kidney and male genital ducts.".

PICK A NUMBER AND YOU WILL FIND WHERE THE CANCER WILL BE. THIS IS THE POWER OF RECEPTORS AND THE POWER OF GENE POLYMORPHISM! 

Let's play:
Full Name mucin 10, submandibular gland salivary mucin

MUC12 »  Mucin-12  (MUC-12)
Protein also known as:  Mucin-11 (MUC-11).
Gene name:  MUC12
This protein has been shown to exist at protein level

Expression

Ubiquitous, with higher expression in colon. Down-regulated in colorectal cancer as well as in the colon of patients with ulcerative colitis (UC) and Crohn's disease (CD).  
  • CuratedUniProtKB
Ubiquitous cytoplasmic expression in all tissues at variable levels. Highest expression in gastrointestinal tract. silver HPA027769; HPA023835

THIS EXERCISE CAN BE DONE WITH ALL ADENOCARCINOMAS!

DO YOU SEE PORTRAYED HERE A TARGET FOR THERAPY OR DIAGNOSIS?  
LET'S GO TO WORK!


In Summary,
Epithelial covers of Mucosa secrete a Mucine to protect it against infection and immune system exactions
and depending on localization the MUCINE is made a different family member of MUC -x  gene
this is helpful when you have a carcinoma of unknown primary, look at the MUC gene amplified

YOU reach the door of MESENCHYMALIZATION when you reach MUC-20, this is where epidermal and endothelial switch, where squamous switch to adenocarcinoma, where the MEK gene is located!

Sunday, February 17, 2013

TTP

THROMBOTIC THROMBOCYTOPENIC PURPURA (HYPOTHESIS CONTINUES)

Here is the example of a metastatic mechanism going bad when it hits the right ADAM.  Remember that ADAM are made of 2 basic domains, one an integrin and one a metalloproteinase domain.  The Metalloproteinase enters the Flippase-floppase (or sometimes scramblase)-like structure and is destined to be rejected outside, the Integrin is sent inside the cell.
Metalloproteinases are sent outside and attack collagen-like molecules to open the way to cell migration and allow Metastatic processes to move forward.  However, the cell membranes have a collagen-like structure, too.  So potentially the released Metalloproteinases could attack the cell.  The cell is not stupid and knows what metalloproteinase it has put out.  So it shields itself with Inhibitors and Decoy receptors from that specific metalloproteinase and the cell goes about its migration.

2 conclusions:

1. Insufficient inhibitors and decoy receptors to Metalloproteinases (and others such as Hydroeicosatetraenoic Acid) will have devastating effects.  If genetically the inhibitors are insufficient, and metalloproteinases are expressed massively, and this happens at the endothelial cell, massive and extensive destruction of endothelial cells throughout the body happens, exposing collagen like structures of the blood vessel walls.  This of course trigger extensive activation of platelets and the Thrombosis of TTP-like syndrome.  So in TTP, it is the inhibitor that is lacking.  (ie Von Willebrand cleaving protease inhibitors have also been cited).  And plasmapheresis removes the the Metalloproteinases (and microbial Antigens/toxin when relevent), stopping the onslaught.

2.What is in the Integrin domain is critical, in ADAM-17, the integrin domain is occupied by TNF-alpha, converting enzyme (TACE) which will free and activate the devastating Tumor Necrosis Factor.  Released massively, TNF can not only induce Apoptosis like certain other Cyclins (interleukine and Interferon ), but also leads directly to NECROSIS.  A massive uncontrolled septic-like syndrome kills rats after infusion of TNF.

ADAM 10, the disintegrin there gives you Amyloid structures of Alzheimer's.  TO BE SHORT, PICK THE ADAM AND SEE THE CONSEQUENT DISEASE ON YOUR OWN!

ADAM! A FLIPPASE, FLOPPASE AND/OR A SCRAMBLASE-LIKE MOLECULE !

Saturday, February 16, 2013

HYPOTHESIS : WHERE DO CYCLINS COME FROM?

There is increasing evidence that Cyclins are integrins and so are Tumor growth factors, Tumor Necrosis factors, interleukins and interferons.
All these are membrane proteins with a particularity to be released from Metalloprotease and related adhesion molecules depending on the nature of stimuli.  The discovery and description of ADAMs as type I membrane protein containing Metalloproteinase and an integrin domain locate the growth factors and Cyclins squarely at the membrane  (surface and reticulum membrane).  These proteins, once released, go straight to the Nucleus to unveil their might by activating transcription factor.  In their track to the nucleus they can amplify and activate signal transduction pathways as well as either molecules. The cyclins find cytoplasmic and protein substrates (mostly enzymes)  which have their specific domains and link to the site to activate them most of the time, changing their shapes so as to expose hidden electrons or atomic groups (such SH) to cause downstream chain activation.

Now as the pathway unfolds at light speed (or electronic speed) it may overwhelm the cell, protection has to be assured to hide death domains (which also are integrins and therefore at the membrane) and pathways to Apoptosis.  Protection at the membrane seems to be offered by the INK while the CIP/Kip.  But deep in the cell are the Bcl-like proteins. The CIP/Kip seems to work like Decoy specific proteins since the have Cyclin domain to stop them from stimulating their respective CDKs (Cyclin dependent Kinases).  Some CDKs need 2 or more different stimulations to accomplish their deed. And with the number of stimulations comes the consequent activation of various substrates.  The Retinoblastoma substrate governs the G1 progression phase in the cell cycle, but it needs at least 2 activations, first by Cyclin D followed by activation by Cyclin E in order for it to free E2F that light up tarnscrptions genes which control the path to S-phase.  This Cyclin E also activates processes leading to Histone Biosynthesis, Centrosome activity and DNA replication.  And in fact, Cyclin E is the one that leads to gene instability that characterize many triple negative breast cancers

(E2F AND CYCLIN E, ARE POWERFUL TARGETS FOR CANCER CURE)

One of the CIP/Kip(s) is the P21 which plays a role in the cell cycle arrest due to P53 activation.
I should note that the Kinase itself may be mutated.  CDK4 is mutated in Melanoma, it renders the INK4 protein unable to occupy its domain and therefore is free to affect the nuclear transcription factor.  Therefore the solution is to increase the ligand to INK4 so as to increase its ubiquitination and and degradation through the proteasome (Ipilimumab/CTLA 4 in T cell/ does not do this unfortunately, so there is more room for you to research).  YES, LIKE FOR MERCEDES, WE NEED THE E CLASS OF PROTEINS TO FURTHER UBIQUITINATION.  A MUTATION IN E CLASS (WHICH INCLUDES MDM2) WILL BE BAD IN MELANOMA!

Suffice is to show that what starts at the membrane moves quickly to the nucleus in a milli-milli second in a flash and turn the life of the host around!

It is worth noting that not only Cyclins can be blocked from entering the Nucleus where they trigger transcription factor formation, but sometimes the Decoy (Cip/Kip) is stopped from entering the nucleus and cannot stop Cyclins which have entered the nucleus: this happens in breast cancer (p27 mislocation)
-----------------------------------------------------------------------------------------
THE INTEGRINS, PRESUMED SOURCE OF CYCLINS!

Thursday, January 17, 2013

POLYUBIQUITINATION

The rise of the role of antiproteasome in the treatment of hematologic malignancies such Multiple Myeloma
requires us to stop a bit and reflect on the basic role of proteasomes which is to destroy used proteins.  To be recognized as old proteins ready for destruction, the protein is Ubiquitinated and ready for disposal.  The anti-proteasomes in effect block this plan.  And sure enough, Ubiquitinated proteins stay alive longer and guess what, it is an ubiquitinated proteins that seems to contribute to the negative effect on Modulators of pathways.   Ubiquitinated proteins forms stops transcriptions factors at check points, block the NF-kB, and drives the effects of Antiproteasomes.
Can a simple infusion of ubiquitinated TNF blocks its effects, can we start just ubiquitinating growth factors and infuse them to stop infectious process or cancer growth?  Remember, DRIVER Pathways are driven most of the time by regulators who seems to have a negative feedback from UBIQUITINATED specific pathway proteins in general terms (rare exception will exist)! What do you think?  Can a polyubiquitinated growth factor still stimulate effectively its receptor or will it dampen the stimulation and slow the devastating effect of say, TNF?