CCL2 is involved in the *neuroinflammatory* processes that takes place in various central nervous system (CNS) diseases characterized by neuronal degeneration.
Its expression by glial cells is increased in epilepsy, brain ischemia, Alzheimer�s disease
experimental autoimmune encephalomyelitis (EAE) (me�that is MS)
Rhizoma Coptidis inhibits LPS-induced MCP-1/CCL2 production in
murine macrophages
via an AP-1 and NFkappaB-dependent pathway.
INTRODUCTION: The Chinese extract Rhizoma coptidis is well known for its anti-inflammatory, antioxidative, antiviral, and antimicrobial activity. The exact mechanisms of action are not fully understood.
METHODS:
We examined the effect of the ***extract and its main compound, berberine***, on LPS-induced inflammatory activity in a murine macrophage cell line.
RAW 264.7 cells were stimulated with LPS and incubated with either Rhizoma coptidis extract or berberine. Activation of AP-1 and NFkappaB was analyzed in nuclear extracts, secretion of MCP-1/CCL2 was measured in supernatants.
RESULTS: Incubation with Rhizoma coptidis and berberine strongly inhibited LPS-induced monocyte chemoattractant protein (MCP)-1 production in RAW cells.
Activation of the transcription factors AP-1 and NFkappaB was inhibited by Rhizoma coptidis in a dose- and time-dependent fashion.
CONCLUSIONS:
Rhizoma coptidis *extract* inhibits LPS-induced MCP-1/CCL2 production in vitro via an AP-1 and NFkappaB-dependent pathway. Anti-inflammatory action of the extract is mediated mainly by its alkaloid compound berberine.
Monocyte chemoattractant protein-1 (MCP-1 or CCL2) regulates blood-brain barrier permeability by inducing morphological and biochemical alterations in the tight junction (TJ) complex between brain endothelial cells.
CCL2 induces brain endothelial hyperpermeability via Rho/PKCa signal pathway interactions.
Inhibiting PKC (with drugs like Tamoxifen for breast caner) isn't enough...gotta go "upstream" and inhibit Rho alpha ALSO.
PLD does this:
PLD catalyzes the*** hydrolysis of phosphatidylcholine*** to form phosphatidic acid (PA) and releases choline.
Chemically, lecithin is a phosphatidylcholine, a phospholipid that plays a key role in the formation of cell membranes and myelin sheaths in the human brain.
Without lecithin, cell structure could harden and collapse.
Lecithin transport fats, is used in metabolic processes, and acts as an emulsifier, protecting the cells from oxidation.
So...PLD1 (upregulated) -> phosphatidylcholine broken down, but phosphatidylcholine is needed in the formation of the myelin sheath!
The reason why this is linked to lyme is because one of Bb's lipoproteins is phosphatidylcholine!
So...in destroying that protein of "his", we destroy "self".
Bb's toxin looks to do this:
The toxin, C3 and C3-like ADP-ribosyltransferases, ***inhibits PLD*** (phospholipase D).
PLD catalyzes the*** hydrolysis of phosphatidylcholine*** to form phosphatidic acid (PA) and releases choline.
If one of Bb's lipoproteins is phosphatidylcholine, it makes sense (is logical) that Bb would NOT want that protein broken down, but we upregulate PLD and destroy self in the process.
This toxin impacts the liver too. That same toxin (C3 ADP-ribosyltransferase is present in botulism also!
MS patients could even have picked it up in:
However, honey sometimes contains dormant endospores of the bacterium Clostridium botulinum, which can be dangerous to infants, as the endospores can transform into toxin-producing bacteria in the infant's immature intestinal tract, leading to illness and even death.
Treating MS With Botulinum Toxin = homeopathy = "like cures like"!
Or�
Berberine cured mice with MS (Th17 implications) � (MS = multiple sclerosis) is believed to be caused by a retroviral protein that is normally within us):
Since we look to not only respond to Bb + self by impacting phosphatidylcholine, but in addition, we look to respond to Bb�s + OUR Hsp60 = heat shock protein 60.
Immunogen: Human Hsp60 Recombinant Protein Isotype: Mouse IgG1
In addition to
its role in protein folding,
Hsp60 has also been implicated in immune function. In macrophages, its binding to the toll-like receptor-4 complex induces production of TNFα and nitric oxide and stimulation of a proinflammatory response.
Thus, the protein folding function of Hsp60 is involved in mitochondrial protein folding in
both normal and apoptotic cells,
while release of Hsp60 during necrosis is thought to stimulate a proinflammatory response.
In both lyme and in MS, what WAS needed was an IgG1K � kappa response. Note the above = Hsp60 = IgG1.
Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody that selectively binds to free human immunoglobulin E (IgE) in the blood and and interstitial fluid and to membrane-bound form of IgE (mIgE) on the surface of mIgE-expressing B lymphocytes.
It is used for moderate to severe asthma.
The target for IgG1k is IgE � Fc region.
The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system.
A confocal microscopy study was undertaken to characterize the bactericidal effects of the Fab fragments of CB2, an immunoglobulin ***G1kappa*** murine monoclonal antibody�
Remember if you read the above, Mg is an anti-histamine (as well as an anti-inflammatory and inhibits HMG CoA reductase).
When lyme patients made the antibodies to Bb (humoral response), the antibody to Bb�s Osp B was incorrect.
Unfortunately copies are made from an original. So it is highly unlikely lyme patients have any way to deal with that outer surface protein effectively and completely.
Since we are making B lymphocytes all the time, the question is�could Omalizumab correct the error?
IgG1k in MS:
Late B Cell Depletion with a Human Anti-Human CD20 IgG1k Monoclonal Antibody Halts the Development of Experimental Autoimmune Encephalomyelitis in Marmosets
�In conclusion, ***B cell depletion*** prevents the development of clinical and pathological signs of EAE, which is associated with impaired activation of MOG-reactive T cells in lymphoid organs.�
The results argue against DNA binding as the primary mechanism of action of berberine and support the hypothesis that its antibacterial properties are due to
***inhibition of the cell division protein FtsZ.***
FtsZ is a protein encoded by the ftsZ gene that assembles into a ring at the future site of the septum of bacterial cell division.
This is a prokaryotic homologue to the eukaryotic protein tubulin. FtsZ has been named after "Filamenting temperature-sensitive mutant Z".
During cell division, FtsZ is the first protein to move to the division site, and is essential for recruiting other proteins that produce a new cell wall between the dividing cells.
FtsZ's role in cell division is analogous to that of actin in eukaryotic cell division, but, unlike the actin-myosin ring in eukaryotes, FtsZ has no known motor protein associated with it.
The origin of the cytokinetic force, thus, remains unclear, but it is believed that the localized synthesis of new cell wall produces at least part of this force.
In liposomes Osawa (2009) showed FtsZ is capable of exerting a contractile force with no other proteins present.
Erickson (2009) proposed how the roles of tubulin-like proteins and actin-like proteins in cell division became reversed in an evolutionary mystery.
The use of the FtsZ ring in dividing chloroplasts and some mitochondria further establishes their prokaryotic ancestry.
***It is interesting to note that L-form bacteria that lack a cell wall do not require FtsZ for division, ***
which implies that bacteria may have retained components of an ancestral mode of cell division.
FtsZ has the ability to bind to GTP and also exhibits a GTPase domain that allows it to hydrolyze GTP to GDP and a phosphate group.
By sequestering FtsZ, the cell can directly link DNA damage to inhibiting cell division.
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