North Medical Center

Ethanol and Cancer

2009-02-03T05:56:00.000-08:00

This will be an unofficial announcement pertaining to anyone who personally or who has a relative who is dying from cancer. There is just one culprit involved……Tumor Necrosis Factor-Alpha. As in the case of the death in toxic shock syndrome the end is shock or cardiovascular collapse. This occurs as a consequence of diminished volume, oncotic pressure (albumin) or pump failure. The greater the chronicity, the greater the loss of albumin,and cardiovascular integrity due to diminished mitochondrial to intercellular functioning.The body in its preferential assimilation of essential amino acids to synthesize TNF literally digests other non-tumor protein sources within the body. The tumor literally digests other parts of the body in an “intelligent” survival of the fittest as it almost instinctively turns off the feedback inhibition of the production of TNF.How does it do this? From studies on the over production of mesangium within the kidney we have learned that HuR blocks the normal deterioration of the mMRNA responsible for making various proteins. ( Ethanol promotes HuR attachment to the mRNA of TNF . Yet NO diminishes the mRNA.)The normal diminution of TNF by IL6 for example, is prevented by increasing its production at the posttranscriptional level.Nevertheless there is an obligatory receptor necessary for TNF’s action. Without it there is no TNF action at the genome level. Blocking the receptor allows for blockage of action. The monoclonal antibody to TNF receptor is available now.

Etanol and cáncer

2009-02-03T05:49:00.000-08:00

Esto será un aviso oficioso referente a cualquier persona que personalmente o que tenga un pariente que esté muriendo de cáncer. Hay apenas una ...... Factor-Alfa implicada culpable de la necrosis del tumor. Como en el caso de la muerte en síndrome tóxico del choque el extremo es choque o derrumbamiento cardiovascular. Esto ocurre como consecuencia de volumen disminuido, de la presión oncótica (albúmina) o de la falta de bomba. Cuanto mayor es la cronicidad, cuanto mayor es la pérdida de albúmina, e integridad cardiovascular debido a mitocondrial disminuida al funcionamiento intercelular. El cuerpo en su asimilación preferencial de los aminoácidos esenciales para sintetizar TNF digiere literalmente otras fuentes de la proteína del no-tumor dentro del cuerpo. ¿El tumor digiere literalmente a otras partes del cuerpo en una supervivencia “inteligente” del más apto mientras que da vuelta casi por instinto apagado a la inhibición de regeneración de la producción de TNF.How él hace esto? De estudios en la producción excesiva de mesangium dentro del riñón hemos aprendido que HuR bloquea la deterioración normal del mMRNA responsable de hacer las varias proteínas. (El etanol promueve el accesorio de HuR al mRNA de TNF. Con todo NINGUÌN disminuye el mRNA.) la disminución normal de TNF por IL6 por ejemplo, es prevenido aumentando su producción en el nivel del posttranscriptional. Sin embargo hay un receptor obligatorio necesario para la acción de TNF. Sin ella no hay acción de TNF en el nivel del genoma. El bloqueo del receptor permite la obstrucción de la acción. El anticuerpo monoclonal al receptor de TNF está disponible ahora.

2009-02-02T18:59:00.001-08:00

Dieses ist eine nicht offizielle Ansage Betreffend jedermann, das persönlich oder, das hat ein Verwandter, der am Krebs stirbt. Es gibt gerade ein Angeklagter mit einbezogenes ...... Tumor-Nekrose Faktor-Alpha. Wie im Falle des Todes im giftigen Schlagsyndrom ist das Ende Schlag oder kardiovaskulärer Einsturz. Dieses tritt als Folge des verminderten Volumens, des oncotic Drucks (Albumin) oder des Pumpe Ausfalls auf. Das grösser die Beständigkeit, das grösser der Verlust des Albumins,und kardiovaskuläre Vollständigkeit passend zu vermindertem mitochondrischem zum interzellulären Arbeiten.Der Körper in seiner bevorzugten Assimilation der essenziellen Aminosäuren, zum von TNF zu synthetisieren verdaut buchstäblich andere Nichttumor Proteinquellen innerhalb des Körpers. Der Tumor verdaut buchstäblich andere Körperteile in einem „intelligenten“ Überleben vom passendsten, während er fast instinktiv die Rückgesprächhemmung der Produktion von TNF abstellt.Wie tut er dies? Von den Untersuchungen über die Überproduktion von mesangium innerhalb der Niere haben wir erfahren, dass HuR die normale Verschlechterung des mMRNA blockiert verantwortlich für die Herstellung der verschiedenen Proteine. (Äthanol fördert HuR Zubehör zu der mRNA von TNF. Dennoch KEIN vermindert den mRNA.)Die normale Verminderung von TNF durch IL6 zum Beispiel, wird verhindert, indem man seine Produktion auf dem posttranscriptional Niveau erhöht.Dennoch gibt es einen obligatorischen Empfänger, der für Tätigkeit TNFS notwendig ist. Ohne sie dortist keine TNF Tätigkeit auf dem Genomniveau. Das Blockieren des Empfängers lässt Blockierung der Tätigkeit zu. Der monoclonal Antikörper zum TNF Empfänger ist jetzt vorhanden. Seine Nebenwirkungen umfassen:

HERE ' TIS

2009-01-23T12:00:00.001-08:00

http://alonzopeters.blogspot.com/

Lethal Factor = MMP = Metaloproteinase

2009-01-23T11:33:00.000-08:00

Well there is absolutely no difference in MMPs that are pathologic and Lethal Factor of ANthrax fame. This 3D is of LF and where there is a will to eliminate suffering and dying from cancer and autoimmunue diseases there is a way.

Now that we know we can can busy at trying to back track from it as a PRION or other nuclearmaterial and diminish its half life by diminishing the HuR substance adherence. This we know.

Doxycycline can also act to diminish the 1/2 life of the mRNA of the MMP

2009-01-15T13:37:00.001-08:00

MMP

2009-01-15T12:54:00.000-08:00

The MMP pictured should say a thousand words. After offering this for free, anyone who is not a patient will have to pay

We used to study normal histology (study of tissues) and anatomy (study of structures within and without the body) in order to be able to recognize the abnormal. Well what Peters' Productions did was propose the normal Cytokine Cycle as well as offer a software to prove it up, so that pathology in immunology can be explained in context to the normal state.
We have since been providing more data to our artificially intelligent database called AMIE (advanced medical informatic education) to relate ALL DISEASE TO IMMUNOLOGY with the CYTOKINE CYCLE.
We are not funded , yet my best effort has been put forth to allow you the patient to have access to the data. This is what we hope for. It will be from the new data and cures that scholarships and rewards will come to the kids and their kids kids. ARE WE CLEAR?
He who began a good work in you shall be faithful to complete it!

Osteosarcoma Still no Joke 30 years later

2009-01-14T09:46:00.000-08:00

Years ago before I received my MD I had a 14 year old patient that had a profound effect on me. He had a disease that we could not cure. I recall speaking to the family about the possibility of recurrence of the osteosarcoma and it was particularly difficult because I had gone to high school with one of the brothers of the patient. In surgery we actually saw the tumor. Unfortunately I had to help give the bad news to the family. It had a very poor prognosis.
Fortunately at the North Medical Center we did not have a patient with this type of disease but we do have more insight as to what the pathology was
The following will be posted in his memory against this dreadful disease that killed him
In hopes of helping some FP out there that has a patient with it or for family members
who would like to know more about MMPs out of control. Let us just call it dedicated to
the Cusamo family which is an abbreviation of the actual name. The AMIE post will probably not make sense but email me at pete4doc@hotmail.com for information

or go to facebook.com

OSTEOSARCOMA/mmp

Am J Physiol Endocrinol Metab 277: E496-E504, 1999;

EPILOGUETriiodothyronine induces collagenase-3 and gelatinase B expression in murine osteoblasts
Renata C. Pereira1,3, Vanda Jorgetti3, and Ernesto Canalis1,2
1 Departments of Research and Medicine, Saint Francis Hospital and Medical Center, Hartford 06105; 2 University of Connecticut School of Medicine, Farmington, Connecticut 06030; and 3 Laboratorio de Fisiopatologia Renal, Universidade de Sao Paulo, Sao Paulo, Brazil 01246-903
Initiator
Prod / Activ
Prod / Activ
Jnl / Vol / Pg
Author / Yr
Misc / Vol / Ed
THYROID HORMONES
oSTEOBLASTIC PRODUCTION OF/ mmp/COLLAGENASES
bone MATRIX/EXOSKELETON
Am J Physiol Endocrinol Metab/ 277/E496-E504
Renata C. Pereira/Vanda Jorgetti/Ernesto Canalis/99
Selected effects of thyroid hormones on bone metabolism may be mediated by the production of local factors, and triiodothyronine (T3) enhances the synthesis of prostaglandin E2 and of insulin-like growth factor (IGF) I by skeletal cells (31, 55).

ABSTRACT

Triiodothyronine (T3) increases bone resorption, but its effects on matrix metalloprotease (MMP) expression in bone are unknown. We tested the effects of T3 on collagenase-3 and gelatinase A and B expression in MC3T3 osteoblastic cells. T3 at 1 nM to 1 µM for 24-72 h increased collagenase-3 and gelatinase B mRNA levels, but it did not increase gelatinase A transcripts. In addition, T3 increased immunoreactive collagenase and gelatinase activity. Cycloheximide prevented the stimulatory effect of T3 on collagenase-3 but not on gelatinase B transcripts. Indomethacin did not prevent the effect of T3 on either MMP. T3 did not alter the decay of collagenase-3 or gelatinase B mRNA in transcriptionally arrested MC3T3 cells, and it increased the rate of collagenase-3 and gelatinase B gene transcription. Although T3 enhanced the expression of the tissue inhibitor of metalloproteinase-1 in MC3T3 cells, it increased collagen degradation in cultured intact rat calvariae. In conclusion, T3 increases collagenase-3 and gelatinase B synthesis in osteoblasts by transcriptional mechanisms. This effect may contribute to the actions of T3 on bone matrix remodeling.
bone remodeling; thyroid hormone; metalloprotease; collagen degradation

INTRODUCTION

THYROID HORMONES have important effects on bone metabolism and enhance bone remodeling. Thyroid hormones increase bone resorption, although their major target cell in bone probably is a cell of the osteoblastic lineage (6, 45, 59, 65). In fact, the presence of osteoblasts is required to detect an increase in bone resorption (6). Thyroid hormones also increase the replication of cells of the osteoblastic lineage and suppress the differentiation of osteoprogenitor cells to osteoblasts (13, 29, 47). Selected effects of thyroid hormones on bone metabolism may be mediated by the production of local factors, and triiodothyronine (T3) enhances the synthesis of prostaglandin E2 and of insulin-like growth factor (IGF) I by skeletal cells (31, 55).
The administration of exogenous T3 to humans results in increased bone remodeling, and postmenopausal females exposed to thyroid hormone excess display decreased bone mineral density (BMD) of the spine and hip as well as of cortical bone (1, 25, 37, 61). Some studies have failed to demonstrate marked changes in BMD, and there appears to be a relationship between the dose of thyroid hormone administered and changes in BMD (4, 22, 23, 39, 61). In addition to changes in BMD, patients with hyperthyroidism have increased urinary excretion of pyridinoline cross-links, confirming the stimulatory actions of thyroid hormone on bone remodeling and suggesting an effect on collagen matrix breakdown (21, 24). This may cause a decrease in a collagen matrix available for mineralization, and in conjunction with an increase in bone resorption, it might explain the decrease in BMD observed in these patients. Although it is tempting to believe that the major actions of thyroid hormone are on bone resorption, its direct effects on bone matrix degradation have not been explored. Bone resorption is a process mediated by the osteoclast, whereas bone matrix degradation is a process mediated by the secretion of proteases by the osteoblast. However, the two processes are closely regulated, and agents that modify bone resorption frequently alter bone collagen degradation by changing the expression of matrix metalloproteinases (MMP) and their inhibitors (9, 48). Furthermore, collagenase, an MMP, appears to play an indirect role in bone resorption (26, 27). Consequently, T3 might alter bone collagen degradation and the expression of collagenase and related metalloproteases.
MMPs are a family of related proteolytic enzymes including collagenases, gelatinases, and stromelysins (19, 41, 42). Collagenases cleave fibrillar collagen at neutral pH and are considered important in matrix remodeling. Three collagenases have been described: collagenase-1, secreted by stimulated human fibroblasts and osteoblasts and by human chondrocytes from osteoarthritic cartilage; collagenase-2, secreted by neutrophils; and collagenase-3, secreted by human breast carcinoma cells, human chondrocytes, and rodent osteoblasts (19, 43, 38, 50, 52). Unstimulated normal human osteoblasts do not secrete detectable levels of collagenase, although human osteosarcoma cell lines synthesize collagenase, and normal human osteoblasts exposed to parathyroid hormone and selected cytokines express the protease (52). Normal rat osteoblasts and rat osteosarcoma cells express collagenase-3, but rodent cells do not express collagenase-1 (48, 50). Type II collagen is preferentially hydrolyzed by collagenase-3, and collagenases-1, -2, and -3 degrade fibrillar type I collagen with similar efficiency (32). Two gelatinases have been described: gelatinase A, a 72-kDa MMP secreted by multiple cell types; and gelatinase B, a 92-kDa MMP secreted by connective tissue cells, monocytes, and various tumor cells (42). Gelatinase A and B are also expressed by skeletal cells and are known to degrade elastin, collagens IV, V, VII, X, and XI, and additional minor components of the extracellular matrix (38, 42). Agents known to enhance bone resorption increase the synthesis of gelatinases by the osteoblast (33, 38). These observations suggest a role for collagenase-3 and gelatinases in connective tissue remodeling in the skeleton, and we postulated that T3 might regulate their expression in osteoblasts.
In the present study, we examined the actions of T3 on the expression of collagenase-3, gelatinase A and B, and on tissue inhibitors of MMPs (TIMP)-1, -2, and -3 in cultures of osteoblastic MC3T3 cells and determined possible consequences in cultures of intact rat calvariae.

MATERIALS AND METHODS
Culture models. MC3T3 cells, clonal mouse osteoblastic cells derived from newborn mouse calvariae, were plated at a density of 8,000-12,000 cells/cm2 and cultured in a humidified 5% CO2 incubator at 37°C until reaching confluence (~50,000 cells/cm2; Ref. 57). Cells were cultured in -modified Eagle's medium (Life Technologies, Grand Island, NY) supplemented with 10% fetal bovine serum (Summit Biotechnology, Fort Collins, CO). MC3T3 cells were grown to confluence, transferred to serum-free medium for 20 to 24 h, and exposed to test or control medium in the absence of serum for 2-72 h as indicated in the text and Figs. 1-11; 3,3',5'-triiodo-L-thyronine sodium salt (Sigma, St. Louis, MO) was added directly to the culture medium. Cycloheximide, 5,6-dichlorobenzimidazole riboside (DRB), and indomethacin (Sigma) were dissolved in ethanol and diluted 1:200 and 1:1,000, respectively, in -modified Eagle's medium. An equal amount of solvent was added to control cultures. In experiments lasting longer than 24 h, the culture medium was replaced with fresh solutions every 24 h. At the end of the incubation, the medium was harvested in the presence of 0.1% polyoxyethylenesorbitan monolaurate (Tween, Pierce, Rockford, IL) for Western blot analyses and in its absence for gelatin zymograms and then was stored at 80°C before analysis. The cell layer was extracted for RNA analysis and stored at 80°C, and nuclei were obtained by Dounce homogenization for nuclear run-on assays.
Cultures of intact rat parietal bones were used to determine changes on collagen degradation, because of the greater accumulation of collagenous protein in the matrix of intact bone than in that of monolayer cultures (54). Parietal bones were obtained from 22-day-old fetal rats immediately after the mothers were killed by blunt trauma to the nuchal area. The project was approved by the Institutional Animal Care and Use Committee of Saint Francis Hospital and Medical Center. Half-calvariae were cultured in flasks containing Biggers, Gwatkin, and Judak medium in the absence of serum. The flasks were gassed with 5% CO2, sealed and placed in a shaking water bath at 37°C for a 24-h period, and labeled with 5 µCi/ml of [2,3-3H]proline (specific activity of 40 Ci/mmol; Du Pont, Wilmington, DE). Bones were transferred to control or test medium in 10 mM proline for a 24- to 72-h "chase period." Calvariae and corresponding culture medium samples were obtained for [3H]hydroxyproline analysis (54).
Northern blot analysis. Total cellular RNA was isolated by RNeasy kit per instructions of the manufacturer (Qiagen, Chatsworth, CA). The RNA recovered was quantitated by spectrophotometry, and equal amounts of RNA from control or test samples were loaded on a formaldehyde-agarose gel after denaturation. The gel was stained with ethidium bromide to visualize RNA standards and ribosomal RNA, before and after transfer, documenting equal RNA loading of the samples. The RNA was blotted onto GeneScreen Plus charged nylon (Du Pont). Restriction fragments containing a 2.6-kb rat interstitial collagenase-3 cDNA (kindly provided by Cheryl Quinn, St. Louis, MO), a 1.1-kb human gelatinase A cDNA (American Type Culture Collection, Rockville, MD), a 1.4-kb murine gelatinase B cDNA (kindly provided by Ghislain Opdenakker, Leuven, Belgium), an 825-bp murine TIMP-1 cDNA, a 700-bp murine TIMP-2 cDNA, a 750-bp murine TIMP-3 cDNA (all TIMP cDNAs kindly provided by Dylan Edwards, Calgary, Alberta, Canada), and an 800-bp rat glyceraldehyde-3-phosphate dehydrogenase (GAPD) cDNA (kindly provided by Ray Wu, Ithaca, NY) were labeled with [ -32P]dCTP and [ -32P]dATP (specific activity of 3,000 Ci/mmol; Du Pont) with the random hexanucleotide primed second strand synthesis method (12, 14, 35, 36, 40, 50, 60). Hybridizations were carried out at 42°C for 16-72 h. Posthybridization washes were performed in 1× saline sodium citrate (SSC) at 65°C for collagenase-3 and TIMP-1, -2, and -3 cDNAs in 0.2× SSC at 65°C for gelatinase A and B and in 0.5× SSC at 65°C for GAPD cDNA. The bound radioactive material was visualized by autoradiography on Kodak X-AR5 or Biomax film (Eastman Kodak, Rochester, NY) or Du Pont reflection film employing intensifying screens. Relative hybridization levels were determined by densitometry. Northern analyses shown are representative of three or more cultures.
Nuclear run-on assay. To examine changes in the rate of transcription, nuclei were isolated by Dounce homogenization in a Tris buffer containing 0.5% Nonidet P-40. Nascent transcripts were labeled by incubation of nuclei in a reaction buffer containing 500 µM each of ATP, CTP, and guanidine triphosphate, 150 U of RNasin (Promega), and 250 µCi of [ -32P]uridine triphosphate (specific activity of 3,000 Ci/mmol; Du Pont; Ref. 3). RNA was isolated by treatment with DNase I and proteinase K, followed by phenol-chloroform extraction and ethanol precipitation. Linearized plasmid DNA containing ~1 µg of cDNA was immobilized onto GeneScreen Plus by slot blotting according to the directions of the manufacturer (Du Pont). The plasmid vector pUC18 (Life Technologies) was used as a control for nonspecific hybridization, and GAPD cDNA was used to estimate uniformity of radioactive counts applied to the membrane. Equal counts per minute of 32P-labeled RNA from each sample were hybridized to cDNAs with the same conditions as for Northern blot analysis and were visualized by autoradiography.
Western immunoblot analysis. Medium samples were fractionated by polyacrylamide gel electrophoresis with denaturing and nonreducing conditions and were transferred onto Immobilon P membranes (Millipore, Bedford, MA). After being blocked with 2% BSA, the membranes were exposed to a 1:1,000 dilution of rabbit antiserum raised against rat collagenase-3 (kindly provided by John Jeffrey, Albany, NY), previously characterized for specificity and immunoreactivity, followed by the addition of goat anti-rabbit IgG conjugated to horseradish peroxidase (28). The blots were washed and developed with a horseradish peroxidase chemiluminescence detection reagent (Du Pont), visualized by autoradiography on Du Pont reflection film employing reflection intensifying screens, and analyzed by densitometry. Data shown are representative of three cultures.
Gelatin zymogram. To assess gelatinase activity, aliquots of conditioned medium were mixed with sample buffer containing 2% sodium dodecyl sulfate. Samples were loaded on a 7.5% polyacrylamide gel containing 1 mg/ml of gelatin and fractionated by electrophoresis as described (33). The gels were incubated 1 h in 50 mM Tris · HCl, 5 mM CaCl2, and 1 µM ZnCl2 buffer (pH 7.5) containing 2.5% Triton X-100 (Sigma). Gels were incubated in the same buffer without Triton X-100 at 37°C overnight. Proteolytic activity was visualized by staining the gels with 0.1% Coomassie blue in 50% methanol and 20% acetic acid and destaining with 30% methanol and 1% formic acid. Data shown are representative of three cultures.
Collagen degradation assay. Calvariae were homogenized in 0.5 M acetic acid, and aliquots of the homogenate and the respective culture medium were hydrolyzed in vacuo in 6 N HCl at 107°C for 24 h. The samples were derivatized with phenylisothiocyanate, and [3H]proline and [3H]hydroxyproline were separated by reverse-phase HPLC with a C18 Nova-Pak column and an acetonitrile solvent system, as previously described (54). Although the method used to hydrolyze collagen from calvariae and medium samples may result in some destruction of hydroxyproline, this effect is minimal because it achieves nearly 100% recovery of hydroxyproline (54). [3H]hydroxyproline was measured in calvaria and medium samples by liquid scintillation counting.
Statistical methods. Data on collagenase-3 and gelatinase B mRNA and protease levels in MC3T3 cells and collagen degradation levels in calvaria are expressed as means ± SE. Statistical differences were calculated by ANOVA, and post hoc examination was performed by the Ryan-Einot-Gabriel-Welch F test (64). Data on collagenase-3 and gelatinase B mRNA decay were analyzed by linear regression, and the slopes of the regression lines obtained for control and treated cells were compared for significant differences with the method of Sokal and Rohlf (56).
Northern blot analysis of total RNA from MC3T3 cells revealed a collagenase-3 transcript of 2.9 kb (Fig. 1). Continuous treatment of MC3T3 cells with T3 at 10 nM caused a time-dependent increase in collagenase steady-state transcripts. No stimulation was observed after 2 or 6 h (not shown) of treatment with T3, whereas at 24 h collagenase-3 mRNA levels were increased by (means ± SE; n = 6) 2.8 ± 0.3-fold. The effects were maximal after 48 h and sustained for 72 h, when T3 increased collagenase transcripts by 9.8 ± 2.7- and 11.3 ± 0.8-fold, respectively (Fig. 1). The effect of T3 was dose dependent, and continued exposure of MC3T3 cells to T3 at 1-1,000 nM for 72 h increased collagenase transcripts by 3.7- to 11.3-fold (Fig. 2). T3 at 10 nM for 24, 48, or 72 h increased the levels of immunoreactive interstitial collagenase-3 in the culture medium of MC3T3 cells by (means ± SE; n = 3) 1.6 ± 0.3, 6.1 ± 1.1, and 4.5 ± 1.2, respectively (Fig. 3). Collagenase-3 was identified by comigration with a purified rat procollagenase-3 standard
The present investigation was undertaken to determine whether T3 regulates the expression of selected MMPs and TIMP-1, -2, and -3 in cultures of osteoblastic MC3T3 cells. T3 caused a time- and dose-dependent stimulation of collagenase-3 mRNA and protease levels. T3 also increased the expression of gelatinase B transcripts and activity without modifying gelatinase A mRNA levels. Although T3 increased TIMP-1 mRNA levels, the effect was modest in relation to the effect on MMPs, and T3 did not stimulate the expression of TIMP-2 or 3. Because TIMPs bind MMPs in a 1:1 stoichiometric fashion, our results suggest that the actions of the increased collagenase-3 and gelatinase B will remain unopposed by the limited expression of TIMPs in the bone microenvironment (32). This is further supported by the demonstration of an induction of active gelatinase B by T3, as detected by zymography. The stimulatory effect of T3 on collagenase and gelatinase B may be relevant to its stimulatory actions on bone resorption and probably explains the increase in bone collagen degradation observed in intact calvariae (27). However, it is important to note that this is a different model, and intact calvaraie contain not only osteoblasts but a mixed cell population and a structured matrix. Therefore, other factors in addition to the induction of collagenase-3 and gelatinase B may play a role in the collagen degradation induced by T3 in this model. The effect of T3 on collagenase transcripts was dependent on de novo protein synthesis, whereas that on gelatinase B was not, indicating that different mechanisms regulate the expression of the two MMPs by T3. Although T3 is known to induce prostaglandin E2 in osteoblasts and prostaglandins are known to enhance collagenase synthesis, we found that the stimulation of collagenase-3 and gelatinase B by T3 in MC3T3 cells was not dependent on prostaglandin synthesis (10, 31). This is in agreement with the actions of T3 on bone resorption, which can be independent of prostaglandin synthesis (31). T3 did not alter collagenase-3 or gelatinase B mRNA stability in transcriptionally arrested Ob cells but did increase the rate of transcription of the collagenase-3 and gelatinase B genes. These results indicate that T3 stimulates rat collagenase-3 and gelatinase B expression by transcriptional mechanisms. The effect of T3 on gelatinase B expression is not surprising because other agents known to induce collagenase-3 synthesis, such as interleukin-1 and -6, also increase gelatinase A or B production by skeletal cells (18, 38).
T3 induces the transcription of the collagenase-3 and gelatinase B gene in osteoblasts, but the gene sequences responsible for the effects have not been determined. In nonskeletal cells, T3 activation of other genes involves a T3 response element (TRE; Refs. 5, 30). The traditional half-site contains the sequence 5'-AGGTCA-3', although optimal binding of T3 receptors may require additional sequences and the formation of a heterodimeric and not of a homodimeric complex. Furthermore, retinoic acid receptor-binding motifs may play a role in T3-receptor binding (46). Examination of the human collagenase-3 gene revealed four TRE consensus sequences in the region of bp 1,550 to 590 (58). The sequence of the rat collagenase-3 gene is known from bp 456 to +62 and that of the murine gene is not known (51). It is possible that rodent collagenase-3 genes contain TREs in a location similar to that described for the human gene that are responsible for the transcriptional effects observed. However, the exact elements responsible for the T3 effects are not known. T3 receptors may also act by regulating activator protein-1 or -2 sequences, present in the collagenase-3 gene, as it has been reported for the activation and suppression of other genes (20, 49). Examination of the gelatinase B gene promoter reveals the presence of a TRE and activator protein-1 and -2 binding sequences, which might be responsible for the effect of T3 (53). Additional studies will be required to define the exact elements responsible for the induction of collagenase-3 and gelatinase B by T3.
The synthesis of collagenase-1 and -3 by human and rat osteoblasts is regulated by systemic hormones and by cytokines present in the bone microenvironment. Consequently, the apparent constitutive level of collagenase expression by the osteoblast is in fine balance and depends on the exposure of the cell to factors that stimulate and factors that inhibit collagenase synthesis (7, 10, 11, 17, 48, 58, 62, 63). It is possible that T3 interacts with other cytokines, such as interleukin-1 or -6, to enhance collagenase-3 expression as it has been reported for the effects of T3 on bone resorption (59). Because the effect of T3 on MMP expression is slow in onset, we tested whether or not T3 induced the expression of local factors known to stimulate collagenase expression in osteoblasts. Treatment of MC3T3 cells with T3 at 10 nM for 2-72 h did not increase the expression of platelet-derived growth factor BB, fibroblast growth factor 2, IL-1, or IL-6, all known stimulators of collagenase-3 expression (Pereira and Canalis, unpublished observations; Refs. 10, 17, 33, 62, 63). The stimulatory effect of T3 on bone resorption requires the presence of osteoblasts and depends on receptors expressed by osteoblastic cells (6, 65). Consequently, it is not surprising that T3 regulates MMP expression in osteoblasts. T3 was tested at concentrations of 1 nM and higher because previous studies from other investigators revealed that T3 was not effective in cultures of intact calvariae, long bones, and cells of the osteoblastic lineage at lower doses (31, 45, 47, 49). It is possible that under the conditions used in these experiments, concentrations lower than 1 nM could have been effective, although they were not tested. The effects of T3 on MMP expression reported here were observed at 1 nM, and this concentration is ~200-fold higher than the concentrations of free T3 found in the serum of normal humans and 50- to 100-fold higher than the concentrations found in patients with hyperthyroidism (34). The effect of T3 on collagenase and gelatinase expression reported here probably explains the increase in bone collagen degradation that we observed in rat calvariae and may be relevant to its stimulatory actions on bone resorption reported previously (6, 45, 59). It may also explain the increased bone remodeling and increased urinary excretion of collagen cross-links in vivo after thyroid hormone administration and be important in the pathogenesis of the osteopenia after thyroid hormone excess (4, 21, 24). The actions of T3 on MMP expression could have additional effects in bone metabolism because collagenase was recently implied in the fragmentation of IGF-binding protein-5, a binding protein with known stimulatory effects on bone formation (2, 14, 15, 16). Although the activity of these fragments remains to be defined, their appearance in conjunction with an increase in IGF-I might be relevant to selected anabolic actions of T3 in the skeleton (29, 55).
In conclusion, the present studies demonstrate that T3 increases collagenase-3 and gelatinase B expression in osteoblasts by transcriptional mechanisms. It is probable that these effects play a role in the degradation of the collagen matrix and in the osteopenia observed in conditions of thyroid hormone excess.

ACKNOWLEDGEMENTS
We thank Dr. Cheryl Quinn for the rat collagenase cDNA, Dr. Ghislain Opdenakker for the murine gelatinase B cDNA, Dr. Dylan Edwards for the murine TIMP-1, -2 and -3 cDNAs, Dr. Ray Wu for GAPD cDNA, and Dr. John Jeffrey for the rat interstitial collagenase antibody. We also thank Cathy Boucher, Deena Durant, and Sheila Rydziel for technical assistance and Charlene Gobeli and Margaret Nagle for secretarial help.

FOOTNOTES
This work was supported by Grant AR-21707 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Renata C. Pereira is a recipient of a Fundaç o Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Student Fellowship Grant from the Universidade de Sao Paulo.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: E. Canalis, Dept. of Research, Saint Francis Hospital and Medical Center, 114 Woodland St., Hartford, CT 06105-1299.
Received 12 February 1999; accepted in final form 29 April 1999.

REFERENCES
TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES
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Sanchez, R. Blasco, J. Tolivia, and C. Lopez-Otin. Molecular cloning and expression of collagenase 3, a novel human matrix metalloproteinase produced by breast carcinomas. J. Biol. Chem. 269: 16766-16773, 1994[Abstract/Free Full Text].20. French, R. P., D. Warshawsky, L. Tybor, N. D. Mylniczenko, and L. Miller. Upregulation of AP-2 in the skin of Xenopus laevis during thyroid hormone-induced metamorphosis. Dev. Genet. 15: 356-365, 1994[Medline].21. Garnero, P., V. Vassy, A. Bertholin, J. P. Riou, and P. D. Delmas. Markers of bone turnover in hyperthyroidism and the effects of treatment. J. Clin. Endocrinol. Metab. 78: 955-959, 1994[Abstract].22. Grant, D. J., J. E. McMurdo, P. A. Mole, C. R. Paterson, and R. R. Davies. Suppressed TSH levels secondary to thyroxine replacement therapy are not associated with osteoporosis. Clin. Endocrinol. (Oxf.) 39: 529-533, 1993[Medline].23. Guo, C. Y., A. P. Weetman, and R. Eastell. Longitudinal changes of bone mineral density and bone turnover in postmenopausal women on thyroxine. Clin. Endocrinol. (Oxf.) 46: 301-307, 1997[Medline].24. Harvey, R. D., K. C. McHardy, I. W. Reid, F. Paterson, P. D. Bewsher, A. Duncan, and S. P. Robins. Measurement of bone collagen degradation in hyperthyroidism and during thyroxine replacement therapy using pyridinium cross-links as specific urinary markers. J. Clin. Endocrinol. Metab. 72: 1189-1194, 1991[Abstract].25. Hasling, C., E. R. Eriksen, P. Charles, and L. Mosekilde. Exogenous triiodothyronine activates bone remodeling. Bone 8: 65-69, 1987[Medline].26. Hill, P. A., A. J. P. Docherty, K. M. K. Bottomley, J. P. O'Connell, J. R. Murphy, J. J. Reynolds, and M. C. Meikle. Inhibition of bone resorption in vitro by selective inhibitors of gelatinase and collagenase. Biochem. J. 308: 167-175, 1995.27. Holliday, L. S., H. G. Welgus, C. J. Fliszar, G. M. Veith, J. J. Jeffrey, and S. L. Gluck. Initiation of osteoclast bone resorption by interstitial collagenase. J. Biol. Chem. 272: 22053-22058, 1997[Abstract/Free Full Text].28. Jeffrey, J. J., W. T. Roswit, and L. S. Ehlich. Regulation of collagenase production by steroids in uterine smooth muscle cells: an enzymatic and immunologic study. J. Cell. Physiol. 143: 396-403, 1990[Medline].29. Kassem, M., L. Mosekilde, and E. F. Eriksen. Effects of triiodothyronine on DNA synthesis and differentiation markers of normal human osteoblast-like cells in vitro. Biochem. Mol. Biol. Int. 30: 779-788, 1993[Medline].30. Katz, R. W., and R. J. Koenig. Nucleotide substitutions differentially affect direct repeat and palindromic thyroid hormone response elements. J. Biol. Chem. 269: 9500-9505, 1994[Abstract/Free Full Text].31. Kawaguchi, H., C. C. Pilbeam, F. N. Woodiel, and L. G. Raisz. Comparison of the effects of 3,5,3'-triiodothyroacetic acid and triiodothyronine on bone resorption in cultured fetal rat long bones and neonatal mouse calvariae. J. Bone Miner. Res. 9: 247-253, 1994[Medline].32. Knauper, V., C. Lopez-Otin, B. Smith, G. Knight, and G. Murphy. Biochemical characterization of human collagenase-3. J. Biol. Chem. 271: 1544-1550, 1996[Abstract/Free Full Text].33. Kusano, K., C. Miyaura, M. Inada, T. Tamura, A. Ito, H. H. Nagase, K. Kamoi, and T. Suda. Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. Endocrinology 139: 1338-1345, 1998[Abstract/Free Full Text].34. Larsen, P. R., J. E. Silva, and M. M. Kaplan. Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications. Endocr. Rev. 2: 87-102, 1981[Medline].35. Leco, K. J., L. J. Hayden, R. R. Sharma, H. Rocheleau, A. H. Greenberg, and D. R. Edwards. Differential regulation of TIMP-1 and TIMP-2 mRNA expression in normal and Ha-ras-transformed murine fibroblasts. Gene 117: 209-217, 1992[Medline].36. Leco, K. J., R. Khokha, N. Pavloff, S. P. Hawkes, and D. R. Edwards. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J. Biol. Chem. 269: 9352-9360, 1994[Abstract/Free Full Text].37. Lehmke, J., U. Bogner, D. Felsenberg, H. Peters, and H. Schleusener. Determination of bone mineral density by quantitative computed tomography and single photon absorptiometry in subclinical hyperthyroidism: a risk of early osteopaenia in post-menopausal women. Clin. Endocrinol. (Oxf.) 36: 511-517, 1992[Medline].38. Lorenzo, J. A., C. C. Pilbeam, J. F. Kalinowsk, and M. S. Hibbs. Production of both 92- and 72-kDa gelatinases by bone cells. Matrix 12: 282-290, 1992[Medline].39. Marcocci, C., F. Golia, G. Bruno-Bossio, E. Vignali, and A. Pinchera. Carefully monitored levothyroxine suppressive therapy is not associated with bone loss in premenopausal women. J. Clin. Endocrinol. Metab. 78: 818-823, 1994[Abstract].40. Masure, S., G. Nys, P. Fiten, J. Van Damme, and G. Opdenakker. Mouse gelatinase B. cDNA cloning, regulation of expression and glycosylation in WEHI-3 macrophages and gene organisation. Eur. J. Biochem. 218: 129-141, 1993[Medline].41. Matrisian, L. M., and B. L. M. Hogan. Growth factor regulated proteases and extracellular matrix remodeling during mammalian development. Curr. Top. Dev. Biol. 24: 219-259, 1990[Medline].42. Mauviel, A. Cytokine regulation of metalloproteinase expression. J. Cell. Biochem. 53: 288-295, 1993[Medline].43. Mitchell, P. G., H. A. Magna, L. M. Reeves, L. L. Lopresti-Morrow, P. J. Rosner, K. F. Geoghegan, and J. E. Hambor. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J. Clin. Invest. 97: 761-768, 1996[Medline].44. Morodomi, T., Y. Ogata, Y. Sasaguri, M. Morimatsu, and H. Nagase. Purification and characterization of matrix metalloproteinase 9 from U937 monocytic leukaemia and HT1080 firbrosarcoma cells. Biochem. J. 285: 603-611, 1992.45. Mundy, G. R., J. L. Shapiro, J. G. Bandelin, E. M. Canalis, and L. G. Raisz. Direct stimulation of bone resorption by thyroid hormones. J. Clin. Invest. 58: 529-534, 1976.46. Muscat, G. E., L. Mynett-Johnson, D. Dowhan, M. Downes, and R. Griggs. Activation of myoD gene transcription by 3,5,3'-triiodo-L-thyronine: a direct role for the thyroid hormone and retinoid X receptors. Nucleic Acids Res. 22: 583-591, 1994[Abstract/Free Full Text].47. Ohishi, K., H. Ishida, T. Nagata, N. Yamauchi, C. Tsurumi, S. Nishikawa, and Y. Wakano. Thyroid hormone suppresses the differentiation of osteoprogenitor cells to osteoblasts, but enhances functional activities of mature osteoblasts in cultured rat calvaria cells. J. Cell. Physiol. 161: 544-552, 1994[Medline].48. Partridge, N. C., J. J. Jeffrey, L. S. Ehlich, S. L. Teitelbaum, C. Fliszar, H. G. Welgus, and A. J. Kahn. Hormonal regulation of the production of collagenase and a collagenase inhibitor activity by rat osteogenic sarcoma cells. Endocrinology 120: 1956-1962, 1987[Abstract].49. Pernasetti, F., L. Caccavelli, C. Van de Weerdt, J. A. Martial, and M. Muller. Thyroid hormone inhibits the human prolactin gene promoter by interfering with activating protein-1 and estrogen stimulations. Mol. Endocrinol. 11: 986-996, 1997[Abstract/Free Full Text].50. Quinn, C. O., D. K. Scott, C. E. Brinckerhoff, L. M. Matrisian, J. J. Jeffrey, and N. C. Partridge. Rat collagenase. Cloning, amino acid sequence comparison, and parathyroid hormone regulation in osteoblastic cells. J. Biol. Chem. 265: 22342-22347, 1990[Abstract/Free Full Text].51. Rajakumar, R. A., and C. O. Quinn. Parathyroid hormone induction of rat interstitial collagenase mRNA in osteosarcoma cells is mediated through an AP-1-binding site. Mol. Endocrinol. 10: 867-878, 1996[Abstract].52. Rifas, L., A. Fausto, M. J. Scott, L. V. Avioli, and H. G. Welgus. Expression of metalloproteinases and tissue inhibitors of metalloproteinases in human osteoblast-like cells: differentiation is associated with repression of metalloproteinase biosynthesis. Endocrinology 134: 213-221, 1994[Abstract].53. Roach, J., S. J. Choi, R. L. Schaub, R. J. Leach, G. D. Roodman, and S. V. Reddy. Further characterization of the murine collagenase (type IVB) gene promoter and analysis of mRNA expression in murine tissues. Gene 208: 117-122, 1998[Medline].54. Rydziel, S., and E. Canalis. Analysis of hydroxyproline by high performance liquid chromatography and its application to collagen turnover studies in bone cultures. Calcif. Tissue Int. 44: 421-424, 1989[Medline].55. Schmid, C., I. Schlapfer, E. Futo, M. Waldvogel, J. Schwander, J. Zapf, and E. R. Froesch. Triiodothyronine (T3) stimulates insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-2 production by rat osteoblasts in vitro. Acta Endocrinol. 126: 467-473, 1992.56. Sudo, H., H.-A. Kodama, Y. Amagai, S. Yamamoto, and S. Kasai. In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria. J. Cell Biol. 96: 191-198, 1983.58. Tardif, G., J.-P. Pelletier, M. Dupuis, J. E. Hambor, and J. Martel-Pelletier. Cloning, sequencing, and characterization of the 5'-flanking region of the human collagenase-3 gene. Biochem. J. 323: 13-16, 1997.59. Tarjan, G., and P. H. Stern. Triiodothyronine potentiates the stimulatory effects of interleukin-1 beta on bone resorption and medium interleukin-6 content in fetal rat limb bone cultures. J. Bone Miner. Res. 10: 1321-1326, 1995[Medline].60. Tso, J. Y., X. H. Sun, T.-H. Kao, K. S. Reece, and R. Wu. Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. Nucleic Acids Res. 13: 2485-2502, 1985[Abstract/Free Full Text].61. Uzzan, B., J. Campos, M. Cucherat, P. Nony, J. P. Boissel, and G. Y. Perrett. Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J. Clin. Endocrinol. Metab. 81: 4278-4289, 1996[Abstract].62. Varghese, S., A. M. Delany, L. Liang, B. Gabbitas, J. J. Jeffrey, and E. Canalis. Transcriptional and posttranscriptional regulation of interstitial collagenase by platelet-derived growth factor BB in bone cell cultures. Endocrinology 137: 431-437, 1996[Abstract].63. Varghese, S., M. L. Ramsby, J. J. Jeffrey, and E. Canalis. Basic fibroblast growth factor stimulates expression of interstitial collagenase and inhibitors of metalloproteinases in rat bone cells. Endocrinology 136: 2156-2162, 1995[Abstract].64. Wall, F. J. 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Is FP dying? H-- NO!

2009-01-14T07:47:00.000-08:00

IN BEHALF OF FAMILY PRACTICE

We have discussed the fact that experiments have shown that the cytokine cycle and MMPs (matrix metaloproteinases) are involved with a myriad of life process pathology such as cell division to metastatic cancer, normal fast conduction nerve fiber with Nodes of Ranvier to myelin sheath loss and dysfunctional nerve conduction seen in MS, and normal renal function to post impetigo glomerulonephritis with renal dysfunction. The normal blood elements/function to clotting seen in myocardial infarctions (acute cardiac syndrome) and strokes also involve a normal MMP and cytokine cycle seen in the nascent immunologic state to ones that have gone awry . This is seen in strokes and heart attacks and other clotting states. A dysfunctional cytokine cycle seen with the inflammatory cytokines IL1, TNF-alpha an IL6 constitute a 3 man team that if unchecked by itself can lead to clotting disorders.

Yet the normal MMP function (specifically remodeling) could be involved in pathologic processes when the process of remodeling goes unchecked. These processes include MS which is a type of “dysfunctional modeling” involved in autoimmune processes. Today we will explore the question. Can you have a normal cytokine cycle and a purely dysfunctional MMP ? I believe the answer is no. This therefore allows for the possibility of cytokine abnormalities as tumor, MI, stroke and autoimmune disorders’
MARKERS with MMP abnormalities being late markers of disease .

This brings up investment opportunities in cytokine measurement and the possibility that the trained the Family Practitioner will again be the best observer in love for these diseases prior to their needing hospitalization and emergency room visits.

MS and Kidney disease ...... Hope

2009-01-13T21:16:00.000-08:00

The following articles/diseases described have something in common...MMP-9

MMP-9 is stabilized by cytokines named IL1 and TNF which are also deemed "inflammatory". They work by promoting a substance called HuR which stabilizes m and t-RNA for MMP.

It appears that IFN has a positive effect in diminishing TNF but the jury is still out on which one (in humans Beta or Gamma).

The hope and take home message is that MMP-9 if diminished will diminish digestion of good kidney mesangial cells and myelin sheaths. Hence we can hope for cures of these dreadful diseases which are more specific.

There also appears to be a tremendous degree of intelligence if you will of the actions of these

actions to hint at their turning on of substances that allow for the proliferation or metastasis

of the original rebellious cell.

Cytokine-mediated modulation of MMPs and TIMPs in multipotential neural precursor cells . Journal of Neuroimmunology , Volume 175 , Issue 1 - 2 , Pages 12 - 18 T . Ben-Hur , Y . Ben-Yosef , R . Mizrachi-Kol , O . Ben-Menachem , A . Miller

Recent studies have implicated the inflammatory process during experimental allergic encephalomyelitis (EAE) in triggering migration and differentiation of transplanted neural precursors cells (NPCs) into the inflamed white matter. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ are key factors in the pathogenesis of brain inflammation in EAE and were shown to enhance NPCs migration in vitro. As cell migration is dependent on extracellular matrix remodeling, involving proteolytic enzyme members of the matrix metalloproteinase (MMPs) family, we characterized the profile of expression of MMPs and their endogenous inhibitors (TIMPs) in rat NPCs, and evaluated the effects of TNF-α, IFN-γ and IFN-β, a clinically proven modulator of brain inflammation, on the expression of these molecules. Newborn rat striatal NPCs were expanded in spheres as nestin+, PSA-NCAM+ and NG2(−) cells, which can differentiate into astrocytes, oligodendrocytes and neurons. NPCs' gelatinase activities of MMP-2 and MMP-9, as determined by zymography, were increased by TNF-α, and to a lesser extent by IFN-γ. Semi-quantitative RT-PCR indicated that TNF-α also upregulated MMP-9 mRNA levels. IFN-β suppressed the TNF-α-induced levels of secreted MMP-9 and MMP-2, while enhancing the expression of TIMP-1 and TIMP-2 mRNA. These results suggest that MMPs activity is induced in NPCs by pro-inflammatory cytokines to mobilize them for promoting reparative processes. IFN-β, on the other hand, appears to have an anti-proteolytic influence that may attenuate such NPC-mediated repair processes.

http://images.google.com/imgres?imgurl=http://www.siumed.edu/~dking2/crr/images/corp5.jpg&imgrefurl=http://www.siumed.edu/~dking2/crr/rnguide.htm&usg=__lA5fcKvFlHGxQBzujMCR0IWfgbE=&h=279&w=350&sz=46&hl=en&start=18&tbnid=re-4xCa0d-9FcM:&tbnh=96&tbnw=120&prev=/images%3Fq%3Drenal%2Bmesangial%2Bcells%26gbv%3D2%26hl%3Den%26sa%3DX

JBiol Chem. 2003 Dec 19;278(51):51758-69. Epub 2003 Oct
ATP potentiates interleukin-1 beta-induced MMP-9 expression in mesangial cells via recruitment of the ELAV protein HuR.
Huwiler A, Akool el-S, Aschrafi A, Hamada FM, Pfeilschifter J, Eberhardt W.
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, D-60590 Frankfurt am Main, Germany.
Renal mesangial cells express high levels of matrix metalloproteinase 9 (MMP-9) in response to inflammatory cytokines such as interleukin (IL)-1 beta. We demonstrate here that the stable ATP analog adenosine 5'-O-(thiotriphosphate) (ATP gamma S) potently amplifies the cytokine-induced gelatinolytic content of mesangial cells mainly by an increase in the MMP-9 steady-state mRNA level. A Luciferase reporter gene containing 1.3 kb of the MMP-9 5'-promoter region showed weak responses to ATP gamma S but conferred a strong ATP-dependent increase in Luciferase activity when under the additional control of the 3'-untranslated region of MMP-9. By in vitro degradation assay and actinomycin D experiments we found that ATP gamma S potently delayed the decay of MMP-9 mRNA. Gel-shift and supershift assays demonstrated that three AU-rich elements (AREs) present in the 3'-untranslated region of MMP-9 are constitutively bound by complexes containing the mRNA stabilizing factor HuR. The RNA binding of these complexes was markedly increased by ATP gamma S. Mutation of each ARE element strongly impaired the RNA binding of the HuR containing complexes. Reporter gene assays revealed that mutation of one ARE did not affect the stimulatory effects by ATP gamma S, but mutation of all three ARE motifs caused a loss of ATP-dependent increase in luciferase activity without affecting IL-1 beta-inducibility. By confocal microscopy we demonstrate that ATP gamma S increased the nucleo cytoplasmic shuttling of HuR and caused an increase in the cytosolic HuR level as shown by cell fractionation experiments. Together, our results indicate that the amplification of MMP-9 expression by extracellular ATP is triggered through mechanisms that likely involve a HuR-dependent rise in MMP-9 mRNA stability.

CIA ....Director??

2008-11-26T08:02:00.000-08:00

Exerted from article by Michael Isikoff and Mark Hosenball from MSN News

The abrupt withdrawal of John Brennan as a candidate to be CIA director could complicate Barack Obama's efforts to assemble a national security team untainted by past policies of the Bush administration. It is also a potential signal of more battles on the intelligence front in the weeks ahead, since many of the other names that have been prominently mentioned for CIA director or director of National Intelligence have their own ties to the intelligence community that include carrying out controversial policies under President Bush.
Brennan, a 25-year intelligence-community veteran, had been a top adviser to Obama on intelligence issues during the campaign and served as a leader of the Obama transition team for the intelligence community. "He was our guy on intelligence," one top Obama adviser told NEWSWEEK (who like all Obama advisors asked not to be identified speaking about personnel matters.) But Brennan made his surprise decision to pull his name from the CIA search after getting pummeled over the past few days by liberal critics for his alleged role in the use of abusive interrogation techniques against high-value Al Qaeda targets during a period he served as a top CIA official under George Tenet.
The irony is that though Brennan would have been a participant in some of the discussions over U.S. interrogation policy, he was never a decision-maker on such issues. Indeed, he insisted in a stinging public retort today that it has been "immaterial to the critics" that he had actually been a "strong opponent of many of the policies of the Bush administration such as the pre-emptive war in Iraq, and coercive interrogation tactics, to include waterboarding." Still, Brennan wrote in his letter to President-elect Obama (and released by the transition staff) that he did not want the issue of his role in Bush administration policies to be a "distraction" and therefore wanted to withdraw from consideration as CIA director.

Sentenced. Still count it all joy!

2008-11-26T05:18:00.000-08:00

Sentenced. Still count it all joy!
I with much joy report to you that I have been sentenced . I KNOW IT SOUNDS CRAZY in the words of Lionel Richey. I originally pled guilty to one count of 54 "evils" that I was accused, namely money laundering. Then I discovered perjury on the part of Ray Taylor and Sam Searcy comparing the testimony of Officer Sandra Kitchen in sworn affidavits from the Poindextor trial, to the statements by Ray Taylor in my original Search warrant issued by Calvin Botley. Was this imagination on my part? There was much malicious pre-trial publicity obviating a jury trial. I tried to withdraw my plea. I was refused. At that point that I thought I would get mercy, instead I got the book thrown at me, without possibility of appeal, or a jury to hear the aforementioned. Still I count it all joy!

I unknowingly blacked the eye as an individual medical practitioner to those DEA and CIA controlled elements who with their agents sell drugs in the poor Houston community, and run prostitution. This was inadvertent professional abuse of my granted license whether knowing or not. I take responsibility for creating a system of trust and trusting the wrong people. I take responsibility for attempting to justify an ends with a means through practicing pain management. My ostentatious behavior is what my enemy used against me as would any corporate attack. I was of no CORPORATE SOCIAL CAPITAL value to them and probably no more good to myself , as an x-slave bent on good medical care and freedom BY ANY MEANS NECESSARY.

The ostentatious emulating of CEO behavior involved my selfish behavior in purchases of assets made me a more attractive parent to the selfishness of my children and other's children. My enemy realized that I had become a direct threat by being a father based controlled parenting structure of daughters and sons of prostitutes. Yet according to Proverbs 31, Deuteronomy 17:17 as a king I should have avoided anything that would pervert MY RELATIONSHIP WITH JESUS CHRIST, including taking on of many wives and being involved with the consumption of alcohol. I did not avoid those distracting elements including being filled by alcohol spirits, and continued to be seduced by a theory of giving as more important than a RELATIONSHIP with JESUS CHRIST . Others convicted did the same thing and their giving was questioned. In turning my head toward evil I was no better than the CEOs of Enron who put overcapitalization ahead of the goal of taking care of more people. (In my case taking care of more patients cheaper than the government.) Still I count it all joy!

If I had known my enemy, I would not have brought a pencil to a computer WAR. This war was generated by false testimony of 1. My terrible record keeping and practice type 2 a DEA agent/ex-communicated patient in obtaining a serach warrant from Brentwood Baptist's Calvin Botley 3. a Texas Board of Medical Examiners Board Liason working with him and 4. a National Database that was never questioned by my oh- so-polite to prosecution and task force people .

I would not have fought a war at all by myself. The Battle was AND IS and will be the Lord's . In lieu of the multitude of precedents of collusion on the part of the ruling class of elite Blacks in Houston caring less for the Black poor community and even less for poor Hispanics that were patients in my practice, I do not find it so difficult as a revolutionary thinker and doer to be ready to report to a federal penal institution. I never fit. Yet my ministereal activity should have allowed for some protection of NON-Profit Corporate assets as to their forfeiture. Is this what we have been attacked for? Ministereral/charitable assets, vs sophisticated laundering? I bet I did more for the poor per capita than MD Anderson and Methodist and St. Lukes combined. I would bet my freedom on that, yet no one has attacked their assets and overcapitalization. Could the legal profession have anything to do with this disparity? Have they ever supported a disparity? Even if I did have some master evil plan concocted to money launder from the outset, should the assets forfeited go to the Justice Dept. /DEA or to the COMMUNITY?

The answer lies upon the tongue of the receiver.

Still I count it all joy! It is not an vain imagination that our bilingual practice at North Medical Center took care of more patients and did it for less money billed to the US, including the very ill with fevers, Herpes encephalitis , pneumonias, mental illness, pain, drug addiction, fractures, pregnancy in an outpatient setting many times, when considering that it was just me and my staff who I still love. Thank you Lourdes, Suey, Yolonda, and Mrs. Plunkett and Tav.

Were the medical establishment, DEA, CIA prostitutes, crack salesmen mad? Heck yes ! I am sorry. We by accident became their competitors by removing their client base and then seeing them flip the script on us which is typical of espionage. I assure you that money laundering and over-prescibing were not the intent of North Medical Center from the outset. I would have gone back to a good salary in Dallas were that the case and avoided this mess. This conduct was was not done on purpose . It is with no bitterness that I still say, thanks. I continue to pray for God's grace. I therefore again wish to count it all joy. GOD IS STILL IN CONTROL. I am 3 going to 33 years sober! I say the serenity prayer, especially THANKFUL during this season for the wisdom to know the difference.

I am going to mind my own business and let Him show His power in ways that I would not have imagined. In the immediate sense all strength and activity will go to 1. Children 2. AMIE (advanced medical/or miscellaneous informatics/ intelligence/information EDUCATION) 3. Gazz (Gospel Lyric straight ahead Jazz music) and last but not least 4. Bibleboost , our daily life coach suggestion until I report for duty otherwise. Thank you, and an explanation of any of this is available through your phone or internet connection.

Input vs. Putting IN

2008-07-07T11:25:00.000-07:00

We continue to offer an informatic database that will be the greatest thing since hotcakes after the tweaks have been made . Thank you for you input. everyone will be putting in more as time goes by.

2008-07-07T11:22:00.001-07:00

2008-01-14T10:58:00.000-08:00

Initiator Prod / Activ Prod / Activ Jnl / Vol / Pg Author / Yr Misc / Vol / Ed

ang II sr induced /ca+2 release/Ca+2 cytosolic accessibility/afferent arteriole/ contraction relaxation of smooth muscle/sr making /Ca+2 accessible Am J Physiol Renal Physiol /294/F212-F219, Susan K. Fellner/William J. Arendshorst/08 with ryanodine (100 µM) and TMB-8 to block SR mobilization via the ryanodine receptor and inositol trisphosphate receptor, respectively

Initiator Prod / Activ Prod / Activ Jnl / Vol / Pg Author / Yr Misc / Vol / Ed Functions

Hope in dietary change for cures !!!

2008-01-14T10:53:00.000-08:00

Since it is utterly impossible for me to see you in person I must continue to offer you information from our invention and allow it to assimilate and integrate data from the internet into pallatable pieces.
Here is the latest AMIE
Advanced Medical Informatics Education
Entry for the day 01-14-08

Initiator Prod / Activ Prod / Activ Jnl / Vol / Pg Author / Yr Misc / Vol / Ed

ang II sr induced /ca+2 release/Ca+2 cytosolic accessibility/afferent arteriole/ contraction relaxation of smooth muscle/sr making /Ca+2 accessible Am J Physiol Renal Physiol /294/F212-F219, Susan K. Fellner/William J. Arendshorst/08 with ryanodine (100 µM) and TMB-8 to block SR mobilization via the ryanodine receptor and inositol trisphosphate receptor, respectively

Initiator Prod / Activ Prod / Activ Jnl / Vol / Pg Author / Yr Misc / Vol / Ed Functions

Abbreviation Abb_Known_As
SR Spiritual Realm
ensrd end stage reneal disease/component of SLE
psr phtotosensitive rash
src self reactive cells/MS path at cyte of myelin sheath
SRS/Robotic/term self reconfigurable system/
SRS/Robotic/term self reconfigurable system/Mtrain II/c 2 /DOF
ang II/SR angiotensin II/ see sarcoplasmic reticulum /Ca+2 involvement
Angiotensin II-stimulated Ca2+ entry mechanisms in afferent arterioles: role of transient receptor potential canonical channels and reverse Na+/Ca2+ exchange
Susan K. Fellner and William J. Arendshorst
Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Submitted 25 May 2007 ; accepted in final form 26 October 2007
In afferent arterioles, the signaling events that lead to an increase in cytosolic Ca2+ concentration ([Ca2+]i) and initiation of vascular contraction are increasingly being delineated. We have recently studied angiotensin II (ANG II)-mediated effects on sarcoplasmic reticulum (SR) mobilization of Ca2+ and the role of superoxide and cyclic adenosine diphosphoribose in these processes. In the current study we investigated the participation of transient receptor potential canonical channels (TRPC) and a Na+/Ca2+ exchanger (NCX) in Ca2+ entry mechanisms. Afferent arterioles, isolated with the magnetized polystyrene bead method, were loaded with fura-2 to measure [Ca2+]i ratiometrically. We observed that the Ca2+-dependent chloride channel blocker niflumic acid (10 and 50 µ M) affects neither the peak nor plateau [Ca2+]i response to ANG II. Arterioles were pretreated with ryanodine (100 µM) and TMB-8 to block SR mobilization via the ryanodine receptor and inositol trisphosphate receptor, respectively. The peak [Ca2+]i response to ANG II was reduced by 40%. Addition of 2-aminoethoxydiphenyl borane to block TRPC-mediated Ca2+ entry inhibited the peak [Ca2+]i ANG II response by 80% and the plateau by 74%. Flufenamic acid (FFA; 50 µM), which stimulates TRPC6, caused a sustained increase of [Ca2+]i of 146 nM. This response was unaffected by diltiazem or nifedipine. KB-R7943 (at the low concentration of 10 µM) inhibits reverse (but not forward) mode NCX. KB-R7943 decreased the peak [Ca2+]i response to ANG II by 48% and to FFA by 38%. We conclude that TRPC6 and reverse-mode NCX may be important Ca2+ entry pathways in afferent arterioles. renal microcirculation; voltage-gated calcium entry; vascular smooth muscle cell
Initiator Prod / Activ Prod / Activ Jnl / Vol / Pg Author / Yr Misc / Vol / Ed

scle cns/renal normality/vasculiti skin lesions/malar rash nephrotic syndrome/esrd/cns activity Harrison 14th/ Vol 2/1875 Hahn,bh/90

War on Drugs = Slander through the internet and obviation of right to fair trial by jury

2007-12-29T01:38:00.000-08:00

Alonzo Peters MD @ North Medical Center vs War on Drugs
The following will include an attempt not to counter but to offer the positive aspect of what to expect from a black man under siege. There is nothing but joy in my heart as I approach this New Year. I realize that the devil has a head wound. he is desperate to accuse others of what he is doing as projection (a primitive psychologic defense mechanism). Great things He has done.The DEA in association with the local police departments have been documented to be a major component in the War on Drugs, which is predominantly a war on the consumer of crack and cocaine which is put back on the streets by the DEA (read Douglas Valentines "The Strength of the Wolf") . This means you. They glorify this by hiring stars and releasing movies from the Super Fly concept, and rap videos glorifying gangsters and wanna-be gangsters who have no regard for community and or health care. They fight for the right to be genocidal agents. They want to dump me into that pile? Yet I am no better in allowing myself to be confused with them in my alcoholic state. To God be the glory!I am no better period, than the drug dealer, yet I am not one. I am not presented as his competitor. That is the insanity of it. I was competing with the militia raising money for wars and the War on Drugs unknowingly. This is my crime of ignorance. To God be the glory and may His grace be evident for the poor of America. Why attack a health care plan that was not taking Medicaid and not billing Medicare who was successfully offering medical , soon to open dental, lab , x-rays, vaccinations and visits for $5 per person? Where is the Federal offence? A Black professional making money?The cold part is that the book that I have since read The Turner Diaries which was Timothy McVeigh's bible (Morrow Federal building bombing), describes the necessity of taking out the professionals with various threats, in order to put more pressure on the Federal government in expenditures. Their attempt is to bankrupt the government. It is almost as if the Civil War is continued in anarchy, and corruption. The South has risen again. The need to defraud in the Savings and Loan monies and now the sub-prime is an attempt to subvert this great country of ours. They let certain groups defraud Medicare. Classes were taught in countries to tell them how to do it. Either you are a participant with them or their enemy. Had I known this before I would never have put my self in a position to be confused with them. To God be the glory.This is how it must stop. Take the money cars ect. confiscated and give them to a church in the community where the alleged offense occurs. Give the capital to .....St. Johns with a record of Ministering and helping Street people. Take it from the greedy, give it to the needy...I will be subjected to possibility of jail time to support that giving, even if I am innocent.Now run and tell that!

Again thank God for Google

2007-12-29T01:16:00.000-08:00

Like James Brown said I'm mad but check out the contrast

North Medical center: Alonzo Peters MD @ North Medical Center vs ...
Posted by Alonzo Peters MD at 12:08 AM ... Alonzo Peters MD: Having the greatest ever Christmas in 2007, despite the fact that I lost my best friend (my ...northmedicalcenter.blogspot.com/2007/12/alonzo-peters-md-north-medical-center_29.html - 4 minutes ago - Similar pages
In the Jar Studios_ Clients in Studio
Alonzo Peters Alonzo Working on some last minute revisions to new song. Alonzo is the master mind behind Kimberly Records. 25 Years of the Finest - The ...www.inthejarstudios.com/Clients%20Studio.htm - 15k - Cached - Similar pages
CYTOKINE NEWS: To all Patients and Staff of North Medical Center ...
Alonzo Peters MD: Having the greatest ever Christmas in 2007, despite the fact that I lost my best friend (my Dad) in 2006 during this season. ...cytokinenews.blogspot.com/2007/12/to-all-patients-and-staff-of-north.html - 58k - Cached - Similar pages

I love ya Google

Thank God for Google

2007-12-29T01:13:00.000-08:00

Peters' Productions
Fast Connection. AMIE DATABASE. Customer ID:. Password:. Forgot Password? New Customer? All rights reserved. © Alonzo Peters, M.D 1983.advancedmedinfo.com/ - 12k - Cached - Similar pages

This is Googles listing

See the difference?

Yahoo the reason for the season of war on citizens

2007-12-29T01:02:00.000-08:00

This is the top listing as of today. No mention of music and scientific contributions, but over three year old mess on top of mess. Thank you yahoo.
To God be the glory!

1. September 13, 2004
This page includes information on the open record policy, process, and ... on Friday suspended the license of Alonzo Peters III, M.D., license number ...
www.tmb.state.tx.us/news/press/2004/091304.php - 11k - Cached
2. july 28, 2006, press release, peters
(PDF)
Alonzo Peters, III, 54, a licensed Texas physician who practiced in the Houston area until ... Peters and the three pharmacists are accused of agreeing to ...
www.usdoj.gov/usao/txs/releases/July2006/060728-peters.pdf - 36k - View as html
3. USAO-SDTX-060728-Peters
Alonzo Peters, III, 54, a licensed Texas physician who practiced in the Houston ... Drug Enforcement Administration arrested Peters, Hogan and Green on ...www.usdoj.gov/usao/txs/releases/July2006/060728-Peters.htm - 11k - Cached

Alonzo Peters MD @ North Medical Center vs War on Drugs

2007-12-29T00:08:00.000-08:00

The following will include an attempt not to counter but to offer the positive aspect of what to expect from a black man under siege. There is nothing but joy in my heart as I approach this New Year. I realize that the devil has a head wound. he is desperate to accuse others of what he is doing as projection (a primitive psychologic defense mechanism). Great things He has done.

The DEA in association with the local police departments have been documented to be a major component in the War on Drugs, which is predominantly a war on the consumer of crack and cocaine which is put back on the streets by the DEA (read Douglas Valentines "The Strength of the Wolf") . This means you. They glorify this by hiring stars and releasing movies from the Super Fly concept, and rap videos glorifying gangsters and wanna-be gangsters who have no regard for community and or health care. They fight for the right to be genocidal agents. They want to dump me into that pile? Yet I am no better in allowing myself to be confused with them in my alcoholic state. To God be the glory!

I am no better period, than the drug dealer, yet I am not one. I am not presented as his competitor. That is the insanity of it. I was competing with the militia raising money for wars and the War on Drugs unknowingly. This is my crime of ignorance. To God be the glory and may His grace be evident for the poor of America. Why attack a health care plan that was not taking Medicaid and not billing Medicare who was successfully offering medical , soon to open dental, lab , x-rays, vaccinations and visits for $5 per person? Where is the Federal offence? A Black professional making money?

The cold part is that the book that I have since read The Turner Diaries which was Timothy McVeigh's bible (Morrow Federal building bombing), describes the necessity of taking out the professionals with various threats, in order to put more pressure on the Federal government in expenditures. Their attempt is to bankrupt the government. It is almost as if the Civil War is continued in anarchy, and corruption. The South has risen again. The need to defraud in the Savings and Loan monies and now the sub-prime is an attempt to subvert this great country of ours. They let certain groups defraud Medicare. Classes were taught in countries to tell them how to do it. Either you are a participant with them or their enemy. Had I known this before I would never have put my self in a position to be confused with them. To God be the glory.

This is how it must stop. Take the money cars ect confiscated and give them to a church in the community where the alleged offense occurs. Give the capital to .....St. Johns with a record of Ministering and helping Street people. Take it from the greedy, give it to the needy...
I will be subjected to possibility of jail time to support that giving, even if I am innocent.

Now run and tell that!

Yahoo is the purveyor of lies

2007-12-28T23:58:00.000-08:00

It is good to read. You know I frequently check to see how low you can go. This US government is the greatest , but sometimes the people in power bow to the lowest to win. This is what I hate.

The following is a top listed portion of the Department of Justice release from Yahoo. It is to them that I need to ultimately give credit in smearing me. To God be the glory. what He will do with this I do not know. We had a pain management program and people were excluded when caught distributing drugs, yet why argue with the devil.

The indictment alleges a conspiracy between Peters and the three pharmacists existed between 1999 through 2005. Peters and the three pharmacists are accused of agreeing to distribute drugs outside the course of professional medical practice "knowing the prescription drugs were to be sold on the street without a medical purpose. "

How can these listings post something of what they think I know? This has taken things to another level. To the people who list rank for Yahoo well tell me why? Why perpetuate a lie?
At least Google mentions my invention and my music.

Alonzo Peters MD @ North Medical Center

2007-12-28T14:01:00.000-08:00

Happy New Year, belated Merry Christmas, and Happy Kwanza. Hello to all my patients. Please excuse me for such a long delay in attempting to reach you. So much has happened. It is all good. The scripture said these things would happen in the last days. Yet I am just becoming digital.

Well, one thing that did not happen was for me to run. You know it felt like I should fly away or something at times. You all know that we offered visits for $5 per person. We made referrals. We drew lab. We did many house calls. We did x-rays. We examined each patient. We did vaccinations. We gave injections. We gave counseling. We offered a global health care plan for all who were participating in Pain Management. In general we loved each other, not for money but for love. Some of you were just like my family. It hurt me bad to close down the office after being put under siege. Believe me I was only following my Juris Doctors' advice. Now even those that I depended on would have me think that I was crazy for helping the poor and serving the needy of the North Side. I could only do what I saw my father do for 55 years. The media would have you believe that I am American Gangster. We are sure that we are on e of the many victims of the War on Drugs, which is a war on the the people.

Yet there were a few things that needed removal 1. Alcohol from my life 2. Betraying people who I lived with and provided for 3. Fair Weather Friends. Only a true son is admonished/punished and I realize for the second set of whippings that I should be true to He and He alone.

At this time we are 1. doing a daily life-coach DVD 2. Still teaching with Bibleboost 3. Still parenting 12 and 20 year old girls Last but not least we are adding daily entries into a medical software that I started in 1983 called AMIE TM. This stands for Advanced Medical Informatics Education. We plan on curing all disease within 3 years. Maybe this is why all this happened including lying DEA agents who are hotly in pursuit of unjust convictions and seizure of assets while denying constitutional rights (pray for dea) and to God be the Glory. Go to http://www.advancedmedinfo.com/ and press Peters' Productions then fill our info and then e-mail me that you did it to pete4doc@hotmail.com

Remember, I never looked better to God and you. Pray for my continued Spiritual development
and for the light of the Lord to shine on the illegal activity commited against me . This includes seized records that I still have not been able to see, even though the dea and its lead agent promised them to me after they were copied. Pray for my mother, sister and family.

I love you

Alonzo Peters III MD
713-882-7209