Arginine is an amino acid that is often taken by height seekers in an attempt to grow taller. Arginine is taken to try to increase growth hormone levels and growth hormone may increase height(GH has been to shown to increase height in GH transgenic mice and in tumors in the pituitary gland plus other homeostatic altering places but those contain several confounding variables that may increase the height other than the GH itself such as altered homeostatic mechanisms in GH transgenic mice). Arginine also increases height via the Nitric Oxide/Guanyl Cyclase/cGMP pathways. CARM1(co-activator associated arginine methyltranferase 1) is a critical regulator of chondrocyte proliferation by regulating the arginine methylation of Sox9. CARM1 disrupts the interaction of Sox9 with Beta-Catenin (which could induce hypertrophic chondrocytes to differentiate into bone) so someone with more CARM1 may grow taller.
L-Arginine is also a key ingredient of Peak Height, Height Maximizer.
Ibuprofen-arginine generates nitric oxide and has enhanced anti-inflammatory effects.
"Ibuprofen, a chiral non-steroidal anti-inflammatory drug chemically related to fenoprofen and naproxen, has moderate but definite anti-inflammatory, analgesic and antipyretic properties. Bioavailability of ibuprofen is increased by salification with various salts. Ibuprofen-arginine [is] of biological interest because l-arginine acts as substrate of the nitric oxide (NO) synthesising enzymes. Using epithelial HeLa cells expressing the endothelial NO synthase we show that ibuprofen-arginine releases NO and that this NO protects against the cytotoxic apoptogenic effects of staurosporine. Ibuprofen-arginine is endowed with enhanced anti-inflammatory effects with respect to ibuprofen, as shown by reduced hind paw oedema, neutrophil infiltration and chondrocyte apoptosis in collagen-induced mouse arthritis, a model of chronic inflammation. NO has pleiotropic beneficial effects that may contribute to limit inflammation and anti-inflammatory compounds able to release NO display higher efficacy than the parent drugs in defined clinical settings. NO generation contributes to the enhanced anti-inflammatory effects of ibuprofen-arginine vs. ibuprofen."
Ibuprofen-arginine may be a potential way to grow taller by increasing NO expression which increases cGK II expression. Nitric Oxide may have negative effects on growth too but this can be alleviated by TP508.
Thrombin peptide TP508 prevents nitric oxide mediated apoptosis in chondrocytes in the endochondral developmental pathway.
"TP508 is a 23-amino acid peptide derived from human prothrombin that increases cartilage matrix production and reduces alkaline phosphatase activity without changing chondrocyte proliferation. TP508 acts by blocking the onset of apoptosis associated with hypertrophy. Rat costochondral resting zone chondrocytes and human auricular chondrocytes were cultured in DMEM containing 50microM ascorbic acid and 10% FBS. Apoptosis was induced by treatment of confluent cultures with chelerythrine, tamoxifen, or inorganic phosphate (Pi) for 24h[chelerythrine, tamoxifen, and inorganic phosphate are bad for growth]. One half of the cultures received TP508 (0, 0.7, or 7microg/ml). Apoptosis was assessed as a function of DNA fragmentation ([3H]-thymidine labeled DNA fragments), TUNEL staining, and cell viability using the MTT assay, as well as by assessing the Bcl-2/Bax mRNA and protein ratios and caspase-3 activity. The universal NO synthase inhibitor l-NMMA was used to assess the effect of NO production on chondrocyte apoptosis and specific NO synthase subspecies were identified using iNOS inhibitor 1400W and nNOS inhibitor vinyl-l-NIO, as well as l-NAME, which inhibits both iNOS and eNOS. Finally, we assessed if TP508 would block NO production induced by the apoptogens. Chelerythrine, tamoxifen and Pi-induced apoptosis and this was reversed by TP508. All apoptogens increased NO production and this was reduced by TP508. TP508 reduced NO levels to the same extent as 1400W but not to the same extent as l-NAME, suggesting that its effects are mediated primarily by iNOS. In addition, TP508 reduced the effect of chelerythrine to the same extent as 1400W and l-NAME, again indicating that it acts via inhibition of an iNOS pathway. TP508 also regulated Bcl-2/Bax[mostly via upregulation of Bax] mRNA in a time and dose-dependent manner. The Bcl-2/Bax mRNA ratio was 0.11 in the absence of TP508 at 1h and 4.95 at 7microg/ml TP508; by 3h the ratio was approximately 1 in both groups. The Bcl-2/Bax protein ratio also increased by 63% at 1h. TP508 did not affect caspase-3 activity. TP508 also caused a dose-dependent increase in protein kinase C (PKC) activity within 9min that was maximal at 270min. TP508 prevents apoptosis in growth plate chondrocytes via inhibition of iNOS-dependent NO [with] PKC [involvement]."
NO activity may result in chondrocyte apoptosis but NO also has positive activities as well. TP508 inhibits the specific pathway that causes growth plate chondrocyte apoptosis. TP508 inhibits apoptosis in human chondrocytes as well.
L-Arginine should increase Nitric Oxide levels by providing more raw materials to increase Nitric Oxide(Nitric Oxide should be increased first by a mechanism like Viagra or Tribulus Terristris). Viagra might be best because it doesn't increase NO but rather it's a PDE5 inhibitor so it doesn't cause Chondrocyte Apoptosis.
Growing taller with a supplement that increases NO(or inhibits PDE5), L-arginine, or TP508 should be possible. If you take something like Viagra which doesn't specifically increases NO but rather targets a by-product on the pathway then you may not need TP508.
Showing posts with label nitric oxide. Show all posts
Showing posts with label nitric oxide. Show all posts
Thursday, October 28, 2010
Wednesday, June 2, 2010
Be Taller with Nitric Oxide?
LSJL genes involved with Nitric Oxide:
Superoxide(byproduct of free radicals and Nitric Oxide):
Sod3{up}(Superoxide Metabolism)
Nox1{up}(Superoxide Release)
Nitric Oxide:
Ddah1{up}(nitric oxide biosynthesis)
Mt1{up}(Nitric Oxide mediated signal transduction)
Mt2{up}(Nitric Oxide mediated signal transduction)
Free Radicals:
Me3{up}(oxygen and reactive oxygen species metabolic process)
There are several ways that mechanical load influences bone growth. How is Nitric Oxide involved in this process and can we manipulate Nitric Oxide to be taller people?
Endothelial nitric oxide synthase deficiency results in reduced chondrocyte proliferation and endochondral bone growth.
"[What are the[ effects of inactivation of endothelial nitric oxide synthase (eNOS) on cartilage development in mice? Skeletal growth and development of mice carrying a null mutation in the eNOS gene was studied in comparison to control littermates. In situ analyses were complemented by experiments with primary chondrocytes and tibial explants from these mice. eNOS-deficient mice show increased lethality and reduced bone growth, with hypocellular growth plates and a marked reduction in the number of proliferating chondrocytes. In vitro studies demonstrated lower chondrocyte numbers and reduced endochondral bone growth in mutants, suggesting that the role of eNOS signaling in chondrocyte proliferation is cell-autonomous[Meaning that the mutation is local per cell rather than system wide]. Reduced chondrocyte numbers appear to be caused by decreased cyclin D1 and increased p57 expression in mutants, resulting in slower cell cycle progression and earlier cell cycle exit. In addition, expression of early chondrocyte markers such as Sox9 was reduced and prehypertrophic markers were expressed prematurely in mutant mice. eNOS [has a role] in chondrocyte proliferation and endochondral bone growth. Loss of eNOS results in premature cell-cycle exit and prehypertrophic chondrocyte differentiation during cartilage development."
"NO is synthesized through l-arginine by NO synthases (NOS) in many cell types. Three different types of NOS have been identified. The neuronal NOS (nNOS or NOS1) and endothelial NOS (eNOS or NOS3) forms are constitutively expressed, and their activity is regulated by intracellular signaling and the calcium-binding protein calmodulin. The inducible form (iNOS or NOS2) is stimulated at the level of expression by factors including lipopolysaccharide and cytokines, such as interleukin-1, tumor necrosis factor α, and interferon-α, and leads to sustained and high levels of NO, mainly in inflammatory disease"
"NO signaling promotes chondrocyte hypertrophy"
"reduced numbers of cells in the proliferative zone are a general feature of eNOS−/− bones"
"the transcription factor ATF-3 is up-regulated during chondrocyte hypertrophy and represses the activity of the cyclin D1 promoter in chondrocytes. ATF-3 expression [increases] in eNOS-deficient growth plates, suggesting that premature induction of ATF-3 expression in mutant mice leads to repression of cyclin D1 transcription and chondrocyte proliferation."<-LSJL heavily upregulates ATF3.
"eNos deficiency [promotes] prehypertrophic gene expression. [Analysis of] neonate cartilage revealed decreased expression of the early chondrocyte markers Col2a1 and Sox9, and increased expression of the prehypertrophic markers RORa and Hif1a in the cartilage of eNOS-knockout mice."
"Both NO and CNP stimulate the production of cGMP via soluble or particulate guanylyl cyclases, these similarities provide further evidence of the importance of cGMP signaling in endochondral bone formation. However, the phenotype of eNOS-null mice does not exactly resemble that of mice lacking CNP or the main effector of cGMP in cartilage, cGMP-dependent kinase II. For example, mice lacking CNP have strikingly narrow growth plates and shorter proliferating and hypertrophic zones "
These results are echoed by this study Reduced chondrocyte proliferation, earlier cell cycle exit and increased apoptosis in neuronal nitric oxide synthase-deficient mice. In this study chondrocytes with neurol nitric oxide deficiency, expressed more c-Fos, ATF3, and ROR-alpha(which inhibits chondrogenesis). Also, eNos and iNos levels were increased in nNOS KO mice. The study also noted that they did not notice the phenotype change of the a decrease in length of the hypertrophic zone which is typical in CNP null mice. The speculated that eNos and iNos may compensate for decreased nNos levels.
Now, Nitric Oxide appears to be only beneficial if you have sufficient quantities of the enzyme whereas exercise Nitric Oxide seems like it wouldn't have an additional effect. Perhaps increasing Cyclin D1 and decreasing p57 can result in supernatural growth. Nitric Oxide can be affected by exercise...
Effect of low-magnitude, high-frequency vibration on osteocytes in the regulation of osteoclasts.
"Osteocytes are the major mechanosensor in bone, responsible for sending signals to the effector cells (osteoblasts and osteoclasts) that carry out bone formation and resorption. osteocytes release various soluble factors (e.g. transforming growth factor-beta, nitric oxide, and prostaglandins) that influence osteoblastic and osteoclastic{and possibly chondrocytes} activities when subjected to a variety of mechanical stimuli, including fluid flow[LSJL but we're more interested in the effects of chondrocytes but this might mean that direct loading of the spinous process of your vertebrae may increase your height], hydrostatic pressure, and mechanical stretching. Low-magnitude, high-frequency (LMHF) vibration (e.g., acceleration less than <1 x g, where g=9.81m/s(2), at 20-90 Hz) can positively influence skeletal homeostasis in animals and humans. Osteocytes are the mechanosensor responsible for detecting the vibration stimulation and producing soluble factors that modulate the activity of effector cells. We applied low-magnitude (0.3 x g) vibrations to osteocyte-like MLO-Y4 cells at various frequencies (30, 60, 90 Hz) for 1h. Osteocytes were sensitive to this vibration stimulus at the transcriptional level: COX-2 maximally increased by 344% at 90Hz, while RANKL decreased most significantly (-55%, p<0.01) at 60Hz[RANKL increases osteoclast activity]. Conditioned medium collected from the vibrated MLO-Y4 cells attenuated the formation of large osteoclasts (> or =10 nuclei) by 36% and the amount of osteoclastic resorption by 20%. The amount of soluble RANKL (sRANKL) in the conditioned medium was found to be 53% lower in the vibrated group, while PGE(2) release was also significantly decreased (-61%)."
"osteocytes have been found to communicate with effector cells through gap junctions and soluble factors"<-these soluble factors may promote chondrocyte differentiation as well.
" PGE2 promotes the differentiation of osteoclasts in bone marrow cultures"
"PGE2 released by bone cells has been found to increase upon fluid flow stimulation and mediate downstream responses such as increased expression of gap junction protein connexin (Cx) 43"
LMHF increased Cox2 but decreased PGE2.
Now, vibrations on the bone can be simulated by impact with exercises like jumping or tapping.
Nitric Oxide can only help in lengthening short, irregular, and flat bones as it affects osteoblasts and not chondrocytes(although there may be a yet unknown effect on chondrocytes). Nitric Oxide is one of the factors released by osteocytes in response to various mechanical strain. Nitric Oxide is affected by exercise as a result of fluid flow on the bone(lateral synovial joint loading which on non-long bones is any direction).
This also means that Lateral Synovial Joint Loading should result in bigger epiphysis of your long bones(bigger ankles/wrists) as the epiphysis is basically a short bone attached to hyaline cartilage.
Inducible nitric oxide synthase-nitric oxide signaling mediates the mitogenic activity of Rac1 during endochondral bone growth.
"chondrocyte-specific deletion of the gene Rac1 in mice leads to severe dwarfism due to reduced chondrocyte proliferation. Rac1-deficient chondrocytes have severely reduced levels of inducible nitric oxide synthase (iNOS) protein and nitric oxide (NO) production. NO donors reversed the proliferative effects induced by Rac1 deficiency, whereas inhibition of NO production mimicked the effects of Rac1 loss of function[so proper NO levels are essential to grow taller]. The growth plate of iNOS-deficient mice [have] reduced chondrocyte proliferation and expression of cyclin D1, resembling the phenotype of Rac1-deficient growth plates. Rac1-NO signaling inhibits the expression of ATF3, a known suppressor of cyclin D1 expression in chondrocytes[note that ATF3 is upregulated by LSJL so perhaps when performing LSJL NO signaling has to be enhanced to counteract the upregulation by LSJL]. "
"Rac1 promotes chondrocyte proliferation through iNOS–NO-mediated induction of cyclin D1 expression."
So for optimal LSJL effectiveness you need to stimulate NO expression to counteract the increase in ATF3. Although ATF3 may help in forming in growth plates.
Inorganic phosphate induces mammalian growth plate chondrocyte apoptosis in a mitochondrial pathway involving nitric oxide and JNK MAP kinase.
Superoxide(byproduct of free radicals and Nitric Oxide):
Sod3{up}(Superoxide Metabolism)
Nox1{up}(Superoxide Release)
Nitric Oxide:
Ddah1{up}(nitric oxide biosynthesis)
Mt1{up}(Nitric Oxide mediated signal transduction)
Mt2{up}(Nitric Oxide mediated signal transduction)
Free Radicals:
Me3{up}(oxygen and reactive oxygen species metabolic process)
There are several ways that mechanical load influences bone growth. How is Nitric Oxide involved in this process and can we manipulate Nitric Oxide to be taller people?
Endothelial nitric oxide synthase deficiency results in reduced chondrocyte proliferation and endochondral bone growth.
"[What are the[ effects of inactivation of endothelial nitric oxide synthase (eNOS) on cartilage development in mice? Skeletal growth and development of mice carrying a null mutation in the eNOS gene was studied in comparison to control littermates. In situ analyses were complemented by experiments with primary chondrocytes and tibial explants from these mice. eNOS-deficient mice show increased lethality and reduced bone growth, with hypocellular growth plates and a marked reduction in the number of proliferating chondrocytes. In vitro studies demonstrated lower chondrocyte numbers and reduced endochondral bone growth in mutants, suggesting that the role of eNOS signaling in chondrocyte proliferation is cell-autonomous[Meaning that the mutation is local per cell rather than system wide]. Reduced chondrocyte numbers appear to be caused by decreased cyclin D1 and increased p57 expression in mutants, resulting in slower cell cycle progression and earlier cell cycle exit. In addition, expression of early chondrocyte markers such as Sox9 was reduced and prehypertrophic markers were expressed prematurely in mutant mice. eNOS [has a role] in chondrocyte proliferation and endochondral bone growth. Loss of eNOS results in premature cell-cycle exit and prehypertrophic chondrocyte differentiation during cartilage development."
"NO is synthesized through l-arginine by NO synthases (NOS) in many cell types. Three different types of NOS have been identified. The neuronal NOS (nNOS or NOS1) and endothelial NOS (eNOS or NOS3) forms are constitutively expressed, and their activity is regulated by intracellular signaling and the calcium-binding protein calmodulin. The inducible form (iNOS or NOS2) is stimulated at the level of expression by factors including lipopolysaccharide and cytokines, such as interleukin-1, tumor necrosis factor α, and interferon-α, and leads to sustained and high levels of NO, mainly in inflammatory disease"
"NO signaling promotes chondrocyte hypertrophy"
"reduced numbers of cells in the proliferative zone are a general feature of eNOS−/− bones"
"the transcription factor ATF-3 is up-regulated during chondrocyte hypertrophy and represses the activity of the cyclin D1 promoter in chondrocytes. ATF-3 expression [increases] in eNOS-deficient growth plates, suggesting that premature induction of ATF-3 expression in mutant mice leads to repression of cyclin D1 transcription and chondrocyte proliferation."<-LSJL heavily upregulates ATF3.
"eNos deficiency [promotes] prehypertrophic gene expression. [Analysis of] neonate cartilage revealed decreased expression of the early chondrocyte markers Col2a1 and Sox9, and increased expression of the prehypertrophic markers RORa and Hif1a in the cartilage of eNOS-knockout mice."
"Both NO and CNP stimulate the production of cGMP via soluble or particulate guanylyl cyclases, these similarities provide further evidence of the importance of cGMP signaling in endochondral bone formation. However, the phenotype of eNOS-null mice does not exactly resemble that of mice lacking CNP or the main effector of cGMP in cartilage, cGMP-dependent kinase II. For example, mice lacking CNP have strikingly narrow growth plates and shorter proliferating and hypertrophic zones "
These results are echoed by this study Reduced chondrocyte proliferation, earlier cell cycle exit and increased apoptosis in neuronal nitric oxide synthase-deficient mice. In this study chondrocytes with neurol nitric oxide deficiency, expressed more c-Fos, ATF3, and ROR-alpha(which inhibits chondrogenesis). Also, eNos and iNos levels were increased in nNOS KO mice. The study also noted that they did not notice the phenotype change of the a decrease in length of the hypertrophic zone which is typical in CNP null mice. The speculated that eNos and iNos may compensate for decreased nNos levels.
Now, Nitric Oxide appears to be only beneficial if you have sufficient quantities of the enzyme whereas exercise Nitric Oxide seems like it wouldn't have an additional effect. Perhaps increasing Cyclin D1 and decreasing p57 can result in supernatural growth. Nitric Oxide can be affected by exercise...
Effect of low-magnitude, high-frequency vibration on osteocytes in the regulation of osteoclasts.
"Osteocytes are the major mechanosensor in bone, responsible for sending signals to the effector cells (osteoblasts and osteoclasts) that carry out bone formation and resorption. osteocytes release various soluble factors (e.g. transforming growth factor-beta, nitric oxide, and prostaglandins) that influence osteoblastic and osteoclastic{and possibly chondrocytes} activities when subjected to a variety of mechanical stimuli, including fluid flow[LSJL but we're more interested in the effects of chondrocytes but this might mean that direct loading of the spinous process of your vertebrae may increase your height], hydrostatic pressure, and mechanical stretching. Low-magnitude, high-frequency (LMHF) vibration (e.g., acceleration less than <1 x g, where g=9.81m/s(2), at 20-90 Hz) can positively influence skeletal homeostasis in animals and humans. Osteocytes are the mechanosensor responsible for detecting the vibration stimulation and producing soluble factors that modulate the activity of effector cells. We applied low-magnitude (0.3 x g) vibrations to osteocyte-like MLO-Y4 cells at various frequencies (30, 60, 90 Hz) for 1h. Osteocytes were sensitive to this vibration stimulus at the transcriptional level: COX-2 maximally increased by 344% at 90Hz, while RANKL decreased most significantly (-55%, p<0.01) at 60Hz[RANKL increases osteoclast activity]. Conditioned medium collected from the vibrated MLO-Y4 cells attenuated the formation of large osteoclasts (> or =10 nuclei) by 36% and the amount of osteoclastic resorption by 20%. The amount of soluble RANKL (sRANKL) in the conditioned medium was found to be 53% lower in the vibrated group, while PGE(2) release was also significantly decreased (-61%)."
"osteocytes have been found to communicate with effector cells through gap junctions and soluble factors"<-these soluble factors may promote chondrocyte differentiation as well.
" PGE2 promotes the differentiation of osteoclasts in bone marrow cultures"
"PGE2 released by bone cells has been found to increase upon fluid flow stimulation and mediate downstream responses such as increased expression of gap junction protein connexin (Cx) 43"
LMHF increased Cox2 but decreased PGE2.
Now, vibrations on the bone can be simulated by impact with exercises like jumping or tapping.
Nitric Oxide can only help in lengthening short, irregular, and flat bones as it affects osteoblasts and not chondrocytes(although there may be a yet unknown effect on chondrocytes). Nitric Oxide is one of the factors released by osteocytes in response to various mechanical strain. Nitric Oxide is affected by exercise as a result of fluid flow on the bone(lateral synovial joint loading which on non-long bones is any direction).
This also means that Lateral Synovial Joint Loading should result in bigger epiphysis of your long bones(bigger ankles/wrists) as the epiphysis is basically a short bone attached to hyaline cartilage.
Inducible nitric oxide synthase-nitric oxide signaling mediates the mitogenic activity of Rac1 during endochondral bone growth.
"Rac1 promotes chondrocyte proliferation through iNOS–NO-mediated induction of cyclin D1 expression."
So for optimal LSJL effectiveness you need to stimulate NO expression to counteract the increase in ATF3. Although ATF3 may help in forming in growth plates.
Inorganic phosphate induces mammalian growth plate chondrocyte apoptosis in a mitochondrial pathway involving nitric oxide and JNK MAP kinase.
"Chondrocytes in the hypertrophic zone of the growth plate undergo apoptosis during endochondral bone development via mechanisms that involve inorganic phosphate (Pi) and nitric oxide (NO){apoptosis may not necessarily be bad for height growth though}. Pi-dependent NO production plays a role in apoptosis of cells in the resting zone as well. Pi decreased the number of viable cells; the number of TUNEL-positive cells and the level of DNA fragmentation were increased, indicating an increase in apoptosis. Blocking NO production using the NO synthase (NOS) inhibitor L: -NAME or cells from eNOS(-/-) mice blocked Pi-induced chondrocyte apoptosis, indicating that NO production is necessary. NO donors NOC-18 and SNOG both induced chondrocyte apoptosis. SNOG also upregulated p53 expression, the Bax/Bcl-2 expression ratio, and cytochrome c release from mitochondria, as well as caspase-3 activity, indicating that NO induces apoptosis via a mitochondrial pathway. Inhibition of JNK, but not of p38 or ERK1/2, MAP kinase was able to block NO-induced apoptosis, indicating that JNK is necessary in this pathway. Pi elevates NO production via eNOS in resting zone chondrocytes, which leads to a mitochondrial apoptosis pathway dependent on JNK."
"Pi induced a concentration-dependent increase in caspase-3 activity, with 7.5 mM Pi causing a 3.4-fold increase compared with control culture"
"Pi regulated p53 abundance in resting zone chondrocytes. Although 2.5 mM Pi did not significantly increase p53, 5 and 7.5 mM Pi treatment increased p53 protein 2.6- and 2.8-fold, respectively. Pi also induced a concentration-dependent increase in levels of Bax and a concentration-dependent decrease in levels of Bcl-2. The Bax/Bcl-2 ratio was greatest in cultures treated with 7.5 mM exogenous Pi, with a sixfold increase compared to control."
Evaluation of methylation status of the eNOS promoter at birth in relation to childhood bone mineral content.
"eNOS is important in bone metabolism; we therefore related the methylation status of the eNOS gene promoter in stored umbilical cord to childhood bone size and density in a group of 9-year-old children. We assess the methylation status of two CpGs in the eNOS promoter in stored umbilical cords of 66 children who formed part of a Southampton birth cohort and who had measurements of bone size and density at age 9 years. Percentage methylation varied greatly between subjects. For one of the two CpGs, eNOS chr7:150315553 + , after taking account of age and sex, there were strong positive associations between methylation status and the child's whole-body bone area, bone mineral content, and areal bone mineral density at age 9 years. These associations were independent of previously documented maternal determinants of offspring bone mass. An association [exists] between methylation status at birth of a specific CpG within the eNOS promoter and bone mineral content in childhood. eNOS [has a role] in bone growth and metabolism."
Unfortunately bone length was not measured.
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