Taurine chloramine inhibits prostaglandin E2

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Prostaglandin E2 (PGE2) is highly inflammatory. Inflammation is associated with major depressive disorder. Taurine chloramine inhibits PGE2.

Taurine chloramine inhibits prostaglandin E2 production in activated RAW 264.7 cells by post-transcriptional effects on inducible cyclooxygenase expression.

Quinn MR, Park E, Schuller-Levis G.

Abstract

Taurine chloramine (Tau-Cl) was recently demonstrated to inhibit production of nitric oxide and tumor necrosis factor-alpha (TNF-alpha) by activated macrophages. Since increased production of prostaglandin E2 (PGE2), a reaction catalyzed by induction of cyclooxygenase-2 (COX-2), is also associated with the inflammatory response, we determined the effects of Tau-Cl on PGE2 production and on expression of COX-2 protein and COX-2 mRNA in activated RAW 264.7 cells, a murine macrophage-like cell line. Tau-Cl inhibited production of PGE2 in a concentration dependent manner with an IC50 of 0.4 mM. The decrease in PGE2 production was largely accounted for by decreased expression of COX-2 protein. Although the kinetics of COX-2 mRNA expression was altered in Tau-Cl treated cells, mRNA expression appeared to be quantitatively unimpaired. These results suggest that Tau-Cl affects the post-transcriptional regulation of COX-2 expression and support the idea that Tau-Cl may function as an inhibitory modulator of the inflammatory response.

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Selective inhibition of cyclooxygenase 2-generated prostaglandin E2 synthesis in rheumatoid arthritis synoviocytes by taurine chloramine.

Kontny E, Rudnicka W, Kowalczewski J, Marcinkiewicz J, Maslinski W.

Objective: To investigate the effects of taurine chloramine (Tau-Cl), a chlorinated derivative of the amino acid taurine, on the expression of cyclooxygenase (COX) isoenzymes and prostaglandin E(2) (PGE(2)) synthesis in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS).

Methods: FLS, isolated from the synovial tissue of RA patients, were treated in vitro with either interleukin-1beta (IL-1beta; 1 ng/ml) alone or together with 200-500 microM Tau-Cl. The expression of COX isoenzymes was evaluated at both the protein (Western blotting) and the messenger RNA (mRNA) (reverse transcriptase-polymerase chain reaction) levels. The concentration of PGE(2) was measured by competitive acetylcholinesterase enzyme immunoassay.

Results: Resting FLS expressed mRNA encoding both COX-1 and COX-2, but only COX-1 was present at the protein level. These cells produced negligible amounts of PGE(2). Upon stimulation with IL-1beta, elevation of COX-2, but not COX-1, mRNA and protein preceded the enhancement of PGE(2) synthesis. In the presence of 300-400 microM Tau-Cl, significant inhibition of IL-1beta-triggered COX-2 mRNA and protein, and a related decrease in PGE(2) production, was observed. In contrast, no significant changes in COX-1 mRNA and protein levels were noted.

Conclusion: Tau-Cl inhibits IL-1beta-triggered elevation of COX-2 and generation of PGE(2) by RA FLS. These results expand the spectrum of known antiinflammatory activities of this compound.

Autism and the transsulfuration pathway

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Dysregulation of the transsulfuration pathway has been implicated in autism with research showing homocysteine and and oxidized glutathione levels were significantly higher in children diagnosed with autism spectrum disorders while cysteine levels, total glutathione and glutathione were remarkably lower in childiren with autism spectrum disorder compared to control subjects. Homocysteine levels levels correlated significantly with increasing Childhood Autism Rating Scale scores.

Taurine is synthesized from l-cysteine. Taurine is involved in calcium homeostasis. Taurine levels in autistic children were lower than than in controls. There may be low taurine levels only in a subset of indivduals with autism. Not all studies show taurine levels are low in autism.

Research points to intracellular calcium homeostasis being dysregulated in autism. Genes for various sub-units of proteins that act as calcium channels are associated with autism. In autism dysregulation of the transsulfuration pathway could dysregulate taurine synthesis which could dysregulate calcium homeostasis.

Whatever the answer is increasing levels of L-cysteine through supplementing with L-cysteine containing amino acids is not the answer. L-cysteine containing amino acids can be very toxic.

CACNA1C (Cav1.2) and psychiatric disease

The calcium channel, voltage-dependent, L type, alpha 1C subunit is a protein that is encoded by the CACNA1C gene. Via calcium channels calcium influxes into cells. Mutations in CACNA1C are associated with bipolar disorder, depression, schizophrenia and autism. Gain of function mutations in CACNA1C are associated with disease, for example, autism.

Taurine regulates intracellular calcium levels by preventing influxes of calcium into cells but not effluxes of calcium out of cells. Via regulating influxes of calcium into cells taurine has a role in the treatment of psychiatric disorders that are in part due to gain of function mutations in CACNA1C.

Bipolar disorder and bone mineral density

There are decreases in bone mineral density in drug naive individuals with bipolar disorder compared to age- and gender-matched healthy controls. Individuals with bipolar I disorder have have high homocysteine levels. High homocysteine levels in individuals with bipolar disorder point to the transsulfuration pathway being dysregulated. Via the transsulfuration pathway L-cysteine is synthesized from homocysteine. L-taurine is synthesized from L-cysteine.

Taurine is required for calcium homeostasis. Taurine, also, is conjugated to various bile acids. Bile acids are are required for absorption of fat-soluble vitamins. Vitamin D and vitamin K are fat-soluble vitamins. Individuals with bipolar disorder are 4.7 times more likely to be vitamin D deficient than individuals amongst the general population of the Netherlands, however, deficient levels of vitamin D are not specific to bipolar disorder but are also present in individuals with schizophrenia. The taurine transporter is present in osteoblasts. Osteoblasts synthesize bone.

With taurine metabolism dysregulated calcium homeostasis is dysregulated and absorption of vitamin D and vitamin K is decreased. Decreases in bone mineral density in bipolar disorder could be due to dysregulation of the transsulfuration pathway which dysregulates calcium homeostasis and vitamin D and vitamin K absorption resulting in low bone mineral density.

Bone mineral density and major depression

Decreased bone mineral density is associated with major depression. There are also low vitamin D levels in individuals who are depressed. Ahedonia in major depression could be due to hidden osteomalicias. Taurine, vitamin D and vitamin K could treat hidden osteomalacias present in major depression. Supplements used to treat hidden osteomalicias, would not be effective for intense sadnesses that frequently occur with major depressions.

Bone mineral density and negative symptoms of schizophrenia

A meta-analysis points to bone mineral density being significantly decreased in individuals with schizophrenia compared to healthy controls. Bone mineral density in schizophrenia could be decreased in individuals with schizophrenia due to dysregulation of the transsulfuration pathway. Taurine is synthesized from L-cysteine which is synthesized via the transsulfuration pathway.

Taurine is required for intracellular calcium homeostasis. Bile acids are required for absorption of fat soluble vitamins. Vitamin D and vitamin K are fat soluble vitamins involved in bone formation. Various bile acids are synthesized from taurine. With deficiencies of taurine calcium homeostasis can be upset and there can also be deficiencies of vitamin D and vitamin K which could lead to low bone mineral density in schizophrenia.

Low bone mineral density in schizophrenia point to there being hidden osteomalicias in schizophrenia. With taurine deficiencies intracellular calcium homeostasis can be upset, though extracellular calcium levels could be normal, leading to a hidden osteomalicias.

Dysregulation of the transsulfuration pathway can result in epigenetic changes whereby there could be localized osteomalacias. Given osteomalacias due to taurine deficiencies develop in the back of the head negative symptoms of schizophrenia could develop due to compressions of cerebellums. There are a wide range of symptoms in schizophrenia so individuals with schizophrenia do not present as only having back of the head pains which makes correct diagnoses difficult though x-ray studies of backs of skulls in individuals with symptoms of schizophrenia could go a long ways in making correct diagnoses straightforward.

Negative symptoms of schizophrenia could be treated by supplementation with taurine, Vitamin K2 MK-7, which a kind of vitamin K that is highly absorbed, and vitamin D3. As negative symptoms of schizophrenia are due to hidden osteomalicias taurine, vitamin K2 MK-7 could take a long while to be completely effective. To treat the range of symptoms seen is schizophrenia due to dysregulations of the transsulfuration pathway supplements, beyond supplements that treat hidden osteomalicias, are required.

Major depressive disorder and taurine

Ketamine is being used in the treatment of major depressive disorder. Ketamine is a glutamate NMDA receptor antagonist. A ‘modulating ‘effect of ketamine on NMDA receptors has been stated as giving rise an antidepressant effect of ketamine in major depressive disorder.

Glutamate toxicity due to calcium influx through L-, P/Q-, N-type voltage-gated calcium channels and NMDA receptor calcium channels is inhibited by taurine with taurine having a neuroprotective effect. Addressing glutamatergic neurotransmission via taurine is much preferable to addressing glutamatergic neurotransmission via ketamine. Research points to supplemental taurine as reducing homocysteine levels (Ahn, 2009), reducing cholesterol levels in animals (Guo et al., 2017; Chen et al., 2012) having an anti-obesity effect, as being negatively associated with ischemic heart disease, as ameliorating diabetes and points to taurine deficiencies as resulting in premature aging. Research on rats points to ketamine resulting in dysregulations in the prefrontal cortex that persist even after ketamine withdrawal. Taurine supplemented alone is not a highly effective treatment for depression

The cerebellum and schizophrenia

The cerebellum sits at the bottom back of the brain. A meta-analysis indicates there are structural and functional abnormalties in the cerebellum in schizophrenia.

Intraellular calcium homeostasis is regulated by taurine. Taurine is synthesized from L-cysteine wihch is synthesized from homocsysteine via the transsulfuration pathway.

Hidden oosteomalacia due to dysregulation of intracellular calcium homeostasis arising from low levels of taurine stemming from dysregulation of the transsulfuration pathway .could be wide spread. In individuals with schizohpenia there could be hidden osteomalacia that do not show as back pain but could affect necks compressing cerebellums leading to severe psychological effects. Calcium blood levels could be low normal or slightly low.

Some x-ray studies of bones is the neck region are called for in schizophrenia. If cerebellums are being compressed by a hidden osteomalacia treatmens for a range of psychological symptoms in schizophrenia could be much, much different. Taurine, vitamin D, vitamin K and calcium carbonate could treat the hidden osteomalicia addressing structural and functional brain abnormalties in schizophrenia. Bone mineral densities are lower in older indivduals with schizophrenia compared to indivduals without schizophrenia. Early diagnosis would be a key.

With cerebellums compressed there could negative symptoms of schizohrenia. Negative symptoms are are deficit symptoms where such deficits could be due to deficits in the ability of the cerebellum to function due to being compressed from hidden osteomalacia.

Taurine chloramine downregulates the production of proinflammatory mediators

Taurine chloramine produced from taurine under inflammation provides anti-inflamnatory and cytoprotective effects

Chaekyun Kim  1 Young-Nam Cha

Abstract

Taurine is one of the most abundant non-essential amino acid in mammals and has many physiological functions in the nervous, cardiovascular, renal, endocrine, and immune systems. Upon inflammation, taurine undergoes halogenation in phagocytes and is converted to taurine chloramine (TauCl) and taurine bromamine. In the activated neutrophils, TauCl is produced by reaction with hypochlorite (HOCl) generated by the halide-dependent myeloperoxidase system. TauCl is released from activated neutrophils following their apoptosis and inhibits the production of inflammatory mediators such as, superoxide anion, nitric oxide, tumor necrosis factor-α, interleukins, and prostaglandins in inflammatory cells at inflammatory tissues. Furthermore, TauCl increases the expressions of antioxidant proteins, such as heme oxygenase 1, peroxiredoxin, thioredoxin, glutathione peroxidase, and catalase in macrophages. Thus, a central role of TauCl produced by activated neutrophils is to trigger the resolution of inflammation and protect macrophages and surrounding tissues from being damaged by cytotoxic reactive oxygen metabolites overproduced during inflammation. This is achieved by attenuating further production of proinflammatory cytokines and reactive oxygen metabolites and also by increasing the levels of antioxidant proteins that are able to scavenge and diminish the production of cytotoxic oxygen metabolites. These findings suggest that TauCl released from activated neutrophils may be involved in the recovery processes of cells affected by inflammatory oxidative stresses and thus TauCl could be used as a potential physiological agent to control pathogenic symptoms of chronic inflammatory diseases.