Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015674 (chronic fatigue syndrome)
 2,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Short-term stressors, capable of increasing nitric oxide levels, act to initiate cases of illnesses including chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia and posttraumatic stress disorder. These stressors, acting primarily through the nitric oxide product, peroxynitrite, are thought to initiate a complex vicious cycle mechanism, known as the NO/ONOO- cycle that is responsible for chronic illness. The complexity of the NO/ONOO- cycle raises the question as to whether the mechanism that switches on this cycle is this complex cycle itself or whether a simpler mechanism is the primary switch. It is proposed here that the switch involves a combination of two variable switches, the increase of nitric oxide synthase (NOS) activity and the partial uncoupling of the NOS activity, with uncoupling caused by a tetrahydrobiopterin (BH4) deficiency. NOS uncoupling causes the NOS enzymes to produce superoxide, the other precursor of peroxynitrite, in place of nitric oxide. Thus partial uncoupling will cause NOS proteins to act like peroxynitrite synthases, leading, in turn to increased NF-kappaB activity. Peroxynitrite is known to oxidize BH4, and consequently partial uncoupling may initiate a vicious cycle, propagating the partial uncoupling over time. The combination of high NOS activity and BH4 depletion will lead to a potential vicious cycle that may be expected to switch on the larger NO/ONOO- cycle, thus producing the symptoms and signs of chronic illness. The role of peroxynitrite in the NO/ONOO- cycle also implies that such uncoupling is part of the chronic phase cycle mechanism such that agents that lower uncoupling will be useful in treatment.
 ...
PMID:Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO- cycle. 1744 11

Sauna therapy has been used to treat a number of different diseases known or thought to have a tetrahydrobiopterin (BH4) deficiency. It has been interpreted to act in multiple chemical sensitivity by increasing chemical detoxification and excretion but there is no evidence that this is its main mode of action. Sauna therapy may act to increase BH4 availability via two distinct pathways. Increased blood flow in heated surface tissues leads to increased vascular shear stress, inducing increased activity of GTP cyclohydrolase I (GTPCH-I) in those vascular tissues which will lead to increasing BH4 synthesis. A second mechanism involves the heat shock protein Hsp90, which is induced by even modest heating of mammalian tissues. Sauna heating of these surface tissues may act via Hsp90, which interacts with the GTPCH-I complex and is reported to produce increased GTPCH-I activity by lowering its degradation. The increased consequent availability of BH4 may lead to lowered nitric oxide synthase uncoupling, such as has been reported for the eNOS enzyme. Increased BH4 synthesis in surface tissues of the body will produce increased circulating BH4 which will feed BH4 to other body tissues that may have been BH4 deficient. Similar mechanisms may act in vigorous exercise due to the increased blood shear stresses and possibly also heating of the exercising tissues and heart. There is a large and rapidly increasing number of diseases that are associated with BH4 depletion and these may be candidates for sauna therapy. Such diseases as hypertension, vascular endothelial dysfunction, multiple chemical sensitivity and heart failure are thought to be helped by sauna therapy and chronic fatigue syndrome and fibromyalgia may also be helped and there are others that may be good candidates for sauna therapy.
 ...
PMID:Do sauna therapy and exercise act by raising the availability of tetrahydrobiopterin? 1958 Oct 54