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Transulfuration enzymes, diabetes, role of H2S as a neuroprotectant, against ER stress

Gondwanaland

Senior Member
Messages
5,092
2012
Hydrogen sulfide protects SH-SY5Y cells against 6-hydroxydopamine-induced endoplasmic reticulum stress.

Abstract
Endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative diseases, including Parkinson's disease. The present study attempted to investigate the effect of hydrogen sulfide (H(2)S) on 6-hydroxydopamine (6-OHDA)-induced ER stress in SH-SY5Y cells. We found in the present study that exogenous application of sodium hydrosulfide (NaHS; an H(2)S donor, 100 μM) significantly attenuated 6-OHDA (50 μM)-induced cell death. NaHS also reversed the upregulation of cleaved poly(ADP-ribose) polymerase and caspase 9 in 6-OHDA-treated cells. Consistent with its cytoprotective effects, NaHS markedly reduced 6-OHDA induced-ER stress responses, including the upregulated levels of eukaryotic initiation factor-2α phosphorylation, glucose-regulated protein 78, and C/EBP homologous protein expression. The protective effect of H(2)S on ER stress was attenuated by blockade of Akt activity with an Akt inhibitor or inhibition of heat shock protein (Hsp)90 with geldanamycin but not by suppression of ERK1/2 with PD-98059. Blockade of Akt also significantly decreased the protein abundance of Hsp90 in SH-SY5Y cells. Moreover, overexpression of cystathionine β-synthase (a main H(2)S-synthesizing enzyme in the brain) elevated the Hsp90 protein level and suppressed 6-OHDA-induced ER stress. In conclusion, the protective effect of H(2)S against 6-OHDA-induced ER stress injury in SH-SY5Y cells involves the Akt-Hsp90 pathway.
2014 (enclosed)
Hydrogen sulfide: a neuromodulator and neuroprotectant in the central nervous system.

Abstract
Hydrogen sulfide (H2S) used to be known as a toxic gas. However, in the last two decades, accumulating evidence has revealed its role as a bioactive molecule in the biological systems. H2S has relatively high expression in the brain, exerting multiple functions in both health and diseases. It modulates neurotransmission by influencing behaviors of NMDA receptors and second messenger systems including intracellular Ca(2+) concentration and intracellular cAMP levels and so forth. H2S shows potential therapeutic value in several CNS diseases including Alzheimer's disease, Parkinson's disease, ischemic stroke, and traumatic brain injury. As a neuroprotectant, H2S produces antioxidant, anti-inflammatory, and antiapoptotic effects in pathological situations. Sulfhydration of target proteins is an important mechanism underlying these effects. This Review summarizes the current understanding of H2S in the central nervous system, with emphasis on its role as a neuromodulator and a neuroprotectant.
2015
Cysteine and hydrogen sulphide in the regulation of metabolism: insights from genetics and pharmacology

Abstract
Obesity and diabetes represent a significant and escalating worldwide health burden. These conditions are characterized by abnormal nutrient homeostasis. One such perturbation is altered metabolism of the sulphur-containing amino acid cysteine. Obesity is associated with elevated plasma cysteine, whereas diabetes is associated with reduced cysteine levels. One mechanism by which cysteine may act is through its enzymatic breakdown to produce hydrogen sulphide (H2S), a gasotransmitter that regulates glucose and lipid homeostasis. Here we review evidence from both pharmacological studies and transgenic models suggesting that cysteine and hydrogen sulphide play a role in the metabolic dysregulation underpinning obesity and diabetes. We then outline the growing evidence that regulation of hydrogen sulphide levels through its catabolism can impact metabolic health. By integrating hydrogen sulphide production and breakdown pathways, we re-assess current hypothetical models of cysteine and hydrogen sulphide metabolism, offering new insight into their roles in the pathogenesis of obesity and diabetes.

2017
Hydrogen Sulfide in the Adipose Tissue-Physiology, Pathology and a Target for Pharmacotherapy

Abstract
Hydrogen sulfide (H₂S) is synthesized in the adipose tissue mainly by cystathionine γ-lyase (CSE). Several studies have demonstrated that H₂S is involved in adipogenesis, that is the differentiation of preadipocytes to adipocytes, most likely by inhibiting phosphodiesterases and increasing cyclic AMP concentration. The effect of H₂S on adipose tissue insulin sensitivity and glucose uptake is controversial. Some studies suggest that H₂S inhibits insulin-induced glucose uptake and that excess of H₂S contributes to adipose tissue insulin resistance in metabolic syndrome. In contrast, other studies have demonstrated that H₂S stimulates glucose uptake and its deficiency contributes to insulin resistance. Similarly, the effect of H₂S on adipose tissue lipolysis is controversial. H₂S produced by perivascular adipose tissue decreases vascular tone by activating ATP-sensitive and/or voltage-gated potassium channels in smooth muscle cells. Experimental obesity induced by high calorie diet has a time dependent effect on H₂S in perivascular adipose tissue; short and long-term obesity increase and decrease H₂S production, respectively. Hyperglycemia has been consistently demonstrated to suppress CSE-H₂S pathway in various adipose tissue depots. Finally, H₂S deficiency may contribute to adipose tissue inflammation associated with obesity/metabolic syndrome.
I would appreciate if someone could summarize in one short paragraph how all the above intersect with real life :D
What comes to my mind is "the liver comes first, not the gut!"
 

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alicec

Senior Member
Messages
1,572
Location
Australia
We tend to think of H2S only as a problem. Certainly too much of it is toxic, but as these reviews and studies point out, it also has beneficial effects, playing an important role as a signalling molecule. Thus it is a gasotransmitter like nitric oxide and carbon dioxide.

Like these molecules, too little is just as problematic as too much.

Beneficial roles include neuroprotection, regulation of glucose and lipid homeostasis, cryoprotective and vasodilatory effects on blood vessels and an anti-inflammatory action.

The papers also describe biosynthetic (transsulfuration and its off-shoots) and catabolic (mitochondrial oxidation, non-enzymatic reactions with non-mitochondrial haem proteins as well as direct reaction with oxygen) pathways and emphasise that it is the balance of these that govern H2S levels.

The redox state of the cell is critical to both the synthetic and catabolic pathways and this is the clue to the intersection with real life. The degree of oxidative stress in the body will profoundly influence steady state levels of H2S. Furthermore, oxygen tension strongly influences its biological actions (eg under normal oxygen tension it is vasodilatory but under hyperoxia it is vasoconstrictive) so circulation efficiency and rate of oxygen use by tissues will also have an influence.
 

Gondwanaland

Senior Member
Messages
5,092
Thank you so much @alicec for your input. I am really cuurious about how methylation supplements affect these interactions. Positively I assume?