The crucial physiological process of heme breakdown yields biliverdin (BV) and bilirubin (BR) as byproducts. BV, BR, and the enzymes involved in their production (the "yellow players-YP") are increasingly documented as endogenous modulators of human health. Mildly elevated serum bilirubin concentration has been correlated with a reduced risk of multiple chronic pro-oxidant and pro-inflammatory diseases, especially in the elderly. BR and BV per se have been demonstrated to protect against neurodegenerative diseases, in which heme oxygenase (HMOX), the main enzyme in the production of pigments, is almost always altered. HMOX upregulation has been interpreted as a tentative defense against the ongoing pathologic mechanisms. With the demonstration that multiple cells possess YP, their propensity to be modulated, and their broad spectrum of activity on multiple signaling pathways, the YP have assumed the role of an adjustable system that can promote health in adults. Based on that, there is an ongoing effort to induce their activity as a therapeutic option, and natural compounds are an attractive alternative to the goal, possibly requiring only minimal changes in the life style. We review the most recent evidence of the potential of natural compounds in targeting the YP in the context of the most common pathologic condition of adult and elderly life.

• Keywords
• Alzheimer’s disease, MAFLD, NRF2, Parkinson’s disease, bilirubin, cancer, heme-oxygenase, herbal medicine, neurodegeneration, nutraceuticals,
• MeSH
• Bilirubin MeSH
• Biliverdine MeSH
• Adult MeSH
• Heme MeSH
• Heme Oxygenase (Decyclizing) MeSH
• Liver MeSH
• Humans MeSH
• Brain Diseases * MeSH
• Health Promotion * MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Bilirubin MeSH
• Biliverdine MeSH
• Heme MeSH
• Heme Oxygenase (Decyclizing) MeSH

Pigment gallstones, which are much less frequent than cholesterol stones, are classified descriptively as "black" or "brown". They are composed mostly of calcium hydrogen bilirubinate, Ca(HUCB)(2), which is polymerized and oxidized in "black" stones but remains unpolymerized in "brown" stones. Black stones form in sterile gallbladder bile but brown stones form secondary to stasis and anaerobic bacterial infection in any part of the biliary tree, including the gallbladder. Other calcium salts coprecipitate in both stone types; crystalline calcium phosphate and/or carbonate in the case of "black" stones and amorphous calcium salts of long chain saturated fatty acids ("soaps") in the case of "brown" stones. Cholesterol is present in variable proportions in "brown" more than "black" stones and in the latter, the bile sterol may be totally absent. The "scaffolding" of both stone types is a mixed mucin glycoprotein matrix secreted by epithelial cells lining the biliary tree. The critical pathophysiological prerequisite for "black" stone formation is "hyperbilirubinbilia" (biliary hypersecretion of bilirubin conjugates). It is due principally to hemolysis, ineffective erythropoiesis, or pathologic enterohepatic cycling of unconjugated bilirubin. Endogenous biliary β-glucuronidase hydrolysis of bilirubin conjugates in gallbladder bile provides HUCB(-) molecules that precipitate as insoluble salts with ionized Ca. Putatively, reactive oxygen species secreted by an inflamed gallbladder mucosa are responsible for transforming the initial soft yellow precipitates into hard black [Ca(HUCB)(2)](n) polymers. Despite "brown" gallstones being soft and amenable to mechanical removal, chronic anaerobic infection of the biliary tree is often markedly resistant to eradication.

• MeSH
• Humans MeSH
• Gallstones etiology   physiopathology   MeSH
• Bile Pigments MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Bile Pigments MeSH