DHEAS on antipatogeeninen

Mol Endocrinol. 2010 Apr;24(4):813-21. Epub 2010 Feb 19. Dehdyroepiandrosterone sulfate directly activates protein kinase C-beta to increase human neutrophil superoxide generation.

Radford DJ, Wang K, McNelis JC, Taylor AE, Hechenberger G, Hofmann J, Chahal H, Arlt W, Lord JM.

Source

Medical Research Council Centre for Immune Regulation, School of Immunity & Infection, University of Birmingham, Birmingham, United Kingdom.

Abstract

Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in the human circulation and is secreted by the adrenals in an age-dependent fashion, with maximum levels during the third decade and very low levels in old age. DHEAS is considered an inactive metabolite, whereas cleavage of the sulfate group generates dehydroepiandrosterone (DHEA), a crucial sex steroid precursor. However, here we show that DHEAS, but not DHEA, increases superoxide generation in primed human neutrophils in a dose-dependent fashion, thereby impacting on a key bactericidal mechanism. This effect was not prevented by coincubation with androgen and estrogen receptor antagonists but was reversed by the protein kinase C inhibitor Bisindolylmaleimide 1. Moreover, we found that neutrophils are unique among leukocytes in expressing an organic anion-transporting polypeptide D, able to mediate active DHEAS influx transport whereas they did not express steroid sulfatase that activates DHEAS to DHEA. A specific receptor for DHEAS has not yet been identified, but we show that DHEAS directly activated recombinant protein kinase C-beta (PKC-beta) in a cell-free assay. Enhanced PKC-beta activation by DHEAS resulted in increased phosphorylation of p47(phox), a crucial component of the active reduced nicotinamide adenine dinucleotide phosphate complex responsible for neutrophil superoxide generation. Our results demonstrate that PKC-beta acts as an intracellular receptor for DHEAS in human neutrophils, a signaling mechanism entirely distinct from the role of DHEA as sex steroid precursor and with important implications for immunesenescence, which includes reduced neutrophil superoxide generation in response to pathogens.

Olisiko K-vitamiinifunktiolla merkitystä?

Intensive Care Med. 2010 Nov;36(11):1852-8. Epub 2010 Jul 28.Human and experimental septic shock are characterized by depletion of lipid droplets in the adrenals.

Polito A, Lorin de la Grandmaison G, Mansart A, Louiset E, Lefebvre H, Sharshar T, Annane D.

Source

General Intensive Care Unit and Laboratoire d'étude de la réponse neuroendocrine au sepsis EA4342, Service de Réanimation, Raymond Poincaré Hospital (AP-HP), University Versailles Saint-Quentin en Yvelines, 92380, Garches, France.

Abstract

RATIONALE:

Cholesteryl ester deficiency which results in adrenal lipid store depletion has been proposed as a potential mechanism of sepsis associated adrenal insufficiency.

OBJECTIVE:

We investigated histological abnormalities associated with sepsis in human and mice adrenals.

METHODS:

From January 2006 to 2008, seven patients who died of septic shock and seven patients with rapidly fatal nonseptic illness were included. Adrenals were sampled within 12 h from death. Adrenals were also taken from 13 lipopolysaccharide (LPS)-challenged mice, 5 cecal ligation and puncture (CLP) mice and 5 controls. We semi-quantitatively analysed intensity of inflammation, necrosis, haemorrhage and lipid depletion.

MEASUREMENTS AND MAIN RESULTS:

In patients, lipid depletion scores were significantly higher in septic shock than in controls (p = 0.011). In animals, lipid depletion was higher following LPS or CLP than in controls (p = 0.003). In adrenal cortex, in patients and not in animals, global scores for inflammation (p = 0.002), necrosis (p = 0.009) and haemorrhage (p = 0.009) were significantly higher in septic shock than in controls. Similarly, in zona fasciculata, in patients and not in animals, scores for inflammation (p = 0.007), necrosis (p = 0.023) and haemorrhage (p = 0.023) were significantly higher in septic shock than in controls.

CONCLUSIONS:

This study shows that diffuse lipid depletion in zona fasciculata is a hallmark of human septic shock, experimental endotoxaemia and sepsis. In patients, sepsis was associated with inflammation, necrosis and haemorrhage predominantly in zona fasciculata.

Olisiko K-vitamiinifunktiolla merkitystä?

Intensive Care Med. 2010 Nov;36(11):1852-8. Epub 2010 Jul 28.

Human and experimental septic shock are characterized by depletion of lipid droplets in the adrenals.

Polito A, Lorin de la Grandmaison G, Mansart A, Louiset E, Lefebvre H, Sharshar T, Annane D.

Source

General Intensive Care Unit and Laboratoire d'étude de la réponse neuroendocrine au sepsis EA4342, Service de Réanimation, Raymond Poincaré Hospital (AP-HP), University Versailles Saint-Quentin en Yvelines, 92380, Garches, France.

Abstract

RATIONALE:

Cholesteryl ester deficiency which results in adrenal lipid store depletion has been proposed as a potential mechanism of sepsis associated adrenal insufficiency.

OBJECTIVE:

We investigated histological abnormalities associated with sepsis in human and mice adrenals.

METHODS:

From January 2006 to 2008, seven patients who died of septic shock and seven patients with rapidly fatal nonseptic illness were included. Adrenals were sampled within 12 h from death. Adrenals were also taken from 13 lipopolysaccharide (LPS)-challenged mice, 5 cecal ligation and puncture (CLP) mice and 5 controls. We semi-quantitatively analysed intensity of inflammation, necrosis, haemorrhage and lipid depletion.

MEASUREMENTS AND MAIN RESULTS:

In patients, lipid depletion scores were significantly higher in septic shock than in controls (p = 0.011). In animals, lipid depletion was higher following LPS or CLP than in controls (p = 0.003). In adrenal cortex, in patients and not in animals, global scores for inflammation (p = 0.002), necrosis (p = 0.009) and haemorrhage (p = 0.009) were significantly higher in septic shock than in controls. Similarly, in zona fasciculata, in patients and not in animals, scores for inflammation (p = 0.007), necrosis (p = 0.023) and haemorrhage (p = 0.023) were significantly higher in septic shock than in controls.

CONCLUSIONS:

This study shows that diffuse lipid depletion in zona fasciculata is a hallmark of human septic shock, experimental endotoxaemia and sepsis. In patients, sepsis was associated with inflammation, necrosis and haemorrhage predominantly in zona fasciculata.

DHEA ja DHEAS , sulfotransferaasi

Tänään kävin biomedisiinisessä kirjastossa ja havaitsin uusien väitöskirjojen joukossa Andreas Muth- nimisen lääkärin väitöskirjan Incidentally discovered adrenal tumours, adrenal metastases , and pheochromocytomas. Clinical and epidemiological aspects. Väitös on ensikuun alkuviikolla.
ISBN 978-91- 628-8263-1.

Kirjassa oli paljon tärkeää asiaa lisämunuaisytimen erittämistä katekoliamineista, joilla on jo tunnettu merkitys muistin ja kognition suhteen.
Mutta tässä kuvattiin myös runsaasti lisämunuaiskuorikerroksesta syntyvää DHEA:ta ja siitä toisaalla on myös annettu tietoa, että sekin vaikuttaa kognitioon.

• Eräs lause kiinnitti huomiotani, sillä se voinee linkkiä DHEA:n metabolian K-vitamiinista riippuvaksi., koska siinä tarvitaan entsyymiä sulfotransferaasi.

The sulfotransferase, responsible for synthesis of DHEA-sulphate, is mainly located in the ZONA RETICULARIS.
Sulfotransferaasi, joka vastaa DHEA:n sulfatoimisesta, sijaitsee retikularis-vylhykkeessä.

Lisämunuaiskuoren ( cortex) n alkuperä on mesodermaalinen
ja uloin vyöhyke on ohut ZONA GLOMERULOSA( se erittää aldosteronia)
keskivyöhyke on lipidipitoinen ZONA FASCICULATA ( se erittää kortisolia)
ja sisävyöhyke on pigmenttipitoinen ZONA RETICULATA ( se erittää androgeeneja kuten DHEA)
Kahden viimemainitun vyöhykkeen välillä on välivyöhyke, ZONA INTERMEDIA, joka on proliferatiivinen.

---
Myös eräitten lipidien synteesissä on K-vitamiini välttämätön. Lipidien laatu lipidikerroksessa ZONA FASCICULATA on siten myös mielenkiintoinen seikka.

Dehydroepiandrosteronisulfaatti (DHEAS) ja muisti

Pol Merkur Lekarski. 2008 Jan;24(139):66-71. [Current views on the role of dehydroepiandrosterone in physiology, pathology and therapy].

[Article in Polish]

Krysiak R, Frysz-Naglak D, Okopień B. Source Slaska Akademia Medyczna w Katowicach, Klinika Chorób Wewnetrznych i Farmakologii Klinicznej Katedry Farmakologii.

Abstract

Dehydroepiandrosterone (DHEA) and its sulfate metabolite (DHEAS) are the major androgens secreted by the human adrenal gland.

Dehydroepiandrosteroni ja sen sulfaatti DHEAS ovat pääasialliset androgeenit, joita erittyy ihmisen lisämunuaisista.

The decline in their production is the most characteristic age-related change in the adrenal cortex.

Niiden tuotannon väheneminen on kaikkein luonteenomaisin vanhenemisen merkki lisämunuaiskuoressa.

This process, known as 'adrenopause' may contribute to the increased incidence of atherosclerosis, cancer, or dementia in older people.

Tämä adrenopaussi saattaa osaltaan olla lisäämässä ateroskleroosin, syövän tai dementian ilmaantumista vanhemmilla henkilöillä.

The possibility of using DHEA in management has attracted considerable attention over recent years.

Viimevuosina on mahdollinen DHEA:n käyttäminen hoitona alkanut pohdituttaa.

Whereas DHEA therapy seems to be effective in treating patients with adrenal insufficiency and systemic lupus erythematosus, clinical studies investigating the potential efficacy of DHEA therapy in multiple other disorders (Alzheimer disease, depression, cardiovascular disease, osteoporosis, sexual dysfunctions) have not provided consistent results.

Kun DHEA-terapia näyttää olevan tehokasta lisämunuaisen vajaatoiminnassa ja systeemisessä lupus erytematosus-taudissa, niin kliiniset tutkimukset, jotka selvittävät DHEA:n mahdollista tehoa monissa muissa häiriöissä ( Alzheimerin tauti, depressio, kardiovaskulaarinen tauti, osteoporoosi, seksuaalinen dysfunktio) eivät ole tuotaneet mitään johdonmukaista tulosta.

Further research is also needed to better assess the efficacy and safety of DHEA supplementation in patients with advanced age.

Lisätutkimuksia tarvitaan myös DHEA:n annostuksen tehon ja turvallisuuden määrittämiseen ikääntyneillä.

This review evaluates current understanding of physiology and pathology of DHEA production and summarizes the possible therapeutic value of this hormone.

Tämä katsaus arvioi nykyistä ( 2008) DHEA-produktion fysiologiaa ja patologiaa ja tekee yhteenvetoa tä-män hormonin terapeuttisesta arvosta.

PMID:

18634257

[PubMed - indexed for MEDLINE]

MeSH Terms

• Adrenal Gland Diseases/drug therapy
• Adrenal Gland Diseases/metabolism
• Adrenal Glands/metabolism*
• Adrenarche/physiology*
• Aged
• Aging/metabolism*
• Atherosclerosis/metabolism
• Atherosclerosis/prevention & control
• Cardiovascular System/metabolism
• Dehydroepiandrosterone/immunology
• Dehydroepiandrosterone/metabolism*
• Dehydroepiandrosterone/therapeutic use*
• Dementia/metabolism
• Dementia/prevention & control
• Humans
• Lupus Erythematosus, Systemic/drug therapy
• Lupus Erythematosus, Systemic/metabolism
• Receptors, Steroid/metabolism

Substances

• Receptors, Steroid
• dehydroepiandrosterone receptor
• Dehydroepiandrosterone

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