The role of pro-opiomelanocortin in the ACTH–cortisol dissociation of sepsis

Abstract Background Sepsis is typically hallmarked by high plasma (free) cortisol and suppressed cortisol breakdown, while plasma adrenocorticotropic hormone (ACTH) is not increased, referred to as ‘ACTH–cortisol dissociation.’ We hypothesized that sepsis acutely activates the hypothalamus to generate, via corticotropin-releasing hormone (CRH) and vasopressin (AVP), ACTH-induced hypercortisolemia. Thereafter, via increased availability of free cortisol, of which breakdown is reduced, feedback inhibition at the pituitary level interferes with normal processing of pro-opiomelanocortin (POMC) into ACTH, explaining the ACTH–cortisol dissociation. We further hypothesized that, in this constellation, POMC leaches into the circulation and can contribute to adrenocortical steroidogenesis. Methods In two human studies of acute (ICU admission to day 7, N = 71) and prolonged (from ICU day 7 until recovery; N = 65) sepsis-induced critical illness, POMC plasma concentrations were quantified in relation to plasma ACTH and cortisol. In a mouse study of acute (1 day), subacute (3 and 5 days) and prolonged (7 days) fluid-resuscitated, antibiotic-treated sepsis (N = 123), we further documented alterations in hypothalamic CRH and AVP, plasma and pituitary POMC and its glucocorticoid-receptor-regulated processing into ACTH, as well as adrenal cortex integrity and steroidogenesis markers. Results The two human studies revealed several-fold elevated plasma concentrations of the ACTH precursor POMC from the acute to the prolonged phase of sepsis and upon recovery (all p < 0.0001), coinciding with the known ACTH–cortisol dissociation. Elevated plasma POMC and ACTH–corticosterone dissociation were confirmed in the mouse model. In mice, sepsis acutely increased hypothalamic mRNA of CRH (p = 0.04) and AVP (p = 0.03) which subsequently normalized. From 3 days onward, pituitary expression of CRH receptor and AVP receptor was increased. From acute throughout prolonged sepsis, pituitary POMC mRNA was always elevated (all p < 0.05). In contrast, markers of POMC processing into ACTH and of ACTH secretion, negatively regulated by glucocorticoid receptor ligand binding, were suppressed at all time points (all p ≤ 0.05). Distorted adrenocortical structure (p < 0.05) and lipid depletion (p < 0.05) were present, while most markers of adrenocortical steroidogenic activity were increased at all time points (all p < 0.05). Conclusion Together, these findings suggest that increased circulating POMC, through CRH/AVP-driven POMC expression and impaired processing into ACTH, could represent a new piece in the puzzling ACTH–cortisol dissociation.

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The role of microRNA-3085 in chondrocyte function

Scientific Reports ◽

10.1038/s41598-020-78606-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Linh Le ◽

Lingzi Niu ◽

Matthew J. Barter ◽

David A. Young ◽

Tamas Dalmay ◽

...

Keyword(s):

Feedback Inhibition ◽

Interleukin 1 ◽

Early Time ◽

Null Cell ◽

Time Points ◽

Vitro Analysis ◽

In Vitro Analysis ◽

Cultured Chondrocytes

AbstractMicroRNAs have been shown to play a role in cartilage development, homeostasis and breakdown during osteoarthritis. We previously identified miR-3085 in humans as a chondrocyte-selective microRNA, however it could not be detected by Northern blot. The aim of the current study was to prove that miR-3085 is a microRNA and to investigate the function of miR-3085 in signaling pathways relevant to cartilage homeostasis and osteoarthritis. Here, we confirm that miR-3085 is a microRNA and not another class of small RNA using (1) a pre-miR hairpin maturation assay, (2) expression levels in a Dicer null cell line, and (3) Ago2 pulldown. MicroRNA-3085-3p is expressed more highly in micromass than monolayer cultured chondrocytes. Transfection of miR-3085-3p into chondrocytes decreases expression of COL2A1 and ACAN, both of which are validated as direct targets of miR-3085-3p. Interleukin-1 induces the expression of miR-3085-3p, at least in part via NFκB. In a feed-forward mechanism, miR-3085-3p then potentiates NFκB signaling. However, at early time points after transfection, its action appears to be inhibitory. MyD88 has been shown to be a direct target of miR-3085-3p and may be responsible for the early inhibition of NFκB signaling. However, at later time points, MyD88 knockdown remains inhibitory and so other functions of miR-3085-3p are clearly dominant. TGFβ1 also induces the expression of miR-3085-3p, but in this instance, it exerts a feedback inhibition on signaling with SMAD3 and SMAD4 shown to be direct targets. This in vitro analysis shows that miR-3085-3p functions in chondrocytes to induce IL-1-signaling, reduce TGFβ1 signaling, and inhibit expression of matrix genes. These data suggest that miR-3085-3p has a role in chondrocyte function and could contribute to the process of osteoarthritis.

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Hyperhomocysteinemia and cardiovascular risk in postmenopausal women: the role of folate supplementation

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2007.067 ◽

2007 ◽

Vol 45 (2) ◽

Cited By ~ 6

Author(s):

Paola Villa ◽

Rosanna Suriano ◽

Barbara Costantini ◽

Francesca Macrì ◽

Luigi Ricciardi ◽

...

Keyword(s):

Endothelial Function ◽

Postmenopausal Women ◽

Plasma Concentrations ◽

High Plasma ◽

Folic Acid Supplementation ◽

Endothelial Damage ◽

Elevated Plasma ◽

Folate Supplementation ◽

Before And After ◽

Artery Flow

AbstractIn the postmenopausal period, cardiovascular diseases are a frequent chronic condition leading to high risk of myocardial infarction and death. Recently hyperhomocysteinemia and even mildly elevated plasma concentrations of homocysteine have been recognized as independent risk factors for vascular damage predisposing to arteriosclerosis. Elevated plasma levels of homocysteine induce vascular endothelial damage and are frequently associated with low folate levels.In this review we evaluate literature data on some aspects related to menopause and homocysteine metabolism. In particular, we show the effect of folic acid supplementation on homocysteine concentrations and on homocysteine-related thiols, such as cysteine and cysteine-glycine, as well as the relationship with glucose, insulin, and lipidic metabolism in postmenopausal women. We also analyze the influence of folate supplementation on endothelial function, by brachial artery flow-mediated dilatation (endothelium-dependent) and nitroglycerine-induced dilatation (endothelium-independent) before and after a methionine load.Folate administration in postmenopausal women is able to reduce high plasma homocysteine levels and to modify impaired endothelial function induced by hyperhomocysteinemia.Clin Chem Lab Med 2007;45:130–5.

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Intracerebroventricular Leptin Administration Reduces Food Intake in Pregnant and Lactating Mice1

Experimental Biology and Medicine ◽

10.1177/153537020222700809 ◽

2002 ◽

Vol 227 (8) ◽

pp. 616-619 ◽

Cited By ~ 16

Author(s):

Anahita M. Mistry ◽

Dale R. Romsos

Keyword(s):

Food Intake ◽

Binding Proteins ◽

Plasma Concentrations ◽

High Plasma ◽

Reduce Food Intake ◽

Elevated Plasma ◽

Female Mice ◽

Pregnancy And Lactation ◽

Pregnant Mice ◽

Plasma Leptin

Leptin acts within the hypothalamus to diminish food intake. During pregnancy and lactation, both circulating leptin concentrations and food intake are elevated, suggesting an ineffectiveness of leptin to reduce food intake in these mice. Thus, this study tested the ability of intracerebroventricular (ICV) leptin administration to alter food intake during pregnancy and lactation. Mice during the first, second, and third trimesters of pregnancy, lactating mice on postpartum Day 7, and age-matched female mice were used. Plasma leptin concentrations averaged 2.9 ± 0.3 ng/ml in control mice, increased steadily as pregnancy progressed (3.4 ± 0.7, 29.8 ± 4.5, and 40.5 ± 0.7 ng/ml during the first, second, and third trimesters, respectively), and remained elevated on Day 7 postpartum (26.4 ± 7.8 ng/ml). Mice were food deprived for 4 h, injected ICV with vehicle or leptin (1 μg), and food intake was subsequently measured hourly for 3 hr, and after 24 hr. Vehicle-treated pregnant mice consumed marginally more food than cycling control mice, whereas nursing dams ate two to three times as much food as controls. As expected, ICV leptin administration reduced 24-hr food intake of control mice by 2 g, or ~50%. ICV-administered leptin was as effective in reducing food Intake of pregnant and lactating mice as observed in control mice. Thus, the elevated circulating leptin concentrations observed in pregnant and nursing mice did not alter the ability of ICV-administered leptin to diminish food intake. High plasma concentrations of leptin-binding proteins observed during pregnancy, and probably during lactation, may limit the amount of endogenous leptin reaching the hypothalamus, and may consequently enable increases in food intake concomitant with elevated plasma leptin during these nutritionally demanding periods.

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Plasma concentrations of YKL-40 in chemo-naive patients with metastatic colorectal cancer treated with FLOX with or without cetuximab: Results from the NORDIC VII study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3548 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3548-3548

Author(s):

Line Schmidt Tarpgaard ◽

Tormod Kyrre Guren ◽

Bengt Glimelius ◽

Per Pfeiffer ◽

Elin Kure ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Healthy Subjects ◽

Performance Status ◽

Plasma Concentrations ◽

Progression Free Survival ◽

High Plasma ◽

Phase Iii ◽

Elevated Plasma ◽

Egfr Inhibition

3548 Background: KRAS status is presently the best biomarker to select patients with metastatic colorectal cancer (mCRC) for therapy with EGFR inhibition even though not confirmed in all phase III studies. In the NORDIC VII study a survival benefit of adding cetuximab to the Nordic FLOX regimen could not be confirmed. Identification of new predictive and prognostic biomarkers is essential. Plasma concentration of YKL-40 is emerging as a new biomarker in patients with cancer and inflammatory diseases. We tested the hypothesis that high plasma YKL-40 associates with short progression free survival (PFS) and short overall survival (OS) in patients included in the NORDIC VII Study. Methods: 566 patients with mCRC were randomized to: A) Nordic FLOX; B) FLOX + cetuximab; and C) FLOX for 16 weeks + cetuximab continuously. Plasma samples were available from 510 patients (90%). Pretreatment plasma YKL-40 was determined by ELISA (Quidel), and the plasma YKL-40 concentration was dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects. Results: Plasma YKL-40 was elevated in 204 patients (40%) and the median plasma YKL-40 was higher in the study group compared to healthy subjects (120 mg/l vs. 40 mg/l, p<0.001). Elevated plasma YKL-40 was associated with short PFS (HR=1.25, 95% CI 1.04-1.51, p=0.02). This relationship was demonstrated only in patients treated with FLOX chemotherapy alone (HR=1.42, 1.02-1.98, p=0.04). High plasma YKL-40 was associated with short OS in all patients (HR=1.55, 1.25-1.92, p<0.001) and in the different treatment groups (A: HR=1.54, 1.05-2.26, p=0.03; B: HR=1.40, 0.97-2.01, p=0.07; C: 1.79, 1.23-2.60, p=0.002). Multivariate analysis (YKL-40, performance status, number of metastatic sites) demonstrated that elevated plasma YKL-40 was an independent biomarker of short OS (HR=1.46, 1.17-1.81, p=0.001). Conclusions: Plasma YKL-40 may be a new prognostic biomarker in patients with mCRC treated with 1st line FLOX chemotherapy, with or without cetuximab. The predictive value of plasma YKL-40 is not yet clarified.

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ELEVATED PLASMA LEVELS OF LAUDANOSINE ARE ASSOCIATED WITH HIGH PLASMA CONCENTRATIONS OF NOREPINEPHRINE DURING ORTHOTOPIC LIVER TRANSPLANTATION IN PIGS

Anesthesiology ◽

10.1097/00000542-198809010-00484 ◽

1988 ◽

Vol 69 (3A) ◽

pp. A484-A484

Author(s):

J. F. Pittet ◽

E. Tassonyi ◽

C. Schopfer ◽

D. R. Morel ◽

M. Fahti ◽

...

Keyword(s):

Liver Transplantation ◽

Orthotopic Liver Transplantation ◽

Plasma Levels ◽

Plasma Concentrations ◽

High Plasma ◽

Elevated Plasma

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The role of vinpocetine in the treatment of cerebrovascular diseases based on human studies

Orvosi Hetilap ◽

10.1556/oh.2007.28115 ◽

2007 ◽

Vol 148 (29) ◽

pp. 1353-1358 ◽

Cited By ~ 27

Author(s):

Edit Bagoly ◽

Gergely Fehér ◽

László Szapáry

Keyword(s):

Cerebrovascular Diseases ◽

Human Studies

Az agyérbetegségek jelentőségét jelzi, hogy a cardiovascularis és tumoros betegségek után a stroke jelenti a harmadik leggyakoribb halálokot világszerte. Mivel stroke során az érintett agyállomány irreverzíbilisen károsodik, az infarktust övező épen maradt, de általában hipoperfundált agyterületek működésének serkentésével lehet a betegek állapotán javítani. Az agyi véráramlás növelése révén várható javulás a stroke-on még át nem esett, de krónikus agyi hipoperfúzióban szenvedő betegek tüneteiben is. Célkitűzés, módszer: Jelen tanulmány célja, hogy áttekintse a vinpocetin akut és krónikus agyérbetegségekben történő alkalmazásának eddig publikált humán vizsgálati eredményeit, és összefoglaló képet adjon a gyógyszer főbb indikációs területeiről, az ott mutatott hatékonyságról. Eredmények: A vinpocetin akut ischaemiás stroke-ban történő alkalmazását vizsgáló tanulmányok száma csekély, eredményeik pedig ellentmondásosak. Krónikus agyérbetegek esetében mind az egyszeri, mind a hosszú távú vinpocetinkezelést követően PET-, SPECT-, TCD- és NIRS-vizsgálatokkal a laesio körüli ép agyterületek perfúziónövekedése, fokozott glükóz- és O 2 -felhasználása igazolódott, és jelentős javulás volt észlelhető a vér reológiai paramétereiben is. A klinikai hatékonyságot értékelő nemzetközi tanulmányok metaanalízise alapján a gyógyszer per os alkalmazásával szignifikáns javulás jelentkezik a kognitív teljesítményben és a napi aktivitásban. Következtetések: A fenti vizsgálatok eredményei alapján kimondható, hogy a vinpocetin sokrétű farmakológiai hatása révén kedvezően befolyásolja az agy ép területeinek perfúzióját és metabolizmusát, a vér áramlási viszonyait, javítva ezzel a krónikus agyérbetegek életminőségét.

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