Sleep‐Wake profiles in patients with primary biliary cirrhosis

Montagnese, Sara; Nsemi, Letizia M.; Cazzagon, Nora; Facchini, Silvia; Costa, Laura Olinda Bregieiro Fernandes; Bergasa, Nora V.; Amodio, Piero; Floreani, Annarosa

doi:10.1111/liv.12026

Cited by 39 publications

(41 citation statements)

References 33 publications

(45 reference statements)

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“…The increase in melatonin serum levels (observed in Mdr2 2/2 mice) was likely caused by enhanced AANAT expression and melatonin secretion by cholangiocytes by a compensatory mechanism related to reduced AANAT expression in the pineal gland of Mdr2 2/2 mice. The latter is supported by studies demonstrating a disturbance in sleep-wake profiles in patients with PBC and in the hepatic circadian clock (both regulated by the pineal gland) in a mouse model of alcohol-induced hepatic steatosis (22,23). In Mdr2 2/2 mice exposed to prolonged dark, the increase in melatonin serum levels is probably caused by enhanced AANAT expression by pineal gland and melatonin secretion by the pineal gland (24); further studies are necessary to understand the decrease in melatonin secretion by cholangiocytes during prolonged dark exposure.…”

Section: Discussionmentioning

confidence: 82%

Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR‐200b down‐regulation

Meng

Zhou

et al. 2017

FASEB j.

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Melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in bile-duct-ligated (BDL) rats; however, no information exists in primary sclerosing cholangitis (PSC). Thus, we aimed to determine the therapeutic effects of prolonged dark therapy or melatonin administration on hepatic fibrosis in the multidrug resistance gene 2-knockout (Mdr2) mouse model of PSC. Melatonin levels, biliary mass, liver fibrosis, angiogenesis and miR-200b expression were evaluated in wild-type and Mdr2 mice exposed to darkness or melatonin treatment or in male patients with PSC and healthy controls. Mdr2 mice were also treated with miR-200b inhibitor or control before evaluating biliary mass, liver fibrosis, and angiogenesis. After overexpression of arylalkylamine -acetyltransferase (AANAT; the enzyme regulating melatonin synthesis) or inhibition of miR-200b in cholangiocytes and hepatic stellate cells, we evaluated angiogenesis and fibrosis gene expression. After exposure to darkness or administration of melatonin, Mdr2 mice show elevated serum melatonin levels and inhibition of biliary mass, along with reduction of liver fibrosis and angiogenesis. MicroRNA PCR analysis demonstrated that miR-200b expression increased in Mdr2 mice and patients with PSC compared with controls and decreased in Mdr2 mice subjected to dark exposure or melatonin treatment. Inhibition of miR-200b in Mdr2 ablates biliary proliferation, liver fibrosis, and angiogenesis. , overexpression of AANAT or inhibition of miR-200b in cholangiocytes and hepatic stellate cells decreased the expression of miR-200b, angiogenesis, and fibrosis genes. Dark therapy or targeting melatonin/miR-200b axis may be important in the management of biliary damage and liver fibrosis in cholangiopathies including PSC.-Wu, N., Meng, F., Zhou, T., Han, Y., Kennedy, L., Venter, J., Francis, H., DeMorrow, S., Onori, P., Invernizzi, P., Bernuzzi, F., Mancinelli, R., Gaudio, E., Franchitto, A., Glaser, S., Alpini G. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation.

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Section: Discussionmentioning

confidence: 82%

Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR‐200b down‐regulation

Meng

Zhou

et al. 2017

FASEB j.

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“…It has been suggested that circadian rhythm and melatonin synthesis is associated with the pathophysiology of cholangiopathies and liver cirrhosis. A previous study using 74 PBC patients, 60 cirrhosis patients, and 79 healthy individuals has found that sleep timing is significantly delayed in patients with PBC or cirrhosis, and delayed sleep timing is associated with impaired sleep quality in PBC patients . Another study using 13 PBC patients, seven cirrhosis patients, and six healthy individuals found that patients with PBC or cirrhosis had poor sleep quality assessed by the Pittsburgh Sleep Quality Index .…”

Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 99%

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress‐induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.

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“…Strikingly, these features were almost entirely absent from patients with low levels of fatigue. Different combinations of these associated features are seen in other CLD, with autonomic dysfunction the prominent association in PBC, and autonomic dysfunction and sleep disturbance the prominent associations in NASH …”

Section: Management Of Fatigue In Practicementioning

confidence: 99%

Fatigue in chronic liver disease: New insights and therapeutic approaches

Swain

Jones

2018

Liver International

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The management of fatigue associated with chronic liver disease is a complex and major clinical challenge. Although fatigue can complicate many chronic diseases, it is particularly common in diseases with an inflammatory component. Fatigue can have both peripheral (i.e., neuromuscular) and central (i.e., resulting from changes in neurotransmission within the brain) causes. However, fatigue in chronic liver disease has strong social/contextual components and is often associated with behavioural alterations including depression and anxiety. Given the increasing awareness of patient-reported outcomes as important components of treatment outcomes and clinical research, there is a growing need to better understand and manage this poorly understood yet debilitating symptom. Although several pathophysiological mechanisms for explaining the development of fatigue have been generated, our understanding of fatigue in patients with chronic liver disease remains incomplete. A better understanding of the pathways and neurotransmitter systems involved may provide specific directed therapies. Currently, the management of fatigue in chronic liver disease can involve a combined use of methods to beneficially alter behavioural components and pharmacological interventions, of which several treatments have potential for the improved management of fatigue in chronic liver disease. However, evidence and consensus are lacking on the best approach and the most appropriate biochemical target(s) whilst clinical trials to address this issue have been few and limited by small sample size. In this review, we outline current understanding of the impact of fatigue and related symptoms in chronic liver disease, discuss theories of pathogenesis, and examine current and emerging approaches to its treatment.

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Sleep‐Wake profiles in patients with primary biliary cirrhosis

Abstract: Patients with PBC exhibited a delay in sleep timing that was associated with impaired sleep quality/quality of life. In addition, an interplay was observed between diurnal preference and the daytime course of pruritus/sleepiness.

Cited by 39 publications

References 33 publications

Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR‐200b down‐regulation

Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR‐200b down‐regulation

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Fatigue in chronic liver disease: New insights and therapeutic approaches

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