Cholangiocyte autophagy contributes to hepatic cystogenesis in polycystic liver disease and represents a potential therapeutic target

Masyuk, Anatoliy I.; Masyuk, Tatyana V.; Pisarello, María J. Lorenzo; Ding, Jingyi Francess; Loarca, Lorena; Huang, Bing; LaRusso, Nicholas F.

doi:10.1002/hep.29577

Cited by 34 publications

(31 citation statements)

References 32 publications

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“…This suggested that the moderate enhancement of autophagy might be beneficial to the culture of stem cells in vitro, which cleared away the impaired cellular components and kept cell homeostasis [ 48 , 49 ]. Moreover, the intensity of autophagy could be regulated by certain drugs, such as rapamycin [ 50 , 51 ] and bafilomycin A1 [ 52 , 53 ]. Since BMSCs are widely applied as seed cells in bone tissue engineering [ 54 ], our study may provide a new strategy to expand BMSCs abundantly in vitro by regulating their autophagy intensity without impairing their self-renewal and pluripotent differentiation abilities.…”

Section: Discussionmentioning

confidence: 99%

Dorsal Root Ganglion Maintains Stemness of Bone Marrow Mesenchymal Stem Cells by Enhancing Autophagy through the AMPK/mTOR Pathway in a Coculture System

Zhang

Jiang

et al. 2018

Stem Cells International

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Our previous studies found that sensory nerve tracts implanted in tissue-engineered bone (TEB) could result in better osteogenesis. To explore the mechanism of the sensory nerve promoting osteogenesis in TEB in vitro, a transwell coculture experiment was designed between dorsal root ganglion (DRG) cells and bone marrow mesenchymal stem cells (BMSCs). BMSC proliferation was determined by CCK8 assay, and osteo-, chondro-, and adipogenic differentiation were assessed by alizarin red, alcian blue, and oil red staining. We found that the proliferation and multipotent differentiation of BMSCs were all enhanced in the coculture group compared to the BMSCs group. Crystal violet staining showed that the clone-forming ability of BMSCs in the coculture group was also enhanced and mRNA levels of Sox2, Nanog, and Oct4 were significantly upregulated in the coculture group. Moreover, the autophagy level of BMSCs, regulating their stemness, was promoted in the coculture group, mediated by the AMPK/mTOR pathway. In addition, AMPK inhibitor compound C could significantly downregulate the protein expression of LC3 and the mRNA level of stemness genes in the coculture group. Finally, we found that the NK1 receptor antagonist, aprepitant, could partly block this effect, which indicated that substance P played an important role in the effect. Together, we conclude that DRG could maintain the stemness of BMSCs by enhancing autophagy through the AMPK/mTOR pathway in a transwell coculture system, which may help explain the better osteogenesis after implantation of the sensory nerve into TEB.

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Section: Discussionmentioning

confidence: 99%

Dorsal Root Ganglion Maintains Stemness of Bone Marrow Mesenchymal Stem Cells by Enhancing Autophagy through the AMPK/mTOR Pathway in a Coculture System

Zhang

Jiang

et al. 2018

Stem Cells International

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“…It is protective through enhanced phosphorylation of the pro-survival kinase ERK1/2 [36]. It efficiently inhibited hepatic cystogenesis in the polycystic kidney disease and affected the autophagy process that increased in polycystic liver disease [37]. HCQ is evaluated in cardiac neonatal lupus model and it gives favorable results.…”

Section: Discussionmentioning

confidence: 99%

Impact of Hydroxychloroquine on Fructose-induced Metabolic Syndrome in Rats: Promising Protective Effect

Shata¹,

Naga²,

Elsawy³

et al. 2020

Open Access Maced J Med Sci

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BACKGROUND: Hydroxychloroquine (HCQ) is used in the treatment of malaria and rheumatoid arthritis for a long time. Its effects on inflammation and immune modulation were noted. AIM: This study aims to investigate the effects of HCQ in fructose-induced metabolic syndrome and to explore its possible mechanisms. METHODS AND MATERIALS: Sixty male Sprague-Dawley rats were divided into Group I (negative control), Group II fed on high-fructose diet, and Group III fed on high fructose and subdivided into Group III-a (HCQ 50 mg/kg), Group III-b (HCQ 100 mg/kg), Group III-c (HCQ 200 mg/kg), and Group III-d (metformin 100 mg/kg). Body weight, blood glucose, liver enzymes, and lipid profile were measured. Insulin level, homeostatic model assessment (HOMA), soluble-intercellular adhesion molecule, and vascular cell adhesion molecule were assayed. Tumor necrosis factor (TNF)-α, adipokines (leptin, resistin, and adiponectin), and histological examination of pancreas were assessed. RESULTS: HCQ induces good effects on lipid profile and improves significantly HOMA, endothelial stress markers, and adiponectin, and reduces leptin and TNF-α levels. In addition, significant improvement in structural changes was noted in pancreas with different doses of HCQ. CONCLUSION: Favorable effects of HCQ in fructose-induced metabolic syndrome are promising and can be used early in those at risk of diabetes.

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“…An aberrant relation between intracellular calcium and c-AMP is proposed as the mechanism of liver cyst formation. 3,7 As discussed, tolvaptan reduces c-AMP in cholangiocytes. 9 Although 14 out of 135 ADPKD patients experienced hepatic events in Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) extension Japan trial, they recovered after the interruption of tolvaptan.…”

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confidence: 95%

“…Recent studies show that cholangiocyte autophagy, which is associated with activation of the cyclic adenosine monophosphate protein signaling pathway, contributes to cystogenesis in polycystic liver disease. 7 Further, follicle-stimulating hormone (FSH) receptors are seen in biliary epithelial cells from normal and ADPKD patients. 8 FSH increases c-AMP in cholangiocytes, inducing biliary growth via ERK.…”

mentioning

confidence: 99%

“…R, right; L, left. ease, 7,9 and suggests that tolvaptan treatment can be performed safely in patients with polycystic liver disease. These provide potential applicability of tolvaptan for polycystic liver disease patients with normal liver function to manage hepatomegaly, and warrant further clinical investigations to examine the effects of tolvaptan as a novel agent militating against liver cyst progression.…”

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confidence: 99%

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The management of polycystic liver disease by tolvaptan

2020

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Cholangiocyte autophagy contributes to hepatic cystogenesis in polycystic liver disease and represents a potential therapeutic target

Abstract: Autophagy is increased in PLD cholangiocytes, contributes to hepatic cystogenesis, and represents a potential therapeutic target for disease treatment. (Hepatology 2018;67:1088-1108).

Cited by 34 publications

References 32 publications

Dorsal Root Ganglion Maintains Stemness of Bone Marrow Mesenchymal Stem Cells by Enhancing Autophagy through the AMPK/mTOR Pathway in a Coculture System

Dorsal Root Ganglion Maintains Stemness of Bone Marrow Mesenchymal Stem Cells by Enhancing Autophagy through the AMPK/mTOR Pathway in a Coculture System

Impact of Hydroxychloroquine on Fructose-induced Metabolic Syndrome in Rats: Promising Protective Effect

The management of polycystic liver disease by tolvaptan

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