4,440 research outputs found
Polycystic liver diseases: advanced insights into the molecular mechanisms
No full textPolycystic liver diseases are genetic disorders characterized by progressive bile duct dilatation and/or cyst development. The large volume of hepatic cysts causes different symptoms and complications such as abdominal distension, local pressure with back pain, hypertension, gastro-oesophageal reflux and dyspnea as well as bleeding, infection and rupture of the cysts. Current therapeutic strategies are based on surgical procedures and pharmacological management, which partially prevent or ameliorate the disease. However, as these treatments only show short-term and/or modest beneficial effects, liver transplantation is the only definitive therapy. Therefore, interest in understanding the molecular mechanisms involved in disease pathogenesis is increasing so that new targets for therapy can be identified. In this Review, the genetic mechanisms underlying polycystic liver diseases and the most relevant molecular pathways of hepatic cystogenesis are discussed. Moreover, the main clinical and preclinical studies are highlighted and future directions in basic as well as clinical research are indicated
Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment
No full textPolycystic liver diseases (PLDs) are a group of genetic hereditary cholangiopathies characterized by the development and progressive growth of cysts in the liver, which are the main cause of morbidity. Current therapies are based on surgical procedures and pharmacological strategies, which show short-term and modest beneficial effects. Therefore, the determination of the molecular mechanisms of pathogenesis appears to be crucial in order to find new potential targets for pharmacological therapy. Ductal plate malformation during embryogenesis and abnormal cystic cholangiocyte growth and secretion are some of the key mechanisms involved in the pathogenesis of PLDs. However, the discovery of the presence of bile acids in the fluid collected from human cysts and the intrahepatic accumulation of cytotoxic bile acids in an animal model of PLD (i.e. polycystic kidney (PCK) rat) suggest a potential role of impaired bile acid homeostasis in the pathogenesis of these diseases. On the other hand, ursodeoxycholic acid (UDCA) has emerged as a new potential therapeutic tool for PLDs by promoting the inhibition of cystic cholangiocyte growth in both PCK rats and highly symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD: most common type of PLD), and improving symptoms. Chronic treatment with UDCA normalizes the decreased intracellular calcium levels in ADPKD human cholangiocytes in vitro, which results in the reduction of their baseline-stimulated proliferation. Moreover, UDCA decreases the liver concentration of cytotoxic bile acids in PCK rats and the bile acid-dependent enhanced proliferation of cystic cholangiocytes. Here, the role of bile acids in the pathogenesis of PLDs and the potential therapeutic value of UDCA for the treatment of these diseases are reviewed and future lines of investigation in this field are proposed.</jats:p
TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation
No full textBackground & Aims: Inflammation, particularly that mediated by bacterial components translocating from the gut to the liver and binding to toll-like receptors (TLRs), is central to cholestatic liver injury. The triggering receptor expressed on myeloid cells-2 (TREM-2) inhibits TLR-mediated signaling and exerts a protective role in hepatocellular injury and carcinogenesis. This study aims to evaluate the role of TREM-2 in cholestasis.Methods: TREM-2 expression was analyzed in the livers of pa-tients with primary biliary cholangitis (PBC) or primary scle-rosing cholangitis (PSC), and in mouse models of cholestasis. Wild-type (WT) and Trem-2 deficient (Trem-2-/-) mice were subjected to experimental cholestasis and gut sterilization. Pri-mary cultured Kupffer cells were incubated with lipopolysac-charide and/or ursodeoxycholic acid (UDCA) and inflammatory responses were analyzed.Results: TREM-2 expression was upregulated in the livers of patients with PBC or PSC, and in murine models of cholestasis. Compared to WT, the response to bile duct ligation (BDL)-induced obstructive cholestasis or alpha-naphtylisothiocyanate (ANIT)-induced cholestasis was exacerbated in Trem-2-/-mice. This was characterized by enhanced necroptotic cell death, in-flammatory responses and biliary expansion. Antibiotic treat-ment partially abrogated the effects observed in Trem-2-/-mice after BDL. Experimental overexpression of TREM-2 in the liver of WT mice downregulated ANIT-induced IL-33 expression and neutrophil recruitment. UDCA regulated Trem-1 and Trem-2 expression in primary cultured mouse Kupffer cells and damp-ened inflammatory gene transcription via a TREM-2-dependent mechanism.Conclusions: TREM-2 acts as a negative regulator of inflamma-tion during cholestasis, representing a novel potential thera-peutic target.Lay summary: Cholestasis (the reduction or cessation of bile flow) causes liver injury. This injury is exacerbated when gut-derived bacterial components interact with receptors (spe-cifically Toll-like receptors or TLRs) on liver-resident immune cells, promoting inflammation. Herein, we show that the anti-inflammatory receptor TREM-2 dampens TLR-mediated signaling and hence protects against cholestasis-induced liver injury. Thus, TREM-2 could be a potential therapeutic target in cholestasis.Spanish Carlos III Health Institute (ISCIII) [J.M. Banales (FIS PI18/01075, PI21/00922 and Miguel Servet Program CPII19/00008); M.J. Perugorria (FIS PI14/00399, PI17/00022 and PI20/00186); J.J.G. Marin (FIS PI16/00598 and PI19/00819); P.M. Rodrigues (Sara Borrell CD19/00254)] cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); “Instituto de Salud Carlos III” [CIBERehd: M.J. Monte, J.J.G. Marin, J.M. Banales, M.J. Perugorria, P. Aspichueta, P.M. Rodrigues and L. Bujanda], Spain; “Diputación Foral de Gipuzkoa” (M.J. Perugorria: DFG18/114), Department of Health of the Basque Country (M.J. Perugorria: 2019111024, 2015111100 and J.M. Banales: 2021111021), “Euskadi RIS3” (J.M. Banales: 2019222054, 2020333010, 2021333003), and Department of Industry of the Basque Country (J.M. Banales: Elkartek: KK-2020/00008); “Junta de Castilla y Leon” (J.J.G. Marin: SA063P17). La Caixa Scientific Foundation (J.M. Banales: HR17-00601). “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); “Centro Internacional sobre el Envejecimiento” (J.J.G. Marin: OLD-HEPAMARKER, 0348_CIE_6_E); Fundació Marato TV3 (J.J.G. Marin: Ref. 201916-31). O Sharif was funded by the Austrian Science Fund (FWF-P35168). Work in the lab of T. Luedde was funded by the European Research Council (ERC) (Grant Agreement 771083), the German Research Foundation (DFG – LU 1360/3-2 (279874820), LU 1360/4-(1461704932) and SFB-CRC 1382-Project A01) and the German Ministry of Health (BMG – DEEP LIVER 2520DAT111). Contributions of M. Marzioni were funded by the Università Politecnica delle Marche PSA2017_UNIVPM grant. Contributions of DAM were supported by programme grants from CRUK (C18342/A23390) and MRC (MR/K0019494/1 and MR/R023026/1). MJ Perugorria was funded by the Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Programme RYC-2015-17755), I. Labiano, A. Agirre-Lizaso, P. Olaizola, A. Echebarria and F. González-Romero by the Basque Government (PRE_2016_1_0152, PRE_2018_1_0184, PRE_2016_1_0269 PRE_2020_1_0080, PRE_2018_1_0120, respectively), I. Olaizola by the Ministry of Universities (FPU 19/03327) and A. Esparza-Baquer by the University of the Basque Country (PIF2014/11). The funding sources had no involvement in study design, data collection and analysis, decision to publish, or preparation of the article
O curso de licenciatura em educação física da Universidade Federal de Santa Catarina: suas concepções de ensino e de educação física
No full textDissertação (mestrado) - Universidade Federal de Santa Maria. Centro de Educação Fisica e Desporto
Awful disclosures of Maria Monk : as exhibited in a narrative of her sufferings during a residence of five years as a novice, and two years as a black nun, in the Hotel Dieu Nunnery at Montreal
No full textMaria Monk's personal narrative as related to Theodore Dwight. Maria Monk's personal narrative as related to Theodore Dwight. Has also been ascribed to John J. Slocum and to William K. Hoyte. Cf. New York herald, Aug. 12, 1836, p.2, col. 1 : The Colophon, pt. 17, 1934; Sabin and Gagnon, P. Essai de bibl. can. Dwight, Theodore, 1796-1866; Slocum, J. J. (John Jay), 1803-1863, supposed author; Hoyte, William K., 9from old Maria Monk's personal narrative as related to Theodore Dwight. Has also been ascribed to John J. Slocum and to William K. Hoyte.Maria Monk's personal narrative as related to Theodore Dwight. Has also been ascribed to John J. Slocum and to William K. Hoyte
PDF: Awful disclosures of Maria Monk : as exhibited in a narrative of her sufferings during a residence of five years as a novice, and two years as a black nun, in the Hotel Dieu Nunnery at Montreal
No full textHigh quality PDF version of Maria Monk's personal narrative as related to Theodore Dwight. Maria Monk's personal narrative as related to Theodore Dwight. Has also been ascribed to John J. Slocum and to William K. Hoyte. Cf. New York herald, Aug. 12, 1836, p.2, col. 1 : The Colophon, pt. 17, 1934; Sabin and Gagnon, P. Essai de bibl. can. Dwight, Theodore, 1796-1866; Slocum, J. J. (John Jay), 1803-1863, supposed author; Hoyte, William K., 9from old Maria Monk's personal narrative as related to Theodore Dwight. Has also been ascribed to John J. Slocum and to William K. Hoyte.Maria Monk's personal narrative as related to Theodore Dwight. Has also been ascribed to John J. Slocum and to William K. Hoyte
First person – Maria Replogle
No full textFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Maria Replogle is first author on ‘
Establishment of a murine culture system for modeling the temporal progression of cranial and trunk neural crest cell differentiation’, published in DMM. Maria is a PhD student (dissertator) in the lab of Ava J. Udvadia at University of Wisconsin-Milwaukee, Milwaukee, USA, investigating the genetic and environmental factors that contribute to developmental birth defects and disorders, particularly those that impact the formation of the skeletal elements in the head
Stimulating healthy tissue regeneration by targeting the 5-HT(2B) receptor in chronic liver disease
No full textLettersTissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood1. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT2B) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT2B enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT2B or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT2B attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT2B is clinically safe in humans and may be therapeutic in chronic liver disease.Mohammad R Ebrahimkhani, Fiona Oakley, Lindsay B Murphy, Jelena Mann, Anna Moles, Maria J Perugorria, Elizabeth Ellis, Anne F Lakey, Alastair D Burt, Angela Douglass, Matthew C Wright, Steven A White, Fabrice Jaffré, Luc Maroteaux & Derek A Man
REVIEW OF: "Kawauchi Akio, Splitting a 4-manifold with infinite cyclic fundamental group, revised, J. Knot Theory Ramifications 22, No. 14, Article ID 1350081, 9 p. (2013)". [DE062730205]
No full textIn [Osaka J. Math. 31(3), 489-495 (1994; Zbl 0849.57018 )], the author stated that every closed connected
orientable 4-manifold M with infinite cyclic fundamental group is TOP-split, i.e. it is homeomorphic to
the connected sum (S1 × S3)#M1, M1 being a closed simply connected 4-manifold. However, in [Manuscr.
Math. 93(4), 435-442 (1997; Zbl 0890.57034)], Hambleton and Teichner obtained a counterexample to the
above general statement.
In the paper under review, the author makes a revision and proves that TOP-splittability holds under the
additional hypothesis that a finite covering of M is TOP-split. In particular, the original statement turns
out to be true in the case of indefinite intersection form, as well as for any smooth spin 4-manifold (with
infinite cyclic fundamental group).
The proof of the revised statement makes use of notions developed in [Knots in Hellas 98, Ser. Knots
Everything. 24 (World Scientific Publishing), 208-228 (2000; Zbl 0969.57020)] and [Atti Semin. Mat. Fis.
Univ. Modena 48(2), 405-424 (2000; Zbl 1028.57019)], together with the key result - proved in [Osaka J.
Math. 31(3), 489-495 (1994; Zbl 0849.57018 )] - that every closed connected orientable 4-manifold M with
infinite cyclic fundamental group is homology cobordant to (S1 × S3)#M1.
Consequences about surface-knots in S4 are also considered (see [J. Knot Theory Ramifications 4(2), 213-224
(1995; Zbl 0844.57020)])
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