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1.
Ann Hematol ; 103(9): 3783-3786, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38871930

RESUMEN

Amyloid Light Chain (AL) Amyloidosis is a rare disorder of protein misfolding and metabolism characterized by insoluble fibrils deposition in various tissues and organs, which could quickly progress and become fatal. The most frequently affected organ is heart being its involvement the most adverse prognostic feature. Kidney and liver could be other organ localizations, defining AL Amyloidosis as a multisystem disorder. Being Budd-Chiari syndrome (BCS) an uncommon congestive hepatopathy caused by blockage of hepatic veins in the absence of cardiac disorders, it could be rarely caused by a massive deposition of amyloid proteins into hepatic sinusoidal spaces, giving an uncommon clinical presentation of AL Amyloidosis.


Asunto(s)
Médula Ósea , Síndrome de Budd-Chiari , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Humanos , Persona de Mediana Edad , Amiloidosis/patología , Amiloidosis/complicaciones , Amiloidosis/etiología , Amiloidosis/diagnóstico , Amiloidosis/metabolismo , Médula Ósea/patología , Síndrome de Budd-Chiari/etiología , Síndrome de Budd-Chiari/patología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/complicaciones , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Hígado/patología , Hígado/metabolismo , Hepatopatías/etiología , Hepatopatías/patología
2.
Liver Int ; 42(8): 1861-1871, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35302273

RESUMEN

BACKGROUND AND STUDY AIM: The traditional endoscopic therapy of anastomotic strictures (AS) after orthotopic liver transplantation (OLT) is multiple ERCPs with the insertion of an increasing number of plastic stents side-by-side. Fully covered self-expanding metal stents (cSEMS) could be a valuable option to decrease the number of procedures needed or non-responders to plastic stents. This study aims to retrospectively analyse the results of AS endoscopic treatment by cSEMS and to identify any factors associated with its success. PATIENTS AND METHODS: Ninety-one patients (mean age 55.9 ± 7.6 SD; 73 males) from nine Italian transplantation centres, had a cSEMS positioned for post-OLT-AS between 2007 and 2017. Forty-nine (54%) patients were treated with cSEMS as a second-line treatment. RESULTS: All the procedures were successfully performed without immediate complications. After ERCP, adverse events occurred in 11% of cases (2 moderate pancreatitis and 8 cholangitis). In 49 patients (54%), cSEMSs migrated. After cSEMS removal, 46 patients (51%) needed further endoscopic (45 patients) or radiological (1 patient) treatments to solve the AS. Lastly, seven patients underwent surgery. Multivariable stepwise logistic regression showed that cSEMS migration was the only factor associated with further treatments (OR 2.6, 95% CI 1.0-6.6; p value 0.03); cSEMS implantation before 12 months from OLT was associated with stent migration (OR 5.2, 95% CI 1.7-16.0; p value 0.004). CONCLUSIONS: cSEMS appears to be a safe tool to treat AS. cSEMS migration is the main limitation to its routinary implantation and needs to be prevented, probably with the use of new generation anti-migration stents.


Asunto(s)
Colestasis , Trasplante de Hígado , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Colestasis/etiología , Colestasis/cirugía , Constricción Patológica/cirugía , Humanos , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Plásticos , Estudios Retrospectivos , Silicatos , Stents/efectos adversos , Resultado del Tratamiento
3.
Semin Liver Dis ; 40(3): 225-232, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31887774

RESUMEN

Interest in understanding the aging process has recently risen in the scientific community. Aging, commonly defined as the functional decline in the function of organs and tissues, is indeed the major risk factor for the development of many chronic diseases, such as cardiovascular diseases, pathologies of nervous system, or cancer. To date, the influence of aging in the pathophysiology of liver and biliary diseases is not fully understood. Although liver cells have a high regenerative capacity, hepatocytes and cholangiocytes undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, liver cells initially activate compensatory mechanisms that, if hyperstimulated, may lead to the decline of regenerative capacity and the development of pathologies. A deeper understanding of molecular aging has undoubtedly the potential to improve the clinical management of patients, possibly unveiling new pathways for selective drug treatment.


Asunto(s)
Envejecimiento/metabolismo , Hígado/metabolismo , Animales , Enfermedades de las Vías Biliares/metabolismo , Enfermedades de las Vías Biliares/fisiopatología , Progresión de la Enfermedad , Humanos , Hígado/fisiopatología , Hepatopatías/metabolismo , Hepatopatías/fisiopatología
4.
Hepatology ; 70(3): 883-898, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30561764

RESUMEN

Disorders of the biliary tree develop and progress differently according to patient age. It is currently not known whether the aging process affects the response to injury of cholangiocytes. The aim of this study was to identify molecular pathways associated with cholangiocyte aging and to determine their effects in the biological response to injury of biliary cells. A panel of microRNAs (miRs) involved in aging processes was evaluated in cholangiocytes of young and old mice (2 months and 22 months of age, respectively) and subjected to a model of sclerosing cholangitis. Intracellular pathways that are common to elevated miRs were identified by in silico analysis. Cell proliferation and senescence were evaluated in Twinfilin-1 (Twf1) knocked-down cells. In vivo, senescence-accelerated prone mice (Samp8, a model for accelerated aging), Twf1-/- , or their respective controls were subjected to DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine). Cholangiocytes from DDC-treated mice showed up-regulation of a panel of aging-related miRs. Twf1 was identified by in silico analysis as a common target of the up-regulated miRs. Twf1 expression was increased both in aged and diseased cholangiocytes, and in human cholangiopathies. Knock-down of Twf1 in cholangiocytes reduced cell proliferation. Senescence and senescence-associated secretory phenotype marker expression increased in Twf1 knocked-down cholangiocytes following pro-proliferative and pro-senescent (10-day lipopolysaccharide) stimulation. In vivo, Samp8 mice showed increased biliary proliferation, fibrosis, and Twf1 protein expression level, whereas Twf1-/- had a tendency toward lower biliary proliferation and fibrosis following DDC administration compared with control animals. Conclusion: We identified Twf1 as an important mediator of both cholangiocyte adaptation to aging processes and response to injury. Our data suggest that disease and aging might share common intracellular pathways.


Asunto(s)
Senescencia Celular/genética , Colangitis Esclerosante/patología , MicroARNs/genética , Proteínas de Microfilamentos/genética , Envejecimiento/genética , Animales , Sistema Biliar/patología , Proliferación Celular/genética , Células Cultivadas , Colangitis Esclerosante/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Distribución Aleatoria , Sensibilidad y Especificidad
5.
Gastrointest Endosc ; 92(2): 405-411, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32145287

RESUMEN

BACKGROUND AND AIMS: In recent years, the feasibility and safety of endoscopic placement of different biodegradable biliary stents have been investigated. New, helicoidally shaped, biliary and pancreatic biodegradable stents have been developed for endoscopic use. Stents are provided in different sizes and with 3 expected speeds of degradation: slow (11 weeks), medium (20 days), and fast (12 days). The aim of this study was to evaluate degradation time, technical outcomes, and safety of these stents. METHODS: This was a single-center, prospective, pilot study (August 2018 to January 2019) of consecutive patients with indication for biliary or pancreatic plastic stent positioning during ERCP. The primary outcome was the evaluation of degradation time of the stents, which was controlled by abdominal radiograph. Secondary outcomes were the evaluation of specific stent-related technical features (loadability, pushability, and fluoroscopic visibility) as compared with commonly used plastic stents and adverse events (AEs). RESULTS: Thirty-eight patients (11 women [28.9%]; median age, 68.05 ± 10.74 years) who received 53 biodegradable stents (34 [64.2%] biliary and 19 [35.8%] pancreatic stents) were enrolled in the study. Thirty-five (66%) slow-degrading stents, 6 (11.3%) medium-degrading stents, and 12 (22.6%) fast-degrading stents were used. At time 1, partial degradation of the stents was present in 48 cases (90.6%). Five stents (9.4%) prematurely migrated. At the subsequent time 2 evaluation, complete degradation occurred in 100% of cases. Stent loadability was defined as excellent in all cases. Pushability of the stent was scored as excellent in 48 cases (90.5%), good in 4 cases (7.5%), and fair in 1 case (1.9%). Fluoroscopic visualization was excellent in 11 cases (20.8%), good in 39 cases (73.6%), and fair in 3 (5.6%). Only 1 AE of mild post-ERCP pancreatitis occurred. CONCLUSIONS: The results of our study suggest that the biodegradation of the new biliary and pancreatic stents is reliable and in line with expected times and technically successful in a variety of indications. Further randomized multicenter studies are required to validate our preliminary findings. (Clinical trial registration number: NCT03767166.).


Asunto(s)
Colangiopancreatografia Retrógrada Endoscópica , Pancreatitis , Anciano , Femenino , Humanos , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Stents , Resultado del Tratamiento
6.
Liver Int ; 40(12): 3127-3139, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33098723

RESUMEN

BACKGROUND AND AIMS: Liver X receptors (LXRs) exert anti-inflammatory effects even though their hepatic activation is associated with hypertriglyceridemia and hepatic steatosis. Selective induction of LXRs in the gut might provide protective signal(s) in the aberrant wound healing response that induces fibrosis during chronic liver injury, without hypertriglyceridemic and steatogenic effects. METHODS: Mice with intestinal constitutive LXRα activation (iVP16-LXRα) were exposed to intraperitoneal injection of carbon tetrachloride (CCl4 ) for 8 weeks, and in vitro cell models were used to evaluate the beneficial effect of high-density lipoproteins (HDL). RESULTS: After CCl4 treatment, the iVP16-LXRα phenotype showed reduced M1 macrophage infiltration, increased expression M2 macrophage markers, and lower expression of hepatic pro-inflammatory genes. This anti-inflammatory effect in the liver was also associated with decreased expression of hepatic oxidative stress genes and reduced expression of fibrosis markers. iVP16-LXRα exhibited increased reverse cholesterol transport in the gut by ABCA1 expression and consequent enhancement of the levels of circulating HDL and their receptor SRB1 in the liver. No hepatic steatosis development was observed in iVP16-LXRα. In vitro, HDL induced a shift from M1 to M2 phenotype of LPS-stimulated Kupffer cells, decreased TNFα-induced oxidative stress in hepatocytes and reduced NF-kB activity in both cells. SRB1 silencing reduced TNFα gene expression in LPS-stimulated KCs, and NOX-1 and IL-6 in HepG2. CONCLUSIONS: Intestinal activation of LXRα modulates hepatic response to injury by increasing circulating HDL levels and SRB1 expression in the liver, thus suggesting this circuit as potential actionable pathway for therapy.


Asunto(s)
Macrófagos del Hígado , Hígado , Animales , HDL-Colesterol , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL
7.
Liver Int ; 39(7): 1355-1362, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30500104

RESUMEN

BACKGROUND: The most appropriate endo-therapeutic approach to biliary anastomotic strictures is yet to be defined. AIM: To retrospectively report on the endo-therapy of duct-to-duct anastomotic strictures during 2013 in Italy. METHODS: Data were collected from 16 Endoscopy Units at the Italian Liver Transplantation Centers (BASALT study group). RESULTS: Complete endo-therapy and follow-up data are available for 181 patients: 101 treated with plastic multistenting, 26 with fully covered self-expandable metal stenting and 54 with single stenting. Radiological success was achieved for 145 patients (80%), that is, 88% of plastic multistenting, 88% of self-expandable metal stenting and 61% of single stenting (P < 0.001 vs plastic multistenting; P < 0.05 vs self-expandable metal stenting). After first-line endo-therapy failure, the patients underwent a second-line endo-therapy with plastic multistenting for 25%, fully covered self-expandable metal stenting for 53% and single stenting for 22% of cases, and radiological success was achieved for 84%, that is, 100%, 85% and 63% with plastic multistenting, self-expandable metal stenting and single stenting (P < 0.05 vs plastic multistenting or self-expandable metal stenting) respectively. Procedure-related complications occurred in 7.8% of endoscopic retrograde cholangiopancreatographies. Overall, clinical success was achieved in 87% of patients after a median follow-up of 25 months. CONCLUSION: Plastic multistenting is confirmed as the preferred first-line treatment, while fully covered self-expandable metal stenting as rescue option for biliary anastomotic strictures. Single stenting has sub-optimal results and should be abandoned.


Asunto(s)
Colangiopancreatografia Retrógrada Endoscópica/instrumentación , Constricción Patológica/cirugía , Trasplante de Hígado/efectos adversos , Stents Metálicos Autoexpandibles , Stents/clasificación , Adulto , Anciano , Enfermedades de las Vías Biliares/etiología , Enfermedades de las Vías Biliares/cirugía , Colestasis/etiología , Constricción Patológica/etiología , Femenino , Humanos , Italia , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Plásticos , Estudios Retrospectivos , Encuestas y Cuestionarios , Análisis de Supervivencia , Resultado del Tratamiento , Adulto Joven
8.
Biochim Biophys Acta Mol Basis Dis ; 1864(4 Pt B): 1270-1278, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28754451

RESUMEN

Cholangiocytes, the epithelial cells lining the bile ducts, are an important subset of liver cells. They are involved in the modification of bile volume and composition, and respond to endogenous and exogenous stimuli. Along the biliary tree, two different kinds of cholangiocytes exist: small and large cholangiocytes. Each type has different features and biological role in physiologic and pathologic conditions, and their immunobiology is important for understanding biliary diseases. Cholangiocytes provide the first line of defence against luminal microbes in the hepatobiliary system. Indeed, they express a variety of pattern recognition receptors and may start an antimicrobial defence activating a set of intracellular signalling cascades. In response to injury, cholangiocytes that are normally quiescent become reactive and acquire a neuroendocrine-like phenotype with the release of proinflammatory mediators and antimicrobial peptides, which support biliary epithelial integrity. These molecules act in an autocrine/paracrine manner to modulate cholangiocyte biology and determine the evolution of biliary damage. Failure or dysregulation of such mechanisms may influence the progression of cholangiopathies, a group of diseases that selectively target biliary cells. In this review, we focus on the response of cholangiocytes in inflammatory conditions, with a particular focus on the mechanism driving cholangiocytes adaptation to damage. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.


Asunto(s)
Neoplasias de los Conductos Biliares/etiología , Colangiocarcinoma/etiología , Colangitis/etiología , Células Epiteliales/fisiología , Animales , Bilis/metabolismo , Bilis/microbiología , Neoplasias de los Conductos Biliares/patología , Conductos Biliares/citología , Conductos Biliares/microbiología , Conductos Biliares/fisiología , Carcinogénesis/inmunología , Carcinogénesis/metabolismo , Carcinogénesis/patología , Colangiocarcinoma/patología , Colangitis/patología , Citocinas/inmunología , Citocinas/metabolismo , Progresión de la Enfermedad , Células Epiteliales/citología , Microbioma Gastrointestinal/fisiología , Humanos , Transducción de Señal/fisiología
9.
Am J Pathol ; 187(2): 366-376, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27912077

RESUMEN

Microbial products are thought to influence the progression of cholangiopathies, in particular primary sclerosing cholangitis (PSC). Inflammasomes are molecular platforms that respond to microbial products through the synthesis of proinflammatory cytokines. We investigated the role of inflammasome activation in cholangiocyte response to injury. Nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing protein 3 (Nlrp3) expression was tested in cholangiocytes of normal and cholestatic livers. Effects of Nlrp3 activation induced by incubation with lipopolysaccharide and ATP was studied in vitro in normal and siRNA-Nlrp3 knocked-down cholangiocytes. Wild-type and Nlrp3 knockout (Nlrp3-/-) mice were fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; a model of sclerosing cholangitis) for 4 weeks. Nlrp3 and its components were overexpressed in cholangiocytes of mice subjected to DDC and in patients affected by PSC. In vitro, Nlrp3 activation stimulated expression of Il-18 but not of Il-1ß and Il-6. Nlrp3 activation had no effect on cholangiocyte proliferation but significantly decreased the expression of Zonulin-1 and E-cadherin, whereas Nlrp3 knockdown increased the permeability of cholangiocyte monolayers. In vivo, the DDC-stimulated number of cytokeratin-19-positive cells in the liver of wild-type animals was slightly reduced in Nlrp3-/- mice, and expression of E-cadherin was reestablished. In conclusion, Nlrp3 is expressed in reactive cholangiocytes, in both murine models and patients with PSC. Activation of Nlrp3 leads to synthesis of proinflammatory cytokines and influences epithelial integrity of cholangiocytes.


Asunto(s)
Colangitis Esclerosante/metabolismo , Colangitis Esclerosante/patología , Interleucina-18/biosíntesis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Humanos , Immunoblotting , Inflamasomas/metabolismo , Ratones , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa
10.
Hepatology ; 66(2): 542-554, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28056490

RESUMEN

The etiopathogenesis of primary sclerosing cholangitis is unknown. Genetic variants of fucosyltransferase 2 (FUT2) have been identified in genome-wide association studies as risk factors for primary sclerosing cholangitis. We investigated the role of Fut2 in murine liver pathophysiology by studying Fut2-/- mice. Fut2-/- mice were viable and fertile, had lower body weight than wild-type (wt) littermates and gray fur. Half of the Fut2-/- mice showed serum bile salt levels 40 times higher than wt (Fut2-/-high ), whereas the remainder were normocholanemic (Fut2-/-low ). Fut2-/- mice showed normal serum liver tests, bile flow, biliary bile salt secretion, fecal bile salt loss, and expression of major hepatocellular bile salt transporters and cytochrome P450 7a1, the key regulator of bile salt synthesis, indicating that elevated serum bile salts in Fut2-/-high mice were not explained by cholestasis. Fut2-/-high mice, but not Fut2-/-low mice, were sensitive to hydrophobic bile salt feeding (0.3% glycochenodeoxycholate); they rapidly lost weight and showed elevation of serum liver tests (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase) and areas of liver parenchymal necrosis. Histomorphological evaluation revealed the presence of paraportal shunting vessels, increased numbers of portal vascular structures, wall thickening of some portal arteries, and periductal fibrosis in Fut2-/-high mice more than Fut2-/-low mice and not wt mice. Unconjugated bilirubin and ammonia were or tended to be elevated in Fut2-/-high mice only. Portosystemic shunting was demonstrated by portal angiography, which disclosed virtually complete portosystemic shunting in Fut2-/-high mice, discrete portosystemic shunting in Fut2-/-low mice, and no shunting in wt littermates. CONCLUSION: Liver pathology in Fut2-/- mice is dominated by consequences of portosystemic shunting resulting in microcirculatory disturbances, mild (secondary) periductal fibrosis, and sensitivity toward human bile salt toxicity. (Hepatology 2017;66:542-554).


Asunto(s)
Colangitis Esclerosante/genética , Colangitis Esclerosante/patología , Fucosiltransferasas/genética , Regulación de la Expresión Génica , Cirrosis Hepática/patología , Sistema Porta/patología , Animales , Ácidos y Sales Biliares/metabolismo , Biopsia con Aguja , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Inmunohistoquímica , Cirrosis Hepática/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Derivación Portocava Quirúrgica , Distribución Aleatoria , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Medición de Riesgo , Galactósido 2-alfa-L-Fucosiltransferasa
11.
Int J Mol Sci ; 19(10)2018 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-30275402

RESUMEN

Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC.


Asunto(s)
Enfermedades de los Conductos Biliares/patología , Enfermedades de los Conductos Biliares/fisiopatología , Tracto Gastrointestinal/patología , Inflamación/patología , Hígado/patología , Animales , Enfermedades de los Conductos Biliares/inmunología , Enfermedades de los Conductos Biliares/microbiología , Microbioma Gastrointestinal , Humanos , Inmunidad Innata
12.
Hepatology ; 60(4): 1324-35, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24925797

RESUMEN

UNLABELLED: The activation of the biliary stem-cell signaling pathway hairy and enhancer of split 1/pancreatic duodenal homeobox-1 (Hes-1/PDX-1) in mature cholangiocytes determines cell proliferation. Neurogenin-3 (Ngn-3) is required for pancreas development and ductal cell neogenesis. PDX-1-dependent activation of Ngn-3 initiates the differentiation program by inducing microRNA (miR)-7 expression. Here we investigated the role Ngn-3 on cholangiocyte proliferation. Expression levels of Ngn-3 and miR-7 isoforms were tested in cholangiocytes from normal and cholestatic human livers. Ngn-3 was knocked-down in vitro in normal rat cholangiocytes by short interfering RNA (siRNA). In vivo, wild-type and Ngn-3-heterozygous (+/-) mice were subjected to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding (a model of sclerosing cholangitis) or bile duct ligation (BDL). In the liver, Ngn-3 is expressed specifically in cholangiocytes of primary sclerosing cholangitis (PSC) patients and in mice subjected to DDC or BDL, but not in normal human and mouse livers. Expression of miR-7a-1 and miR-7a-2 isoforms, but not miR-7b, was increased in DDC cholangiocytes compared to normal ones. In normal rat cholangiocytes, siRNA against Ngn-3 blocked the proliferation stimulated by exendin-4. In addition, Ngn-3 knockdown neutralized the overexpression of insulin growth factor-1 (IGF1; promitotic effector) observed after exposure to exendin-4, but not that of PDX-1 or VEGF-A/C. Oligonucleotides anti-miR-7 inhibited the exendin-4-induced proliferation in normal rat cholangiocytes, but did not affect Ngn-3 synthesis. Biliary hyperplasia and collagen deposition induced by DDC or BDL were significantly reduced in Ngn-3(+/-) mice compared to wild-type. CONCLUSION: Ngn-3-dependent activation of miR-7a is a determinant of cholangiocyte proliferation. These findings indicate that the reacquisition of a molecular profile typical of organ development is essential for the biological response to injury by mature cholangiocytes.


Asunto(s)
Lesión Pulmonar Aguda/fisiopatología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Conductos Biliares/fisiopatología , Proliferación Celular/fisiología , Colestasis/fisiopatología , MicroARNs/fisiología , Proteínas del Tejido Nervioso/fisiología , Transducción de Señal/fisiología , Lesión Pulmonar Aguda/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Conductos Biliares/metabolismo , Conductos Biliares/patología , Colestasis/metabolismo , Colestasis/patología , Colágeno/metabolismo , Modelos Animales de Enfermedad , Exenatida , Humanos , Técnicas In Vitro , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ratones , Ratones Endogámicos , Proteínas del Tejido Nervioso/efectos de los fármacos , Proteínas del Tejido Nervioso/genética , Oligonucleótidos/farmacología , Péptidos/metabolismo , ARN Interferente Pequeño/farmacología , Ratas , Ponzoñas/metabolismo
13.
Dig Dis ; 33(3): 397-407, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26045275

RESUMEN

BACKGROUND: Destruction of cholangiocytes is the hallmark of chronic cholangiopathies such as primary biliary cirrhosis. Under physiologic conditions, cholangiocytes display a striking resistance to the high, millimolar concentrations of toxic bile salts present in bile. We recently showed that a 'biliary HCO3(-) umbrella', i.e. apical cholangiocellular HCO3(-) secretion, prevents cholangiotoxicity of bile acids, and speculated on a role for extracellular membrane-bound glycans in the stabilization of this protective layer. This paper summarizes published and thus far unpublished evidence supporting the role of the glycocalyx in stabilizing the 'biliary HCO3(-) umbrella' and thus preventing cholangiotoxicity of bile acids. KEY MESSAGES: The apical glycocalyx of a human cholangiocyte cell line and mouse liver sections were visualized by electron microscopy. FACS analysis was used to characterize the surface glycan profile of cultured human cholangiocytes. Using enzymatic digestion with neuraminidase the cholangiocyte glycocalyx was desialylated to test its protective function. Using lectin assays, we demonstrated that the main N-glycans in human and mouse cholangiocytes were sialylated biantennary structures, accompanied by high expression of the H-antigen (α1-2 fucose). Apical neuraminidase treatment induced desialylation without affecting cell viability, but lowered cholangiocellular resistance to bile acid-induced toxicity: both glycochenodeoxycholate and chenodeoxycholate (pKa ≥4), but not taurochenodeoxycholate (pKa <2), displayed cholangiotoxic effects after desialylation. A 24-hour reconstitution period allowed cholangiocytes to recover to a pretreatment bile salt susceptibility pattern. CONCLUSION: Experimental evidence indicates that an apical cholangiocyte glycocalyx with glycosylated mucins and other glycan-bearing membrane glycoproteins stabilizes the 'biliary HCO3(-) umbrella', thus aiding in the protection of human cholangiocytes against bile acid toxicity.


Asunto(s)
Ácidos y Sales Biliares/metabolismo , Glicocálix/metabolismo , Bicarbonato de Sodio/metabolismo , Animales , Conductos Biliares/citología , Supervivencia Celular , Células Cultivadas , Células Epiteliales/metabolismo , Glicocálix/efectos de los fármacos , Humanos , Glicoproteínas de Membrana/metabolismo , Mucinas/metabolismo , Neuraminidasa/farmacología
14.
Semin Liver Dis ; 34(3): 273-84, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25057951

RESUMEN

Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by selective destruction of intrahepatic cholangiocytes. Mechanisms underlying the development and progression of the disease are still controversial and largely undefined. Evidence suggests that PBC results from an articulated immunologic response against an immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2); characteristics of the disease are also the presence of disease-specific antimitochondrial autoantibodies (AMAs) and autoreactive CD4 and CD8 T cells. Recent evidence suggests that cholangiocytes show specific immunobiological features that are responsible for the selective targeting of those cells by the immune system. The immune reaction in PBC selectively targets small sized, intrahepatic bile ducts; although a specific reason for that has not been defined yet, it has been established that the biliary epithelium displays a unique heterogeneity, for which the physiological and pathophysiological features of small and large cholangiocytes significantly differ. In this review article, the authors provide a critical overview of the current evidence on the role of cholangiocytes in the immune-mediated destruction of the biliary tree that characterizes PBC.


Asunto(s)
Autoinmunidad , Conductos Biliares Intrahepáticos/inmunología , Células Epiteliales/inmunología , Cirrosis Hepática Biliar/inmunología , Animales , Apoptosis , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Proliferación Celular , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Humanos , Cirrosis Hepática Biliar/metabolismo , Cirrosis Hepática Biliar/patología , Transducción de Señal
15.
Cancers (Basel) ; 16(7)2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38611050

RESUMEN

Endoluminal biliary radiofrequency ablation (RFA) has been proposed as a palliative treatment for patients with malignant biliary obstruction (MBO) in order to improve stent patency and survival. However, the existing data on patients with inoperable extrahepatic cholangiocarcinoma (eCCA) are conflicting. We performed a meta-analysis of randomized trials comparing RFA plus stenting versus stenting alone in patients with inoperable eCCA. We searched for trials published in the PubMed/MEDLINE, Scopus, and Cochrane databases up to November 2023. Data extraction was conducted from published studies, and a quality assessment was carried out in accordance with the guidelines recommended by the Cochrane Collaboration. Hazard ratios (HRs) with 95% CI were estimated from the trials. The primary endpoints of interest were overall survival and stent patency. Out of 275 results, 5 randomized trials and 370 patients were included. While overall survival was not different between the groups (HR 0.62; 95% CI 0.36-1.07; p = 0.09; I2 = 80%;), the subgroup analysis of studies employing plastic stents showed a trend toward better survival in the RFA-treated group (HR 0.42; 95% CI 0.22-0.80; p = 0.009; I2 = 72%). Stent patency was improved in patients receiving RFA (HR 0.64; 95% CI 0.45-0.90; p = 0.01; I2 = 23%). Adverse events were not different between the groups (OR 1.21; 95% CI 0.69-2.12; p = 0.50; I2 = 0%). Despite the promising results, high heterogeneity and potential biases in the included studies suggest the need for further high-quality randomized trials to explore the potential cumulative effects of RFA on CCA treatment outcomes.

16.
J Clin Med ; 12(17)2023 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-37685780

RESUMEN

Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease with a heterogeneous presentation, symptomatology, disease progression, and response to therapy. The current risk stratification assessment, aimed at identifying patients with a higher risk of disease progression, encompasses an in-depth analysis of demographic data, clinical and laboratory findings, antibody profiles, and the evaluation of liver fibrosis using both invasive and noninvasive techniques. Treatment response scores after one year of therapy remain to date a major factor influencing the prognosis of PBC patients. While the initial therapeutic approach with ursodeoxycholic acid (UDCA) is universally applied, new second-line treatment options have recently emerged, with many others under investigation. Consequently, the prevailing one-size-fits-all approach is poised to be supplanted by tailored strategies, ensuring high-risk patients receive the most appropriate treatment regimen from diagnosis. This will require the development of a risk prediction model to assess, at the time of diagnosis, the course, outcome, and response to first and additional treatments of PBC patients. This manuscript provides a comprehensive overview of the current and emerging tools used for risk stratification in PBC and speculates on how these developments might shape the disease landscape in the near future.

17.
Minerva Gastroenterol (Torino) ; 69(2): 268-276, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36255283

RESUMEN

BACKGROUND: Inflammatory bowel disease (IBD) patients on biological therapy are receiving vaccines against severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). However, it is unclear if IBD therapy could influence the response to this vaccine. In a case-control study, we assessed the antibody profiling after anti-SARS-CoV-2 BNT162b2 vaccine in IBD patients on biological therapy. METHODS: We analyzed seroprevalence and antibody titer, after 14 weeks from the first BNT162b2 vaccine dose, in IBD patients on biological therapy and health care workers (HCWs). In IBD patients, medical history and disease data were recorded. RESULTS: Eighty-two subjects were enrolled in this study. Among them, 40 were IBD patients on biological therapy and 42 were HCWs. All subjects developed an IgG anti-Spike antibody titer above the cut-off. IBD patients on biological therapy developed a lower antibody titer than HCWs (P<0.00001). No differences were reported in patients who received at least one dose of the vaccine within a period of 7 days from the last biological drug administration, compared to all other IBD patients. A difference was found between patients who were on concomitant immunosuppressive therapy and patients on sole biological therapy (P=0.0287). Patients with presence of any sign of disease activity (clinical, endoscopic or laboratory) showed a higher development of antibody titer compared to those in complete disease remission (P=0.0468). CONCLUSIONS: Our data indicate that in IBD patients, treatment with biological therapies do not affect the seroprevalence but leads to a lower antibody titer development after anti-SARS-CoV-2 BNT162b2 vaccine.


Asunto(s)
COVID-19 , Enfermedades Inflamatorias del Intestino , Humanos , Vacunas contra la COVID-19/uso terapéutico , Vacuna BNT162 , Estudios de Casos y Controles , Estudios Seroepidemiológicos , COVID-19/prevención & control , SARS-CoV-2 , Terapia Biológica , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico
18.
Transplantation ; 107(8): 1764-1775, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-36978227

RESUMEN

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic progressive pathological process, related to inflammatory bowel disease and subsequent bacterial translocation. Liver transplantation (LT) is the only curative therapy, but outcomes are compromised by recurrence of PSC (rPSC). The aim of the study was to investigate a potential link between intestinal bacteremia, fucosyltransferase-2 (FUT2), and rPSC after LT. METHODS: LT recipients with PSC (n = 81) or without PSC (n = 271) were analyzed for clinical outcomes and positive bacterial blood cultures. A link between bacteremia and the genetic variant of the FUT2 gene was investigated. RESULTS: The incidence of inflammatory bowel disease was significantly higher in PSC recipients but not associated with rPSC. Bacteremia occurred in 31% of PSC recipients. The incidence of rPSC was 37% and was significantly more common in patients with intestinal bacteremia versus no bacteremia (82% versus 30%; P = 0.003). The nonsecretor polymorphism of the FUT2 gene was identified as a genetic risk factor for both intestinal bacteremia and rPSC. Combined FUT2 genotype and intestinal bacteremia in recipients resulted in the highest risk for rPSC (hazard ratio, 15.3; P < 0.001). CONCLUSIONS: Thus, in this article, we showed that bacterial translocation is associated with rPSC after LT and related to the FUT2 nonsecretor status.


Asunto(s)
Bacteriemia , Colangitis Esclerosante , Enfermedades Inflamatorias del Intestino , Trasplante de Hígado , Humanos , Trasplante de Hígado/efectos adversos , Colangitis Esclerosante/cirugía , Factores de Riesgo , Intestinos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/cirugía , Enfermedades Inflamatorias del Intestino/complicaciones , Recurrencia , Bacteriemia/diagnóstico , Bacteriemia/epidemiología
19.
Curr Opin Gastroenterol ; 28(3): 253-7, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22450897

RESUMEN

PURPOSE OF REVIEW: To critically review most recent experimental evidence for the protective action of biliary HCO(3)(-) secretion against bile acid-induced bile duct damage and development of fibrosing cholangiopathy in humans and experimental animals. RECENT FINDINGS: Studies in human cholangiocytes in vitro indicate that a biliary HCO(3)(-) umbrella protects against bile acid-induced cholangiocyte damage and apoptosis in humans. The Cl(-)/HCO(3)(-) exchanger, AE2, and an intact biliary glycocalyx appear crucial for its stability. Related studies with experimental animal models in vivo have to be interpreted with caution as humans and mice differ not only with regard to bile salt pool, but also their expression patterns of transport proteins and signalling molecules. SUMMARY: Adequate biliary HCO(3)(-) secretion may protect against bile salt-induced cholangiopathies. Future therapeutic strategies in biliary diseases will aim at stabilizing the biliary HCO(3)(-) umbrella.


Asunto(s)
Bicarbonatos/farmacología , Ácidos y Sales Biliares/metabolismo , Conductos Biliares/metabolismo , Sistema Biliar/patología , Colangitis Esclerosante/patología , Animales , Sistema Biliar/metabolismo , Antiportadores de Cloruro-Bicarbonato/metabolismo , Colangitis Esclerosante/metabolismo , Fibrosis , Humanos , Ratones
20.
Dig Liver Dis ; 54(5): 583-597, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34509394

RESUMEN

Gastroenterology, Digestive Endoscopy and Hepatology have faced significant improvements in terms of diagnosis and therapy in the last decades. However, many fields still remain poorly explored, and many questions unanswered. Moreover, basic-science, as well as translational and clinical discoveries, together with technology advancement will determine further steps toward a better, refined care for many gastroenterological disorders in the future. Therefore, the Young Investigators of the Italian Society of Gastroenterology (SIGE) joined together, offering a perspective on major future innovations in some hot clinical topics in Gastroenterology, Endoscopy, and Hepatology, as well as the current pitfalls and the grey zones.


Asunto(s)
Gastroenterología , Endoscopía Gastrointestinal , Predicción , Humanos , Italia , Sociedades Médicas
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