Background and Aims: Diabetes and obesity are associated with an increased risk of cardiovascular and renal diseases. Cellular senescence associates with many age-related diseases and metabolic disorders, but the underlying mechanisms are not fully understood. This study evaluates how hypercholesterolemia and hyperglycaemia affect biological functions and senescence of vascular and kidney cells in experimental diabetes.

Background and Aims: Dysregulated expression and/or activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway have been linked to several cardiovascular diseases including atherosclerosis. Suppressors of cytokine signaling (SOCS) negatively regulate the JAK/STAT pathway and have been considered an attractive target for therapeutic intervention. We hypothesize that SOCS1 protein could influence atheroma plaque development and composition by inhibiting JAK/STAT activity. Herein, we investigated the potentialities of a peptidomimetic of SOCS1, named PS5, to limit the progression of atherosclerotic disease.

The liver centralizes the systemic metabolism and thus controls and modulates the functions of the central and peripheral nervous systems, the immune system, and the endocrine system. In addition, the liver intervenes between the splanchnic and systemic venous circulation, determining an abdominal portal circulatory system. The liver displays a powerful regenerative potential that rebuilds the parenchyma after an injury. This regenerative mission is mainly carried out by resident liver cells. However, in many cases this regenerative capacity is insufficient and organ failure occurs. In normal livers, if the size of the liver is at least 30% of the original volume, hepatectomy can be performed safely. In cirrhotic livers, the threshold is 50% based on current practice and available data. Typically, portal vein embolization of the part of the liver that is going to be resected is employed to allow liver regeneration in two-stage liver resection after portal vein occlusion (PVO). However, hepatic resection often cannot be performed due to advanced disease progression or because it is not indicated in patients with cirrhosis. In such cases, liver transplantation is the only treatment possibility, and the need for transplantation is the common outcome of progressive liver disease. It is the only effective treatment and has high survival rates of 83% after the first year. However, donated organs are becoming less available, and mortality and the waiting lists have increased, leading to the initiation of living donor liver transplantations. This type of transplant has overall complications of 38%. In order to improve the treatment of hepatic injury, much research has been devoted to stem cells, in particular mesenchymal stem cells (MSCs), to promote liver regeneration. In this review, we will focus on the advances made using MSCs in animal models, human patients, ongoing clinical trials, and new strategies using 3D organoids.

Abstract Introduction Abdominal aortic aneurysm (AAA) is a multifactorial vascular disease characterized by chronic inflammation, oxidative stress and proteolytic activity in the aortic wall, which contribute to extracellular matrix degradation and aortic dilation. Altered expression and activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway have been implicated in several cardiovascular diseases including atherosclerosis and aneurysm formation. Suppressors of cytokine signaling (SOCS) are key negative regulators of JAK/STAT pathway and have been considered an attractive target for therapeutic intervention. AIM We hypothesize that SOCS1 protein could influence AAA development by inhibiting JAK activity and, consequently, STAT activation and target gene expression. Therefore, this study investigates the effect of a SOCS1-derived synthetic peptide in a rodent model of AAA and in cultured vascular smooth muscle cells (VSMC). Methods Experimental AAA was induced in C57BL/6 mice (males, 12 weeks old) by transient elastase perfusion of the aorta. Mice were randomly divided into control (vehicle, i.p.) and treatment (SOCS1 peptide, 3 mg/kg/day, i.p.) groups. Fourteen days after AAA induction, mice were sacrificed, and aorta segments were collected for histology (n=10/group) and mRNA and protein expression analysis (n=8/group). Results Compared to the AAA control group, SOCS1-treated mice exhibited a significant decrease in aortic diameter (68±6% vs. control; p<0.005) and aortic wall thickness, (67±3% vs. control; p<0.001). Histological analyses of aortic tissues showed a higher content of VSMC (α-actin) along with reduced leukocyte infiltration (macrophages, neutrophils and T-cells) and oxidative stress markers (superoxide anion and 8-hydroxyguanosine) in SOCS1-treated mice. SOCS1 therapy also attenuated the gene expression of inflammatory cytokines (CCL2, CCL5, TNF, IFNγ) and matrix metalloproteinases (MMP2, MMP9) in aortic lesions, and altered the expression levels of macrophage M1 (ArgII, iNOS) and M2 (ArgI, CD206) polarization markers. In vitro experiments in murine VSMC revealed that SOCS1 peptide prevented the expression of cytokines and chemokines induced by non-toxic dose of elastase (5 ug/ml, 24 hours). Effects of SOCS1 treatment were accompanied by a reduction in STAT1 and STAT3 phosphorylation and gene expression, both in AAA lesions and cultured VSMC. Conclusion Our results suggest that SOCS1 peptide presents protective effects in experimental AAA by suppressing JAK/STAT pathway-mediated inflammation. Acknowledgement/Funding MINECO-FEDER (SAF2015-63696-R), ISCII (FIS-FEDER PI17/01495), Spanish Society of Arteriosclerosis.

Portal hypertension induces a splanchnic and systemic low-grade inflammatory response that could induce the expression of three phenotypes, named ischemia-reperfusion, leukocytic, and angiogenic phenotypes.During the splanchnic expression of these phenotypes, interstitial edema, increased lymph flow, and lymphangiogenesis are produced in the gastrointestinal tract. Associated liver disease increases intestinal bacterial translocation, splanchnic lymph flow, and induces ascites and hepatorenal syndrome. Extrahepatic cholestasis in the rat allows to study the worsening of the portal hypertensive syndrome when associated with chronic liver disease. The splanchnic interstitium, the mesenteric lymphatics, and the peritoneal mesothelium seem to create an inflammatory pathway that could have a key pathophysiological relevance in the production of the portal hypertension syndrome complications. The hypothetical comparison between the ascitic and the amniotic fluids allows for translational investigation. From a phylogenetic point of view, the ancestral mechanisms for amniotic fluid production were essential for animal survival out of the aquatic environment. However, their hypothetical appearance in the cirrhotic patient is considered pathological since ultimately they lead to ascites development. But, the adult human being would take advantage of the potential beneficial effects of this “amniotic-like fluid” to manage the interstitial fluids without adverse effects when chronic liver disease aggravates.

Background and Aims:The association between Budd Chiari syndrome (BCS) and coeliac disease (CD) is uncommon.13 cases had been reported in the litterature.We report 9 new cases.Methods: The diagnosis of BCS was based on usual criteria of non invasive imaging.All patients had duodenal biopsy, transglutaminase antibodies (TGAb) and gliadin antibodies (GAb).7 patients had PCR-SSO test for CD-specific HLA genotypes.We looked for other prothrombotic disorders: myeloproliferative disease (MPD) (bone marrow biopsy, JAK2 mutation), autoimmune disorder, anticardiolipin antibodies, hyperhomocysteinemia, and prothrombin gene mutation.Inherited protein C, S deficiency was assessed in 5 patients, others had low prothrombin time.All patients were treated with anticoagulants and gluten free diet (GFD).Results: Mean age of patients was 27 years (20-42), and sex-ratio (F/M): 2/1.Mean follow up was 25 months (2-48).CD was diagnosed before BCS in 3 cases.For these patients, hepatopathy was diagnosed fortuitously, and GFD wasn't correctly observed.In 6 other patients, diagnosis of BCS-CD was simultaneous, revealed by ascites in 84% (n = 5), abdominal pain in 16% (n = 1).One patient had a history of chronic diarrhea and an other was treated for chronic anemia.BCS was due to hepatic vein (HV) obstruction in 66% (n = 6), HV and inferior vena cava obstruction in 34% (n = 3).All patients had typical endoscopic aspect of CD.Duodenal biopsy confirmed the diagnosis.GAb/TGAb were found in 78% (n = 7).HLA DQb1*02 predominates, occuring in 6 patients and DQb1*03 in the remainder.One patient had latent MPD and an other used oral contraceptives during 3 years.No other prothrombotic state was identified in the 7 other patients.2 patients have persistant ascites.One wasn't compliant on GFD and the other had an extended obstruction of IVC and HV.The other patients are asymptomatic. Conclusion:The association of BCS and CD seems to be relatively frequent in our country.Prot C, S deficiency, hyperhomocysteinemia and geophagia, incriminated in the occuring of BCS were absent in our patients.HLA alleles found are strongly associated with CD, without any particularity for the association CD-BCS.

Background and Aims:The association between Budd Chiari syndrome (BCS) and coeliac disease (CD) is uncommon.13 cases had been reported in the litterature.We report 9 new cases.Methods: The diagnosis of BCS was based on usual criteria of non invasive imaging.All patients had duodenal biopsy, transglutaminase antibodies (TGAb) and gliadin antibodies (GAb).7 patients had PCR-SSO test for CD-specific HLA genotypes.We looked for other prothrombotic disorders: myeloproliferative disease (MPD) (bone marrow biopsy, JAK2 mutation), autoimmune disorder, anticardiolipin antibodies, hyperhomocysteinemia, and prothrombin gene mutation.Inherited protein C, S deficiency was assessed in 5 patients, others had low prothrombin time.All patients were treated with anticoagulants and gluten free diet (GFD).Results: Mean age of patients was 27 years (20-42), and sex-ratio (F/M): 2/1.Mean follow up was 25 months (2-48).CD was diagnosed before BCS in 3 cases.For these patients, hepatopathy was diagnosed fortuitously, and GFD wasn't correctly observed.In 6 other patients, diagnosis of BCS-CD was simultaneous, revealed by ascites in 84% (n = 5), abdominal pain in 16% (n = 1).One patient had a history of chronic diarrhea and an other was treated for chronic anemia.BCS was due to hepatic vein (HV) obstruction in 66% (n = 6), HV and inferior vena cava obstruction in 34% (n = 3).All patients had typical endoscopic aspect of CD.Duodenal biopsy confirmed the diagnosis.GAb/TGAb were found in 78% (n = 7).HLA DQb1*02 predominates, occuring in 6 patients and DQb1*03 in the remainder.One patient had latent MPD and an other used oral contraceptives during 3 years.No other prothrombotic state was identified in the 7 other patients.2 patients have persistant ascites.One wasn't compliant on GFD and the other had an extended obstruction of IVC and HV.The other patients are asymptomatic. Conclusion:The association of BCS and CD seems to be relatively frequent in our country.Prot C, S deficiency, hyperhomocysteinemia and geophagia, incriminated in the occuring of BCS were absent in our patients.HLA alleles found are strongly associated with CD, without any particularity for the association CD-BCS.

Hepatectomies in the rat can be improved using microsurgical techniques. The distribution variations of the vascular and biliar lobular branches of the liver are observed under magnification with an operative microscope and, therefore their dissection, ligation and section are more accurate. The vascularization and bile drainage of the caudate process, a liver sector located between the right lateral and the caudate lobes, can be identified using microsurgery. The viability of the animal's evolution after different types (90%, 95%, 97%) of subtotal hepatectomies depends on an effective identification of these vascular and biliary branches.

Background: Because most of the characteristics of the portal hypertensive enteropathy can be explained on the basis of increased levels of mast cell mediators, the purpose of the present paper was to study mast cell splanchnic infiltration.Methods: Duodenum, jejunum, ileum and mesenteric lymph node complex infiltration by mast cells was assayed by a stereological technique in control rats (group I; n = 5) and in an experimental model of portal hypertension (the portal vein-stenosed rat, group II; n = 5) at 6 weeks after operation.Results: Intestinal and mesenteric lymph node complex infiltration by mast cells increased in the animals with partial portal vein ligation. The mast cell density progressively increased distally along the small bowel. The mast cell increase in the mesenteric lymph node complex in portal vein-stenosed rats was greater than in the duodenum (P = 0.001), jejunum (P = 0.006) and ileum.Conclusion: The rise of mast cells density in the small bowel and mesenteric lymph node complex in rats with partial portal vein ligation suggests that these cells are involved in the etiopathogenesis of experimental portal prehepatic hypertensive enteropathy.(C) 2005 Blackwell Publishing Asia Pty Ltd.

An experimental model of microsurgical cholestasis is studied as an alternative to the most frequently used surgical techniques, based on the section of the common bile duct. This microsurgical technique consists of the resection of the extrahepatic biliary tract, that is, of the common bile duct in continuity with the bile ducts that drain the four lobes of the rat liver. At 30 days of evolution, rats with microsurgical cholestasis do not develop biliary pseudocysts or intraperitoneal hilar hepatopulmonary abscesses and show an increase (p < 0.001) in total bilirubin (9.50 +/- 1.50 mg/dL vs. 1.60 +/- 0.35 mg/dL), bile acids (225 +/- 87 micromol/L vs. 12.5 +/- 14.50 micromol/L), gamma-glutamyltranspeptidase (375 +/- 143 U/L vs. 8 +/- 11 U/L), and alkaline phosphatase (73 +/- 25 U/L vs. 23 +/- 4 U/L) levels. The histological study shows fibrosis with biliary proliferation. The microsurgical cholestasis technique is a valid alternative to other techniques and can be an adequate experimental model for the study of etiopathogenic mechanisms of obstructive jaundice and especially to study extrahepatic biliary atresia.

The long‐term (5‐week) evolution of two experimental models of extrahepatic cholestasis, i.e., macrosurgical by bile duct ligation (n = 20) and microsurgical by biliary tract resection (n = 13), is studied. All cholestatic animals showed jaundice, choluria, and portosystemic collateral circulation. Macrosurgical cholestasis causes greater hepatosplenomegaly, hilar biliary pseudocysts, and ascites. Microsurgical extrahepatic cholestasis occurs with a lower degree of hepatosplenomegaly as well as with serum increase (P < 0.001) of γ‐GT and alkaline phosphatase. The bile ductular proliferation in the four hepatic lobes is very intense (P < 0.001) in both experimental models. The differences between both experimental models may be considered secondary to the increase of the predisposition to infection in rats with bile duct ligation, that complicates their evolution. The microsurgical cholestasis model could be useful in studying cholestasis secondary to biliary atresia. © 2004 Wiley‐Liss, Inc. Microsurgery 24:442–447, 2004.

The electrophoretic pattern of serum proteins has been studied in short-term prehepatic portal hypertensive rats since atrophy is produced in the liver, which is the main origin of most of these proteins, during this postoperative period. After 28 days of evolution, rats (n = 9) with triple stenosing ligated portal vein showed hypoalbuminemia, hypo-alpha-globulinemia, hyper-alpha2-globulinemia and hyper-gamma-globulinemia, the albumin/globulin ratio decreased with respect to the control animals (n = 8). These alterations are associated with hepatic atrophy, portosystemic and portohepatic (44.4%) collateral circulation. The proteinogram alterations found in rats with short-term prehepatic portal hypertension suggest that hepatic failure exists in spite of potential portohepatic revascularization which is frequently originated by the development of portohepatic collateral circulation.