chondroitin-sulfates and Liver-Cirrhosis

Decreased antithrombin III (ATIII) activity and large splenic vein diameter (SVD) are risk factors for portal vein thrombosis (PVT) after splenectomy in liver cirrhosis with portal hypertension. Antithrombin III concentrates can prevent PVT. This study was designed to stratify risks for PVT after splenectomy in cirrhotic patients and to develop prophylactic protocols for PVT.. In 53 patients (testing cohort), the cutoff level of preoperative ATIII activity (≤60%) was evaluated for administration of ATIII concentrates. Antithrombin III activity and SVD were re-evaluated as criteria for prophylaxis of PVT. In 57 patients (validation cohort), the risk stratification of PVT and prophylactic protocols were validated.. In the testing cohort, 10 (19%) of 53 patients had PVT. Risk level of PVT was stratified and prophylactic protocols were developed. Patients at low risk (ATIII activity ≥70% and SVD <10 mm) were not treated; those at high risk (ATIII activity <70% or SVD ≥10 mm) received ATIII concentrates (1,500 U/day) for 3 days; and those at highest risk (SVD ≥15 mm) received ATIII concentrates for 3 days, followed by danaparoid sodium (2,500 U/day) for 14 days and warfarin. In the validation cohort, 0 of 14 low-risk and 2 of 32 high-risk patients had PVT. Although 8 of 11 patients at highest risk had temporary PVT, it disappeared within 3 months postoperatively. Finally, only 2 (3.5%) of 57 patients had PVT.. Risk stratification of PVT after splenectomy and prophylaxis with ATIII concentrates and danaparoid sodium dramatically reduced the incidence of PVT.

Topics: Adult; Aged; Anticoagulants; Antithrombin III; Chondroitin Sulfates; Clinical Protocols; Decision Support Techniques; Dermatan Sulfate; Drug Therapy, Combination; Female; Fibrinolytic Agents; Heparitin Sulfate; Humans; Hypertension, Portal; Laparoscopy; Liver Cirrhosis; Male; Middle Aged; Portal Vein; Postoperative Complications; Prospective Studies; Risk Assessment; Risk Factors; ROC Curve; Splenectomy; Venous Thrombosis; Warfarin

The upregulated autophagy fuels the activation of hepatic stellate cells (HSCs) to promote hepatic fibrosis. However, the lack of specific inhibitors targeting autophagy and high requirements for cell targeting impede the application of antifibrotic therapy that targets autophagy. RNA interference (RNAi)-based short interfering RNA (siRNA) provides an approach to specifically inhibit autophagy. The therapeutic potential of siRNA, however, is far from being exploited due to the lack of safe and effective delivery vehicles. The cytoplasmic delivery of siRNA is essential for RNAi, and the intracellular trafficking pathway of vehicles determines the fate of siRNA. Unfortunately, the lysosomal degradation pathway, the intracellular fate of most gene vehicles, impedes RNAi efficiency. Inspired by the trafficking pathway of some viruses infecting cells, KDEL-grafted chondroitin sulfate (CK) was designed to alter the intracellular delivery fate of siRNA. The well-designed CD44-Golgi-ER trafficking pathway of CK was realized by triple cascade targeting including (1) CD44 targeting mediated by chondroitin sulfate, (2) Golgi apparatus targeting mediated by the caveolin-mediated endocytic pathway, and (3) endoplasmic reticulum (ER) targeting mediated by coat protein I (COP I) vesicles. CK was adsorbed on the complex of cationic liposomes (Lip) encapsulating siRNA targeting autophagy-related gene 7 (siATG7) to afford Lip/siATG7/CK. Lip/siATG7/CK functions as a drifting boat that follows the CD44-Golgi-ER flow and travels downstream to its destination (ER), bypassing the lysosomal degradation pathway and endowing HSCs with excellent RNAi efficiency. The efficient downregulation of ATG7 leads to an excellent antifibrotic effect both in vitro and in vivo.

Topics: Autophagy; Chondroitin Sulfates; Endoplasmic Reticulum; Golgi Apparatus; Humans; Hyaluronan Receptors; Liver Cirrhosis; RNA Interference; RNA, Small Interfering; RNAi Therapeutics

Chronic liver diseases have both high incidence and mortality rates; therefore, a deeper understanding of the underlying molecular mechanisms is essential. We have determined the content and sulfation pattern of chondroitin sulfate (CS) and heparan sulfate (HS) in human hepatocellular carcinoma and cirrhotic liver tissues, considering the etiology of the diseases. A variety of pathological conditions such as alcoholic liver disease, hepatitis B and C virus infections, and primary sclerosing cholangitis were studied. Major differences were observed in the total abundance and sulfation pattern of CS and HS chains. For example, the 6-O-sulfation of CS is fundamentally different regarding etiologies of cirrhosis, and a 2-threefold increase in HS N-sulfation/O-sulfation ratio was observed in hepatocellular carcinoma compared to cirrhotic tissues.

Topics: Carcinoma, Hepatocellular; Chondroitin Sulfates; Glycosaminoglycans; Heparitin Sulfate; Humans; Liver Cirrhosis; Liver Neoplasms; Pilot Projects

Components of the extracellular matrix (ECM) are overexpressed in fibrotic liver. Collagen is the main component of the liver fibrosis stroma. Here we demonstrate that chondroitin sulfate coated multilayered 50-nm nanoparticles encapsulating collagenase and silibinin (COL + SLB-MLPs) break down the dense collagen stroma, while silibinin inhibits activated hepatic stellate cells. The nanoparticles were taken up to a much greater extent by hepatic stellate cells than by normal hepatocytes, and they down-regulated production of type I collagen. In addition, chondroitin sulfate protected the collagenase from premature deactivation. COL + SLB-MLPs were delivered to the cirrhotic liver, and the collagenase and silibinin synergistically inhibited fibrosis in mice. Immunofluorescence staining of liver tissues revealed that CD44, mediated by chondroitin sulfate, delivered the nanoparticles to hepatic stellate cells. This strategy holds promise for degrading extracellular stroma and thereby facilitating drug penetration into fibrotic liver and related diseases such as liver cirrhosis and liver cancer.

Topics: Animals; Capsules; Cell Line; Chondroitin Sulfates; Collagenases; Disease Models, Animal; Hepatic Stellate Cells; Humans; Hyaluronan Receptors; Liver; Liver Cirrhosis; Mice; Nanoparticles; Silybin

Portal vein thrombosis (PVT) is a common complication of cirrhosis. However, in patients with PVT and cirrhosis, there is no clear evidence supporting effective treatment modalities. In this study, we examined the effectiveness and safety of anticoagulation therapy using danaparoid sodium for PVT in patients with cirrhosis.. This retrospective study assessed 52 cirrhotic patients with PVT treated with danaparoid sodium for 2 weeks between November 2008 and September 2018. The primary outcome measure was the post-treatment status of PVT assessed by reduction in thrombus volume and safety of the therapeutic intervention. PVT status was evaluated with contrast-enhanced computed tomography (CECT). All patients received 1250 units of danaparoid sodium twice daily by intravenous injection for 14 days. Patients on antithrombin III (AT-III) combination therapy were additionally administered 1500 units of AT-III on days 1-5 and days 8-12. Effectiveness was evaluated by CECT from between days 13 and 18. The secondary outcome measure was the prognosis of PVT.. All patients showed reduction in PVT volume without complications. Return of plasma AT-III level to > 70% during the treatment period contributes to ≥75% reduction of PVT volume. The prognosis in PVT patients depends on hepatic reserve capacity. When limited to Child-Pugh B and C liver cirrhosis patients, a ≥ 75% reduction of PVT volume improved the prognosis.. Danaparoid sodium-based anticoagulation therapy was effective and safe for PVT in patients with cirrhosis. Return of plasma AT-III level to the normal range during the treatment period contributes to reduction of PVT volume. A reduction of ≥75% in PVT volume may improve the prognosis of Child-Pugh B and C decompensated cirrhosis patients with PVT.

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparitin Sulfate; Humans; Liver Cirrhosis; Male; Portal Vein; Prognosis; Retrospective Studies; Venous Thrombosis

Liver fibrosis is a serious liver disease associated with high morbidity and mortality. The activation of hepatic stellate cells (HSCs) and the overproduction of extracellular matrix proteins are key features during disease progression. In this work, chondroitin sulfate nanomicelles (CSmicelles) were developed as a delivery system targeting HSCs for the treatment of liver fibrosis. CS-deoxycholic acid conjugates (CS-DOCA) were synthesized via amide bond formation. Next, retinoic acid (RA) and doxorubicin (DOX) were encapsulated into CSmicells to afford a DOX+RA-CSmicelles codelivery system. CSmicelles were selectively taken up in activated HSCs and hepatoma (HepG2) cells other than in normal hepatocytes (LO2), the internalization of which was proven to be mediated by CD44 receptors. Interestingly, DOX+RA-CSmicelles preferentially accumulated in the Golgi apparatus, destroyed the Golgi structure, and ultimately downregulated collagen I production. Following tail-vein injection, DOX+RA-CSmicelles were delivered to the cirrhotic liver and showed synergistic antifibrosis effects in the CCl

Topics: Animals; Antineoplastic Agents; Chondroitin Sulfates; Deoxycholic Acid; Doxorubicin; Drug Carriers; Drug Delivery Systems; Golgi Apparatus; Hep G2 Cells; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Male; Micelles; Rats; Rats, Wistar; Tretinoin

Portal vein thrombosis (PVT) is a serious complication in liver cirrhosis with portal hypertension. We examined the treatment, recurrence and prognosis of PVT in cirrhotic patients.. The study subjects were all 90 cirrhotic patients with PVT treated with danaparoid sodium (DS) at our department between July 2007 and September 2016. The mean age was 68 years and mean Child-Pugh score was 7. All patients received 2500 U/day of DS for 2 weeks, and repeated in those who developed PVT recurrence after the initial therapy.. Complete response was noted in 49% (n = 44), partial response (shrinkage ≥70%) in 33% (n = 30), and no change (shrinkage <70%) in 18% (n = 16) of the patients after the initial course of treatment. DS treatment neither caused adverse events, particularly bleeding or thrombocytopenia, nor induced significant changes in serum albumin, total bilirubin, prothrombin time, and residual liver function. Re-treatment was required in 44 patients who showed PVT recurrence and 61% of these responded to the treatment. The cumulative recurrence rates at 1 and 2 posttreatment years were 26 and 30%, respectively. The recurrence rates were significantly lower in patients with acute type, compared to the chronic type (p = 0.0141). The cumulative survival rates at 1 and 3 years after treatment (including maintenance therapy with warfarin) were 83 and 60%, respectively, and were significantly higher in patients with acute type than chronic type (p = 0.0053).. We can expect prognostic improvement of liver cirrhosis by warfarin following two-week DS therapy for the treatment of PVT in patients with liver cirrhosis safety and effectiveness. An early diagnosis of PVT along with the evaluation of the volume of PVT on CT and an early intervention would contribute to the higher efficacy of the treatment.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Chondroitin Sulfates; Contrast Media; Dermatan Sulfate; Female; Heparitin Sulfate; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Portal Vein; Recurrence; Survival Rate; Tomography, X-Ray Computed; Treatment Outcome; Venous Thrombosis; Warfarin

An 84-year-old woman with hepatitis C virus-related cirrhosis, hepatocellular carcinoma and atrial fibrillation, who presented with hematemesis, was initially treated with endoscopic variceal ligation (EVL) for an esophageal varix hemorrhage. However, computed tomography (CT) upon admission had revealed portal vein thrombosis, despite having received warfarin for existing atrial fibrillation. We subsequently initiated a 2-week treatment with danaparoid;warfarin being discontinued in order to reduce the risk of re-hemorrhage. A follow-up CT after treatment revealed complete reduction of the portal vein thrombosis. This is the first successful report of danaparoid use in the treatment of portal vein thrombosis that developed in a patient who had received warfarin.

Topics: Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparitin Sulfate; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Portal Vein; Thrombosis; Warfarin

We report a case of hepatitis B type liver cirrhosis with portal venous thrombosis in which danaparoid sodium was very effective. The portal venous thrombosis in this case disappeared 2 weeks commencing after administration of danaparoid sodium. The patient had not adverse effects or complications such as hemorrhage, and the clinical course was good. We consider that danaparoid sodium is an anticoagulant unlikely to cause adverse effects such as hemorrhage, and that it might be effective for treatment of portal venous thrombosis. We intend to examine the indications of treatment with danaparoid sodium, clarify the best administration method, and establishment of maintenance therapy by investigating more cases.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Heparitin Sulfate; Hepatitis B; Humans; Liver Cirrhosis; Male; Middle Aged; Portal Vein; Tomography, X-Ray Computed; Ultrasonography; Venous Thrombosis

Hepatic fibrosis involves the interplay of many factors including reactive oxygen species. Recent reports described antioxidant properties of glycosaminoglycans (GAGs). Since several findings have shown that hyaluronic acid (HYA) and chondroitin-4-sulphate (C4S) may act as antioxidant molecules, the aim of this research was to evaluate the antioxidant effects of HYA and C4S treatment in a rat model of liver fibrosis. The effect on tissue inhibitors of metalloproteinases (TIMPs) was also studied. Liver fibrosis was induced in rats by eight intraperitoneal injections of CCl4, twice a week for 6 weeks. HYA or C4S alone (25 mg/kg) or HYA and C4S in combination (12.5 + 12.5 mg/kg) were administered daily by the same route during the 6 weeks. At the end of the 6-week treatment period (24 h after the last dose of GAGs), the following parameters were evaluated: (1) serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, as index of hepatic cell disruption; (2) hepatic conjugated dienes (CD), as index of lipid peroxidation; (3) hepatic TIMPs activity and expression; (4) hepatic superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity, as index of endogenous defences; (5) hepatic hydroxyproline, as index of collagen deposition. CCl4-induced liver fibrosis enhanced lipid peroxidation and TIMPs activation, increased ALT and AST, depleted antioxidants SOD and GPx, and caused collagen deposition in liver tissue. Treatment with GAGs, especially when in combination, successfully reduced ALT and AST rise, lipid peroxidation by evaluating conjugated dienes, TIMPs activation and mRNA expression, partially restored SOD and GPx activities, and limited collagen deposition in the hepatic tissue. The data obtained showed that these molecules were able to limit hepatic injury induced by chronic CCl4 intoxication and especially limited liver fibrosis. They also confirm that HYA and C4S may exert antioxidant mechanism, while reduction of TIMPs expression suggests that GAGs may influence MMPs and TIMPs imbalance in liver fibrosis.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Chondroitin Sulfates; Collagen; Disease Models, Animal; Glycosaminoglycans; Hyaluronic Acid; Injections, Intraperitoneal; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Rats; Rats, Sprague-Dawley

Acidic glycosaminoglycan (AGAG) components in normal human liver and at different stages of liver cirrhosis were studied at the constitutional disaccharide level by enzymatic assay methods. The AGAG content in human cirrhotic liver was 5-6 times that in the normal state. The most predominant AGAG components in normal human liver tissue were heparan sulfates (HS) which accounting for 63% of the total AGAG, followed by a moderate amount of dermatan sulfate (DS) and small amounts of chondroitin sulfate isomers and hyaluronic acid (HA). In addition, the oversulfated DS detected in human liver. The increase in both HS and DS content reflects an increase in total AGAG with advancing liver cirrhosis. The ratio of non-sulfated AGAG, HA plus chondroitin, to DS plus its oversulfated isomer was 0.24 in the normal state but it increased to 0.80 at the early stage of liver cirrhosis. However, the ratio decreased to 0.36 and 0.21 at the typical and advanced stages of liver cirrhosis, respectively, with progress in the fibrotic process.

Topics: Chondroitin Sulfates; Chromatography, Paper; Dermatan Sulfate; Electrophoresis; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Liver; Liver Cirrhosis

Derangements in iron metabolism following liver damage were studied with special reference to iron deposit in relation to reticuloendothelial functions. In clinical studies, the metabolic fate of chondroitin sulfuric 59Fe, given intravenously, was examined in patients with chronic hepatitis or liver cirrhosis, diagnosed by liver biopsy. In experimental studies, liver damage was induced in rats by carbon tetrachloride (CCl4) injection and the labeled iron was similarly administered. 1) In patients with chronic hepatitis or liver cirrhosis, a reduction in uptake and utilization rates of the labeled iron was observed. 2) In rats with CCl4-induced liver damage, these parameters of the reticuloendothelial function were more reduced in parallel with the extent of hepatic fibrosis. 3) Similar conclusion was obtained from the analysis of iron distribution among tissues and of iron incorporation into several fractions of the liver: that is the uptake into non-hemin iron was less as the fibrosis advanced. In addition, more iron was incorporated into hemosiderin fraction and less into ferritin fraction. The findings may suggest a derangement in apoferritin synthesis as well as in release mechanism of deposit iron. 4) It is suggested that derangements in iron metabolism following liver damage are mainly due to reduction of the reticuloendothelial functions, but are partly due to changes in hematopoiesis and protein metabolism.

Topics: Animals; Carbon Tetrachloride Poisoning; Chondroitin; Chondroitin Sulfates; Chronic Disease; Hepatitis; Humans; Iron; Liver Cirrhosis; Male; Mononuclear Phagocyte System; Rats