Addition Of Ursodeoxycholic Acid Research Articles

Synergistic effects of ursodeoxycholic acid, and quercetin on liver function and systemic inflammation in non-alcoholic fatty liver disease and atrial fibrillation patients

Background. Non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) co-occur with signifi­cant clinical implications, necessitating therapeutic strategies that address the multifaceted nature of these conditions. This study evaluated the efficacy of standard treatment alone versus combined treatments with ursodeoxycholic acid (UDCA) and quercetin in patients with NAFLD and AF, focusing on improvements in liver function, lipid profile, systemic inflammation, and fibrosis markers. Aim: to evaluate and compare the efficacy of standard treatment alone versus standard treatment combined with ursodeoxycholic acid with and without quercetin in patients with non-alcoholic fatty liver disease and concurrent atrial fibrillation. Materials and methods. In a prospective, randomi­zed, controlled trial, 127 patients with diagnosed NAFLD and concurrent AF were enrolled. They were divided into three groups: group 1 — standard treatment (n = 42), group 2 — standard treatment plus UDCA (n = 44), and group 3 — standard treatment plus UDCA and quercetin (n = 41). The primary outcomes included changes in liver function tests (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase, alkaline phosphatase), lipid profile (total cholesterol, low- and high-density lipoprotein cholesterol (HDL-C), triglycerides), and non-invasive liver fibrosis scores (NFS, FIB-4). Secondary outcomes focused on systemic inflammation markers (C-reactive protein, galectin-3, soluble ST2) and fibronectin levels. Results. All treatment groups showed significant improvements in liver function tests and lipid profiles. Group 3 exhibited the most substantial reductions in ALT, AST, and improvements in HDL-C, indicating enhanced hepatoprotective and lipid-modulating effects. Systemic inflammation markers and fibronectin levels decreased significantly in groups receiving UDCA and quercetin, with the most pronounced effects observed in group 3, suggesting potent anti-inflammatory and anti-fibrotic action. Additionally, significant improvements in NFS and FIB-4 scores in group 3 highlight the anti-fibrotic potential of combining UDCA and quercetin with standard treatment. Conclusions. The addition of UDCA and quercetin to standard treatment for patients with NAFLD and AF significantly improves liver function, lipid metabolism, and reduces systemic inflammation and fibrosis, compared to standard treatment alone. These findings suggest a synergistic effect of UDCA and quercetin, offering a promising therapeutic strategy for managing the complex interplay between NAFLD and AF.

Evaluating the effect of ursodeoxycholic acid on total bilirubin of neonates with glucose-6-phosphate dehydrogenase deficiency complicated by indirect hyperbilirubinaemia.

This study aimed to investigate the effect of adding ursodeoxycholic acid (UDCA) to phototherapy in neonates with glucose-6-phosphate dehydrogenase (G6PD) deficiency and hyperbilirubinaemia. G6PD deficiency is a common cause of severe hyperbilirubinaemia in neonates. This study was a triple blind, clinical trial study of 40 neonates with G6PD deficiency and hyperbilirubinaemia who admitted for phototherapy in hospitals affiliated to the University of Medical Sciences. The treatment group (n= 20) received UDCA 10mg/kg (2cc/kg) daily divided into 2 doses every 12 h. The control group (n= 20) received the same volume of placebo syrup. The drug and placebo treatments were continued until the bilirubin level dropped below 171 μmol/L. Both the control and treatment group received continuous phototherapy. Independent sample t-test, survival analysis and logrank test were used to statistically analyse the results. The mean total bilirubin level was 231.9± 18.8μmol/L and 184.3± 18.6μmol/L in the control and intervention group respectively, 24 h after drug administration and 209.7± 19.3μmol/L and 157.4± 16.4μmol/L, respectively, 48 h after intervention (P < 0.05). The median length of hospitalisation in the treatment group was approximately 1day lower than the control group (logrank test P value: <0.001). The study showed that the addition of UDCA to phototherapy accelerates the reduction of total bilirubin level in neonates with G6PD deficiency and can reduce the duration of hospitalisation.

Динаміка клінічних симптомів й функціонального стану біліарної системи у хворих на хронічний безкам’яний холецистит на тлі цукрового діабету 2 типу під впливом комплексної терапії

The urgent problem of modern medical science and practice is the rapid increase of comorbid pathology spreading among the population of the whole world. Among the nosological forms, which are quite often combined with each other, there are cardiovascular system, digestive tract and endocrine diseases, namely type 2 diabetes mellitus. Diseases of the biliary tract, in the form of chronic acalculous cholecystitis, occur in patients with type 2 diabetes more often than in its absence. There is no doubt that the combination of diseases of the gallbladder and type 2 diabetes significantly affects the course and prognosis of both diseases, and the development of complications is one of the main causes of disability and mortality in patients. In this regard, the priority areas of health protection are the search for preventive measures to eliminate the development of diseases, their complications and the amendment of therapeutic patterns. The purpose of the study was to evaluate the efficacy of complex therapy with the addition of ursodeoxycholic acid and alpha-lipoic acid in patients with concomitant chronic acalculous cholecystitis and type 2 diabetes on the basis of studying the dynamics of clinical symptoms and the content of bile acids in blood serum, as well as parameters of cholecystosonography (in overview and dynamic versions). Material and methods. In the course of the study, 62 patients with the combined course of chronic hepatitis and diabetes mellitus were examined. The age of the patients ranged from 44 to 75 years old. The duration of type 2 diabetes was from 1 to 19 years. The group was representative in terms of age and number of male and female probands. Upon admission to the hospital, all patients underwent a thorough examination using generally accepted clinical, laboratory and instrumental studies. Results and discussion. The complex treatment included hypoglycemic drugs, medical nutrition, prescription of antispasmodic and antibacterial therapy, ursodeoxycholic acid drugs at a dose of 15 mg / kg / day for 4 weeks, as well as preparations of alpha-lipoic acid 600 I / V drip for 10 days, followed by oral administration in within 12 weeks. In order to assess the effectiveness of therapy, clinical symptoms, serum levels of fatty acids, indicators of survey and dynamic cholecystosonography were evaluated after 3 months in the dynamics of treatment. Conclusion. The study showed that the addition of ursodeoxycholic acid and alpha-lipoic acid to the complex therapy was accompanied by positive effects due to an improvement in the contractility of the gallbladder, a decrease in the serum fatty acid content, improved the motor and cholesecretory functions of the gallbladder and the clinical condition of patients by eliminating abdominal pain and reducing the percentage of patients with chronic acalculous cholecystitis and type 2 diabetes with manifestations of dyspeptic, neuro-vegetative and asthenic syndromes

Diversely Responsive Turn-On Fluorescent Cyclodextrin Chemosensors: Guest Selectivities and Mechanism Insights

Chemosensors have attracted considerable attention among the numerous strategies for detecting organic molecules in water. A turn-off mechanism was previously employed for the construction of a cyclodextrin (CD) chemosensor. This mechanism is greatly effective but has several shortcomings. In order to overcome these shortcomings, new fluorescent chemosensors NC0αCD, NC0βCD, and NC0γCD, which were (7-nitrobenz-2-oxa-1,3-diazol-4-yl)amine-modified α-CD, β-CD, and γ-CD, respectively, were prepared. Their guest selectivities were different from those of previously reported CD chemosensors. Here, the mechanism of new CD chemosensors was investigated using nuclear magnetic resonance (NMR) spectroscopy and molecular mechanics calculations. The fluorescence intensity of NC0βCD and NC0γCD slightly decreased and largely increased, respectively, upon the addition of ursodeoxycholic acid as a guest. This is due to the fact that the fluorophore of NC0βCD moved away to the hydrophilic bulk water to form hydrogen bonds between the host and the guest, while the fluorophore of NC0γCD remained located at the primary hydroxy side of the γ-CD unit to form a stable inclusion complex with hydrogen bonds between the fluorophore and the guest. NC0αCD also acted as a turn-on chemosensor for small guests, which could not be detected by the previous CD chemosensors. The motion restriction of the fluorophore through the generation of inclusion complexes could also contribute to increase in fluorescence intensity.

REGULATION OF MICRORNA EXPRESSION LEVEL BY CHOLERETIC THERAPY IN FUNCTIONAL DISORDERS OF THE GALLBLADDER AND ОDDI’S SPHINCTER IN CHILDREN

The alm: To study the effect of choleretic therapy on the level of microRNA expression in functional disorders of the gallbladder and Oddi's sphincter in children. Materials and methods: Fifty patients with functional disorders of the gallbladder and Oddi's sphincter who received standard therapy in combination with ursodeoxycholic acid, 20 patients - standard therapy without ursodeoxycholic acid, and 20 healthy children were examined. The level of expression of microRNA-378f, microRNA-4311, microRNA-4714- 3p in the blood serum by the method of real-time polymerase chain reaction with reverse transcription according to the protocol TaqMan Gene Expression Assays was performed. Results: It was demonstrated that the activity profile of microRNA-4714-3p was significantly lower in those examined with functional disorders of the gallbladder and Oddi's sphincter than in practically healthy children (p<0.05). After standard therapy combined with ursodeoxycholic acid in children with functional disorders of the gallbladder and Oddi's sphincter, the level of expression of microRNA-378f is significantly higher than before therapy (5.23±0.70 SU and 2.02±0.57 SU respectively) (p<0.05). Against the background of standard therapy with the addition of ursodeoxycholic acid or without it, the expression profile of microRNA-4714-3p in the blood serum in children with functional disorders of the gallbladder and Oddi's sphincter significantly decreased (1.93±0.58 SU and 1,14±0,53 SU respectively) (p<0.05). Conclusions: Ursodeoxycholic acid in children with functional disorders of the gallbladder and Oddi's sphincter affects the activity of generation of gene regulators of the cellular mechanisms of microRNA-378f and microRNA-4714-3p.

Dynamics of changes in lipid peroxidation and antioxidant protection under the influence of complex treatment in patients with comorbid course of non-alcoholic steatohepatitis

O. Yu. Filippova The aim to assess the effect of various complex treatment regimens on lipid peroxidation (LPO) and antioxidant protection (AOP) in patients with non-alcoholic steatohepatitis (NASH) in combination with obesity (OB) and biliary tract pathology (BT), based on 6-month follow-up data. Materials and methods. We examined 100 patients with NASH in combination with OB and pathology of BT. The control group consisted of 30 practically healthy persons. Patients of all groups within 6 months have been prescribed a lifestyle correction, in particular: diet, exercise, work and rest. Patients of the 1 group (n = 34) received standard treatment for 30 days. Patients of the 2 group (n = 33) were prescribed standard treatment combined with the use of ursodeoxycholic acid (UDCA) for 30 days at a dose of 15 mg·kg -1 ·d -1 . Patients of the 3 group (n = 33) received standard treatment and UDCA combined with the use of arginine glutamate for 30 days. All LPO-AOP were performed at the beginning and at the end of treatment in all patients and 6 months after treatment in 20 patients in each group of observation. Results. A more significant decrease in the levels of intermediate and final products of lipid peroxidation in blood serum (from P < 0.05 to P < 0.001) was observed in patients of the 2 group and especially of the 3 group, as compared to the same values in the 1 group. The maximum effect of UDCA and glutamate arginine on the decrease in the formation of LPO toxic products in the blood was observed in the 3 group compared to the 2 group when studying the indices of diene conjugates and isolated double bonds 6 months after the treatment (P < 0.05). Conclusions. Combination therapy (non-medicamentous and medicamentous) with the addition of UDCA and glutamate arginine to the standard treatment in the comorbid course of NASH can be considered as a promising direction in the treatment of this category of patients, which allows to restore the basic indices of lipoperoxidation and antioxidant protection.

Characterization of a novel bile acid-based delivery platform for microencapsulated pancreatic β-cells

Introduction In a recent study, we confirmed good chemical and physical compatibility of microencapsulated pancreatic β-cells using a novel formulation of low viscosity sodium alginate (LVSA), Poly-L-Ornithine (PLO), and the tertiary bile acid, ursodeoxycholic acid (UDCA). This study aimed to investigate the effect of UDCA on the morphology, swelling, stability, and size of these new microcapsules. It also aimed to evaluate cell viability in the microcapsules following UDCA addition. Materials and methods Microencapsulation was carried out using a Büchi-based system. Two (LVSA-PLO, control and LVSA-PLO-UDCA, test) pancreatic β-cells microcapsules were prepared at a constant ratio of 10:1:3, respectively. The microcapsules’ morphology, cell viability, swelling characteristics, stability, mechanical strength, Zeta potential, and size analysis were examined. The cell contents in each microcapsule and the microencapsulation efficiency were also examined. Results The addition of UDCA did not affect the microcapsules’ morphology, stability, size, or the microencapsulation efficiency. However, UDCA enhanced cell viability in the microcapsules 24 h after microencapsulation (p < 0.01), reduced swelling (p < 0.05), reduced Zeta potential (− 73 ± 2 to − 54 ± 2 mV, p < 0.01), and increased mechanical strength of the microcapsules (p < 0.05) at the end of the 24-h experimental period. Discussion and conclusion UDCA increased β-cell viability in the microcapsules without affecting the microcapsules’ size, morphology, or stability. It also increased the microcapsules’ resistance to swelling and optimized their mechanical strength. Our findings suggest potential benefits of the bile acid UDCA in β-cell microencapsulation.

Ursodeoxycholic acid attenuates colonic epithelial secretory function

Dihydroxy bile acids, such as chenodeoxycholic acid (CDCA), are well known to promote colonic fluid and electrolyte secretion, thereby causing diarrhoea associated with bile acid malabsorption. However, CDCA is rapidly metabolised by colonic bacteria to ursodeoxycholic acid (UDCA), the effects of which on epithelial transport are poorly characterised. Here, we investigated the role of UDCA in the regulation of colonic epithelial secretion. Cl(-) secretion was measured across voltage-clamped monolayers of T84 cells and muscle-stripped sections of mouse or human colon. Cell surface biotinylation was used to assess abundance/surface expression of transport proteins. Acute (15 min) treatment of T84 cells with bilateral UDCA attenuated Cl(-) secretory responses to the Ca(2+) and cAMP-dependent secretagogues carbachol (CCh) and forskolin (FSK) to 14.0 ± 3.8 and 40.2 ± 7.4% of controls, respectively (n = 18, P < 0.001). Investigation of the molecular targets involved revealed that UDCA acts by inhibiting Na(+)/K(+)-ATPase activity and basolateral K(+) channel currents, without altering their cell surface expression. In contrast, intraperitoneal administration of UDCA (25 mg kg(-1)) to mice enhanced agonist-induced colonic secretory responses, an effect we hypothesised to be due to bacterial metabolism of UDCA to lithocholic acid (LCA). Accordingly, LCA (50-200 μm) enhanced agonist-induced secretory responses in vitro and a metabolically stable UDCA analogue, 6α-methyl-UDCA, exerted anti-secretory actions in vitro and in vivo. In conclusion, UDCA exerts direct anti-secretory actions on colonic epithelial cells and metabolically stable derivatives of the bile acid may offer a new approach for treating intestinal diseases associated with diarrhoea.

Refeeding syndrome in a patient with advanced Kidney failure due to Nephronophthisis

Refeeding syndrome (RS) is a serious and potentially fatal disorder. It is caused by a shift of fluids, sodium, potassium, magnesium and phosphorus as well changes in the metabolism of glucose, protein, fat and vitamins following the refeeding of malnourished patients, whether enterally or parenterally. RS has rarely been reported in patients with advanced kidney disease probably due to the pre-existing hyperphosphatemia, hypermagnesemia and hyperkalemia in these patients. In the following report, we present a patient with nephronophthisis type 1 deletion syndrome in whom her main previous nutrition was limited to simply rehydration to avoid renal replacement therapy. On presentation, she was cachectic and dehydrated with advanced kidney failure. She was treated with medical nephrectomy using non-steroidal anti-inflammatory drugs and then placed on maintenance hemodialysis. Percutaneous endoscopic gastrostomy was used for her initial feeding. Care was exercised during her early refeeding with regard to correction of fluids and essential electrolytes, viz. potassium, phosphorus and magnesium, as well as multivitamins to avoid the cardiovascular and neurological complications of RS. However, the changes in the gut, pancreas and liver as well as her hyperlipidemia were a clear obstacle. Fortunately, the ileus and pancreatitis she developed on refeeding improved dramatically with a decrease of the feeding dose to half; however, the liver abnormalities and hyperlipidemia were severe and slow to recover. These improved after addition of ursodeoxycholic acid and permitted successful increase of the dose of feeding subsequently.

Effect of biliary drainage on inducible nitric oxide synthase, CD14 and TGR5 expression in obstructive jaundice rats

To investigate the effect of biliary drainage on inducible nitric oxide synthase (iNOS), CD14 and TGR5 expression in rats with obstructive jaundice (OJ). Male adult Sprague-Dawley rats were randomly assigned to four groups: OJ, sham operation (SH), internal biliary drainage (ID) and external biliary drainage (ED). Rat models were successfully established by two operations and succumbed for extraction of Kupffer cells (KCs) and liver tissue collection on the 8(th) and 15(th) day. KCs were isolated by in situ hepatic perfusion and digested with collagen IV, density gradient centrifuged by percoll reagent and purified by cell culture attachment. The isolated KCs were cultured with the endotoxin lipopolysaccharide (LPS) with and without the addition of ursodeoxycholic acid (UDCA). The expression of iNOS, CD14 and bile acid receptor-TGR5 protein in rat liver tissues was determined by immunohistochemistry. The expression of iNOS and CD14 messenger RNA (mRNA) on the isolated KCs was detected by reverse transcription polymerase chain reaction (PCR) and the TGR5 mRNA level in KCs was measured by real-time quantitative PCR. The iNOS protein was markedly expressed in the liver of OJ rats, but rare expressed in SH rats. After relief of OJ, the iNOS expression was decidedly suppressed in the ID group (ID vs OJ, P < 0.01), but obviously increased in rats of ED (ED vs OJ, P = 0.004). When interfered only with LPS, the expression of iNOS mRNA by KCs was increased in the OJ group compared with the SH group (P = 0.004). After relief of biliary obstruction, the iNOS mRNA expression showed slight changes in the ED group (ED vs OJ, P = 0.71), but dropped in the ID group (ID vs OJ, P = 0.001). Compared with the simple intervention with LPS, the expressions of iNOS mRNA were significantly inhibited in all four groups after interfered with both LPS and UDCA (P < 0.01, respectively). After bile duct ligation, the CD14 protein expression in rat liver was significantly strengthened (OJ vs SH, P < 0.01), but the CD14 mRNA level by KCs was not up-regulated (OJ vs SH, P = 0.822). After relieving the OJ, the expression of CD14 protein was reduced in the ID group (ID vs OJ, P < 0.01), but not reduced in ED group (ED vs OJ, P = 0.591). And then the CD14 mRNA expression was aggravated by ED (ED vs OJ, P < 0.01), but was not significantly different between the ID group and the SH and OJ groups (ID vs SH, P = 0.944; ID vs OJ, P = 0.513, respectively). The expression of TGR5 protein and mRNA increased significantly in OJ rats (OJ vs SH, P = 0.001, respectively). After relief of OJ, ID could reduce the expression of TGR5 protein and mRNA to the levels of SH group (ID vs SH, P = 0.22 and P = 0.354, respectively), but ED could not (ED vs SH, P = 0.001, respectively). ID could be attributed to the regulatory function of activation of KCs and release of inflammatory mediators.

Ursodeoxycholic acid and its emerging role in attenuation of tumor growth in gastrointestinal malignancies

Dear Editor, I read with great interest the recent article by Tschirner et al. [1]. Interestingly, recent data suggest that ursodeoxycholic acid (UDCA) may attenuate tumor growth in a number of gastrointestinal malignancies. For instance, tauro-ursodeoxycholic acid when administered along with celecoxib attenuates proliferation and tumor growth in colonic adenomas [2]. Interestingly, UDCA decreases the odds of advanced lesions in males only [3]. Similarly, UDCA downregulates c-Myc expression [4]. As a result, it attenuates tumor growth in colon carcinomas. CDK6 expression is also decreased secondary to UDCA administration. UDCA downregulates Cox-2 also, thus further inhibiting tumor growth. It also attenuates CCAAT/enhancer binding protein beta (C/EBPbeta) at the same time [5]. It also effects p38 and Ras expression and thereby further modulates Cox-2 function. Recently, UDCA conjugates with glutamic acid have been developed that result in enhanced intraluminal delivery of UDCA inside the colon [6]. Similarly, UDCA inhibits gastric carcinogenesis. It does this by modulating the MEK/ERK pathway. It accentuates MEK1/2 phosphorylation as well as ERK1/2 phosphorylation [7]. DR 5 receptors are necessary for UDCA-mediated apoptosis. Modulation of the raft formation/ROS production/PKCδ activation pathway can effect UDCA-mediated apoptosis as it in turn effects and controls DR5 expression [8]. Apoptosis secondary to UDCA is attenuated by U0126 as well as by PD98059. Similarly, DLC1 degradation by proteosomes is attenuated by UDCA [9]. Subsequently, there is decreased proliferation and growth in hepatocellular carcinomas. UDCA administration is simultaneously accompanied by a decrease in RhoA activity. Similarly, UDCA upregulates Bax expression and downregulates Bcl-2 expression. Interestingly, the p53-caspase 8 pathway is activated by UDCA which mediates the conversion from oxaliplatin-induced necrosis to apoptosis in hepatocellular carcinomas [10]. At the same time, UDCA inhibits ROS production. Hence, combination therapy in hepatocellular carcinomas may benefit from the addition of UDCA. Similarly, UDCA has a negative impact on the incidence rate of cholangiocarcinomas in patients with primary sclerosing cholangitis [11]. It is clearly evident from the above examples that UDCA can play a major role in attenuating carcinogenesis in the gastrointestinal tract. There is a clear and urgent need for further studies in this regard.

Patients With Autoimmune Hepatitis Who Have Antimitochondrial Antibodies Need Long-term Follow-up to Detect Late Development of Primary Biliary Cirrhosis

Patients with autoimmune hepatitis (AIH) who have antibodies against mitochondrial proteins (AMA positive) are believed to have an autoimmune syndrome that should be managed as AIH. Of patients with AMA-positive AIH, we report on 3 individuals to demonstrate how autoimmune liver disease can progress over time. Specific features of primary biliary cirrhosis (PBC) overlapped in time in these patients. Our observations indicate the importance of careful follow up of patients with AMA-positive AIH; health care professionals that treat such patients should therefore be aware of longitudinal clinical changes that might indicate development of PBC in this setting.

Liver transplantation in autoimmune liver diseases

Liver transplantation is indicated for terminal phases of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Indications for transplantation in autoimmune liver diseases are similar to those used in other acute or chronic liver diseases. Therapeutic advances have reduced the need for transplantation for autoimmune hepatitis and primary biliary cirrhosis but not for primary sclerosing cholangitis. Overall, outcomes of transplantation for autoimmune liver diseases are excellent. However, recurrence of autoimmune liver diseases in the allograft has variable impacts on graft and patient survivals. Treatment of recurrent diseases requires changes in immunosuppression or addition of ursodeoxycholic acid. Among autoimmune liver diseases, only autoimmune hepatitis occurs de novo in recipients transplanted for other diseases. Patients transplanted for autoimmune hepatitis or primary sclerosing cholangitis are at risk for reactivation or de novo onset of ulcerative colitis. Better understanding of the pathogenesis of recurrent autoimmune liver diseases is needed to devise effective means of prevention and treatment.

Ursodeoxycholic acid inhibits hepatocyte-like cell apoptosis by down-regulating the expressions of Bax and Caspase-3

To investigate the mechanism of ursodeoxycholic acid (UDCA) in hepatocyte apoptosis using differentiated hepatocytes derived from bone marrow mesenchymal cells. Rat bone marrow mesenchymal cell was induced into mature hepatocytes in vitro and then treated with PBS (Cont), deoxycholic acid (DCA), DCA plus UDCA (U + D) or UDCA alone (UDCA). Cell apoptosis was detected by Hoechst staining and Caspase-3 activity measurement. The mRNA expressions of p53 and Bax were measured by semi-quantitative RT-PCR and real-time RT-PCR. The Bax protein expression was detected by immunohistochemistry. In comparison with Cont, DCA obviously induced hepatocyte apoptosis as measured by an increased cell count and a higher Caspase-3 activity (P < 0.05). These increments could be inhibited by addition of UDCA. The expressions of p53 and Bax in hepatocytes were up-regulated by DCA. These up-expressions could also be inhibited by UDCA. The DCA-induced increased count of Bax-positive cells could be reduced by UDCA. UDCA inhibits DCA-induced hepatocyte apoptosis by down-regulating the expression of p53/Bax signal molecule.

The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett’s esophagus

Bile acids may play a role in the pathogenesis of Barrett's esophagus (BE). Bile composition can be influenced by oral administration of ursodeoxycholic acid (UDCA). We prospectively investigated the effect of proton pump inhibitors (PPI) supplemented with UDCA in vivo in patients with BE. Patients with no or low-grade dysplasia who were clinically asymptomatic on PPI were eligible for the study. In order to exclude the effects of acid reflux, all patients were initially treated with 40 mg esomeprazole (ESO) twice daily for 6 months and continued on this dose till the end of the study (t = 12 months). During a period of 6 months (t = 6 month - t = 12 month) patients were treated with oral UDCA (600 mg twice daily). Patients underwent endoscopy at t = 0 months, t = 6 months and t = 12 months with multiple biopsies of the distal and proximal BE segment, normal squamous and gastric cardia. In addition, pH was measured at t = 0 months and t = 6 months using a BRAVO wireless pH capsule. Bile was sampled at the beginning of the UDCA treatment and 6 months later (t = 6 month and t = 12 month). All biopsies were reviewed for the extent of metaplasia, dysplasia, and acute and chronic inflammation. In addition, proliferation (Ki67), differentiation (villin, cytokeratins 7 and 20) and inflammation (COX-2) were investigated by immunohistochemistry (IHC). Nine patients (mean age 60 years, median BE length 7 cm) were included, of whom six had no dysplasia and three had low-grade dysplasia. pH measurements revealed a normal acid exposure in most patients at t = 0 and t = 6 months. In addition, bile composition analysis demonstrated the efficacy of UDCA. Combining the results of both phases of the study, no significant changes were seen in any of the histological or IHC parameters. Differentiation and proliferation parameters showed no significant changes. In this study, in BE patients who were clinically asymptomatic on PPI, increasing the PPI dose to the maximum for 6 months followed by the addition of UDCA for 6 months did not result in significant histological or IHC changes in their BE.

Supramolecular assembly system depended on guest species based on bis-naphthane modified β-cyclodextrin dimer

The supramolecular assembly system based on bis naphtahlene modified β-cyclodextrin dimer linked with ethylenediamine unit was studied. The synthesis of the titled compound (β-1) was succeeded in a 7% synthetic yield. It was observed that β-1 showed monomer emission, which was decreased concurrently with appearance of excimer emission in an addition of guest species such as 1-adamantanol or ursodeoxycholic acid. When γ-CyD was added to the system, two types of fluorescent spectra were obtained, which was depended on guest species. It was indicated that both of naphthalene units of β-1 were included in the γ-CyD cavity in the presence of 1-adamantanol in a fashion of 2:1 complex. On the other hand, an addition of ursodeoxycholic acid gave disappearance of the excimer emission as well as increase of monomer emission. In the system, each of the appended units was trapped by the each of two γ-CyDs, which is 2:2 complex formation.

Effects of ursodeoxycholic acid on photodynamic therapy in a murine tumor model.

We previously reported that the efficacy of photodynamic therapy (PDT) in cell culture was enhanced by ursodeoxycholic acid (UDCA), a nontoxic bile acid. In this study, we examined the ability of UDCA to promote tumor control by PDT in the mouse, using the radiation-induced fibrosarcoma tumor and the photosensitizing agent tin etiopurpurin (SnET2). These experiments revealed that the addition of UDCA to a PDT protocol promoted inhibition of tumor growth, a phenomenon unrelated to either altered SnET2 biodistribution or the level of vascular shutdown during irradiation. These results indicate that UDCA acts solely by promoting direct tumor cell kill by PDT.

Reduction of hepatocarcinogenesis by ursodeoxycholic acid in rats.

Ursodeoxycholic acid (UDCA) is used worldwide for treatment of primary biliary cirrhosis and chronic liver diseases. However, its action on hepatocarcinogenesis remains to be explored. To clarify its effect, in vivo and in vitro experiments were performed. Ninety Fisher 344 rats were fed a standard diet (Group 1, n = 30), a standard diet supplemented with 0.1% UDCA (Group 2, n = 30) and 0.3% UDCA (Group 3, n = 30). The rats were given an i.p. injection of diethylnitrosamine (DEN) weekly for 6 weeks. Fifteen additional rats were fed 0.3% UDCA supplemented diet without DEN treatment (Group 4). The rats were killed at 5, 10 and 18 weeks after the last injection of DEN. The number of liver tumor and percentage of the GST-P-positive hepatocytes were significantly reduced by UDCA treatment. The PCNA-positive cells were decreased by administration of UDCA at 18 weeks. The increased number of apoptotic cells was observed in the GST-P-negative area at 5, 10 and 18 weeks and in the GST-P-positive area at 18 weeks in the UDCA group. Expression of Bax in mitochondria and cytochrome c in cytosol was increased by UDCA treatment. Caspase 3 activity was also increased in the UDCA groups. The addition of UDCA into the culture of Huh7 and Fao hepatocellular carcinoma (HCC) cells induced apoptosis in a dose-dependent manner. The data of the present study suggest that UDCA treatment reduces hepatocarcinogenesis via inducing apoptosis of 'initiated hepatocytes' as well as inhibiting proliferation.

Guest-responsive fluorescence variations of gamma-cyclodextrins labeled with hetero-functionalized pyrene and tosyl moieties.

Regioselectively hetero-labeled hosts, 6A-pyrenebutylate-6X-tosyl-modified gamma-cyclodextrins (X = B or H, C or G, D or F, and E for gamma-1, gamma-2, gamma-3, and gamma-4, respectively), were synthesized in order to investigate their chemo-sensor properties for applications to organic compounds, such as bile acids and terpenes. The hosts (gamma-1, gamma-2, gamma-3, and gamma-4) exhibit pure monomer fluorescence. The guest-induced fluorescence emissions of these hosts were suppressed in the presence of guests. The extent of fluorescence variations of these hosts with guests was recognized as a manifestation of the sensing ability of the hosts. A sensing parameter (deltaI/I0, where I and I0 are the fluorescence intensities in the presence and absence of a guest and deltaI = I0-I) was used to describe the sensing ability of these hosts. Host gamma-analogs were able to detect progesterone, ursodeoxycholic acid, chenodeoxycholic acid, and (-)-borneol with high sensitivity. The behaviors of the appended moieties of these hosts during the formation of host-guest complexes were studied using induced circular dichroism (ICD) spectra, fluorescence spectra and the MM2-energy-minimized structure. The host gamma-analogs exhibited different ICD spectra patterns before and after the addition of ursodeoxycholic acid. The guest-induced variations of ICD and the fluorescence spectra and MM2-minimized structures suggest that the pyrene and tosyl moieties move by altering the spatial relationship between them, in which the pyrene moiety works as a hydrophobic cap and the tosyl moiety is speculated to act as a spacer.

Geranylgeraniol, an intermediate product in mevalonate pathway, induces apoptotic cell death in human hepatoma cells: death receptor-independent activation of caspase-8 with down-regulation of Bcl-xL expression.

Geranylgeraniol (GGOH), an intermediate of mevalonate metabolism, is known to induce apoptosis in various lines of cancer cells. The present study was undertaken to clarify the signaling pathways of apoptosis induced by GGOH in human hepatoma cells. HuH‐7 human hepatoma cells were incubated in the absence or presence of GGOH. Activation of caspase‐8/‐9/‐3 in HuH‐7 cells was found after 8 h treatment with GGOH, at which tune DNA fragmentation and loss of mitochondrial transmembrane potential (ΔΨm) occurred. HuH‐7 cells do not express Bcl‐2; however, down‐regulation of Bcl‐xL expression preceded activation of the caspase cascade in GGOH‐treated HuH‐7 cells, while Bax expression was not changed by GGOH treatment. Addition of caspase inhibitors restored the decreased cell viability of HuH‐7 cells by GGOH, including ΔΨm, to the baseline level, which indicated that caspase triggers mitochondria‐dependent apoptotic pathways in GGOH‐treated HuH‐7 cells. Similarly, GGOH‐mediated apoptosis of HuH‐7 cells was clearly prevented by coadministration of ursodeoxycholic acid (UDCA), which led to restoration of the level of Bcl‐xL expression. Activation of caspase‐8/‐9/‐3, as well as ΔΨm, by GGOH treatment was suppressed by addition of UDCA. Our results indicate that activation of the caspase cascade initiating from caspase‐8, which could be accelerated by down‐regulation of Bcl‐xL expression, plays a key role in an apoptotic process induced by GGOH in human hepatoma cells.