Search

Актуальність. Захворювання гепатобіліарної системи — одна з найбільш поширених проблем педіатричної гастроентерології. Захворювання біліарного тракту (БТ) супроводжуються стійкими змінами обміну ліпідів, що сприяє тривалому холестазу і прогресуванню біліарної патології. Мета дослідження — вивчити ефективність застосування препарату Урсофальк® у комплексній терапії захворювань БТ і коморбідних станів у дітей. Матеріали та методи. У міському гастроентерологічному відділенні м. Харкова обстежено 55 дітей віком від 5 до 18 років (31 дівчинка та 24 хлопчика). Критерії включення пацієнтів у дослідження: захворювання БТ, що супроводжуються біліарним сладжем (БС) і порушенням ліпідного профілю (ЛП) сироватки крові. Діагностичний комплекс включав: аналіз клінічних даних, УЗД органів черевної порожнини, біохімічне дослідження сироватки крові («печінкові проби», ЛП). Усі діти отримували комплексне лікування з урахуванням коморбідної патології. Тривалість курсу терапії — 1 місяць. Пацієнти були розділені на дві групи залежно від жовчогінної терапії: 1-ша (основна) група отримувала традиційні жовчогінні засоби, 2-га (група порівняння) — препарат Урсофальк®. При статистичній обробці використані ліцензовані програмні продукти (Statistica, Excel). Результати. Клінічні прояви у дітей груп спостереження були представлені больовим і диспептичним синдромами. У всіх обстежених виявлено коморбідні стани і наявність БС до початку лікування. Після закінчення курсу лікування відзначалася позитивна динаміка клінічних симптомів, лабораторних показників і гомогенності структури жовчі. Застосування в комплексній терапії Урсофальку® дозволило повністю компенсувати відчуття тяжкості та іррадіацію болю, тоді як у дітей групи порівняння зберігалися больовий синдром, тяжкість у правому підребер’ї, диспептичні скарги. Слід зазначити, що застосування Урсофальку® дозволяє також нормалізувати структуру жовчі і біохімічні показники, що характеризують ліпідний обмін. Зареєстровано вірогідно (p < 0,05) більш виражений ефект зменшення частоти порушень гомогенності жовчі в основній групі — на 65,5 % порівняно з групою порівняння — 27,3 %. Позитивна динаміка біохімічних показників при контрольному обстеженні відзначалася в обох групах пацієнтів, при цьому вірогідно (p < 0,05) більш вираженими були зміни в групі дітей, які приймали Урсофальк®. Висновки. Застосування урсодезоксихолевої кислоти (УДХК) патогенетично обґрунтоване для корекції функціональних, метаболічних порушень при біліарній патології та коморбідних станах, що підтверджують результати спостереження. При призначенні Урсофальку® в комплексній терапії захворювань жовчовивідної системи у дітей відзначається швидка регресія і купіювання клінічних симптомів, нормалізація лабораторно-інструментальних показників. Урсофальк® є референтним препаратом УДХК. Наявність офіцінальної форми препарату Урсофальк® у спеціальній лікарській формі для дітей у вигляді суспензії дозволяє застосовувати УДХК в дитячому віці, починаючи з перших днів життя.

Патология гепатобилиарного тракта широко распространена во всем мире. При не соответствующем по количеству и качеству поступлении желчи в кишечник нарушается его перистальтика, наблюдается раздражение его стенок, неадекватное пристеночное пищеварение и, как следствие, синдром мальабсорбции и расстройство водно-электролитного баланса. Глистно-паразитарные инвазии часто являются причиной возникновения функциональных нарушений. При пролонгированном течении функциональных заболеваний желчевыделительной системы создаются условия для развития органических поражений билиарного тракта, в том числе и механической окклюзии. Одним из механизмов воздействия при глистно-паразитарном персистировании является повышение степени литогенности желчи как результат дегидроксилирования желчных кислот под влиянием микробных ферментов. При этом хенодезоксихолевая кислота превращается в литохолевую, которая не образует мицелл и, следовательно, способствует кристаллизации холестерина. На поражение гепатобилиарной системы паразитарного генеза могут указывать как специфические, так и неспецифические симптомы: слабость, раздражительность, перепады настроения, нарушения сна. В результате токсического воздействия самих паразитов, продуктов их распада, препаратов, направленных на их уничтожение, развивается патология гепатобилиарного тракта. В связи с этим в комплексную терапию при глистно-паразитарных инвазиях должны входить препараты, восстанавливающие функцию печени и желчевыводящих путей. Растительный комплекс Вормил Фито, созданный с целью удаления последствий дегельминтизации и защиты от повторного заражения, с уникальной композицией трав оказывает гепатопротекторное, желчегонное действие, нормализует моторику желудочно-кишечного тракта. Таким образом, использование комбинации препарата Вормил и растительного комплекса Вормил Фито имеет оптимальный эффект в лечении гельминто-паразитарных инвазий.

Актуальность.На современном этапе важное значение приобретает ранняя диагностика функциональных расстройств желчного пузыря и сфинктера Одди (ФР ЖП и СФО) у детей и своевременное назначение эффективной холеретической терапии. Цель работы: определить прогностические факторы риска развития ФР ЖП и СФО у детей и спрогнозировать эффективность холеретической терапии с добавлением препаратов урсодезоксихолевой кислоты (УДХК). Материалы и методы. Обследованы и пролечены 70 детей с ФР ЖП и СФО в возрасте от 4 до 14 лет. С помощью последовательного (секвенционного) анализа Вальда проанализированы 140 клинико-лабораторных, молекулярно-генетических и инструментально-диагностических параметров, для каждого из них рассчитан относительный риск (ОР) и диагностический коэффициент. Результаты.Факторами риска развития ФГ ЖП и СФО установлены: наличие ФР ЖП и СФО у отца и родственников по линии матери (ОР = 1,60 и ОР = 1,60 соответственно), масса тела при рождении менее 3 кг (ОР = 1,95), возникновение первого эпизода клинико-параклинических проявлений в возрасте от 2 до 6 лет (ОР = 1,47), уровни показателей биохимической гепатограмы: холестерина — 43,7–52,0 ммоль/л (ОР = 1,83), аспартатаминотрансферазы — 45,0–59,0 н/л (ОР = 3,21) и аланинаминотрансферазы — 28,3–38,0 н/л (ОР = 3,21). Определена высокая эффективность холеретической терапии с добавлением препаратов УДХК при ФР ЖП и СФО у детей (ОР = 4,13). Существенное значение приобретает использование УДХК в холеретический терапии в анамнезе заболевания (ОР = 3,67). Установлено, что после получения лечения у детей в качестве протекторного фактора определены уровни экспрессии микро-РНК-378f — 3,07–6,14 усл.ед. (ОР = 0,37), микро-РНК-4311 — 2,51–5,01 усл.ед. (ОР = 0,18), микро-РНК-4714-3р — 3,19–6,38 усл.ед. (ОР = 0,31). Разработаны математические модели, которые можно использовать для установления вероятности развития функциональных расстройств желчного пузыря и сфинктера Одди у детей и для определения эффективности их холеретической терапии. Выводы. Высокие показатели эффективности и простота в использовании математических моделей прогноза вероятности развития функциональных расстройств желчного пузыря и сфинктера Одди у детей и прогнозирования эффективности холеретический терапии с добавлением препаратов урсодезоксихолевой кислоты позволяют рекомендовать их в практической деятельности педиатра, семейного врача и детского гастроэнтеролога для своевременного назначения рациональной терапии и проверки ее эффективности.

Bile secretion by hepatocytes is an osmotic process. The output of bile salts and other organic anions (e.g. glutathione), through the bile salt transporter BSEP/ABCB11 and the organic anion transporter MRP2/ABCC2, respectively, are considered to be the major osmotic driving forces for water secretion into bile canaliculi mainly via aquaporin-8 (AQP8) channels. The down-regulated canalicular expression of these key solute transporters and AQP8 would be a primary event in the establishment of hepatocellular cholestasis. Recent studies in animal models of hepatocellular cholestasis show that the hepatic delivery of AdhAQP1, an adenovector encoding for the archetypical water channel human aquaporin-1 (hAQP1), improves bile secretion and restores to normal the elevated serum bile salt levels. AdhAQP1-transduced hepatocytes show that the canalicularly-expressed hAQP1 not only enhances osmotic membrane water permeability but also induces the transport activities of BSEP/ABCB11 and MRP2/ABCC2 by redistribution in canalicular cholesterol-rich microdomains likely through interactions with the cholesterol-binding protein caveolin-1. Thus, the hepatic gene transfer of hAQP1 improves the bile secretory failure in hepatocellular cholestasis by increasing both biliary output and choleretic efficiency of key osmotic solutes, such as, bile salts and glutathione. The study of hepatocyte aquaporins has provided new insights into the mechanisms of bile formation and cholestasis, and may lead to innovative treatments for cholestatic liver diseases.

A large number of people suffer from gall stone worldwide and this problem is now being increased significantly due to the malnutrition, changes in living style, lack of exercise and conditions i.e. industrialization. Medicinal plants are used from centuries due to their cultural acceptability, efficacy, safety and fewer side effects as compared to modern synthetic medicines. The aim of this review is to gather the information of the plants utilized in various parts and societies of the world against gallstones. The information provided is not only useful for common people but also for the scientific community for further phytochemical, toxicological and pharmacological studies which may lead to discovery of new, more effective and safer medicines for gallstones.

Introduction: Yerba mate has several nutritional and medicinal properties, acting as a diuretic stimulant and digestion facilitator. Therefore, the use of yerba mate is being modernized and alternatives for its use and innovation are being investigated. Among the pharmacological activities attributed to the compounds present in yerba mate extracts, the following stand out: chemopreventive activity (prevention of cellular damage caused by chronic diseases), inhibition of glycation, inhibition of oxidative stress, choleretic effect (increased bile flow) and intestinal tract propulsion, vasodilator effect and antioxidant activity. The objective of this study is to analyze the organoleptic and pharmacological characteristics of mate teas marketed in Teresina Piauí, through a physical-chemical control, and comparing the information contained on the labels with the Brazilian Pharmacopeia, a physical-chemical control was carried out, through tests moisture content, total ash, acid-insoluble ash, pH, foreign material and label analysis. Result and discussion: After performing the physical and chemical tests of the mate tea samples, the organoleptic properties showed characteristic color and smell. The results of loss on drying were satisfactory, except for samples A and D. In the tests of total ash and acid-insoluble ash, the samples showed satisfactory results for all samples. Conclusion: There is a need for greater inspection by the Health Surveillance regarding the quality, safety and effectiveness of plant products sold in supermarkets. Introducción: La yerba mate tiene varias propiedades nutricionales y medicinales, actuando como estimulante diurético y facilitador de la digestión. Por ello, se está modernizando el uso de la yerba mate y se investigan alternativas para su uso e innovación. Entre las actividades farmacológicas atribuidas a los compuestos presentes en los extractos de yerba mate se destacan: actividad quimiopreventiva (prevención del daño celular causado por enfermedades crónicas), inhibición de la glicación, inhibición del estrés oxidativo, efecto colerético (aumento del flujo biliar) e intestinal. propulsión del tracto, efecto vasodilatador y actividad antioxidante. El objetivo de este estudio es analizar las características organolépticas y farmacológicas de los tés de mate comercializados en Teresina Piauí, a través de un control físico-químico, y comparando la información contenida en las etiquetas con la Farmacopea Brasileña, se realizó un control físico-químico, a través de pruebas de contenido de humedad, cenizas totales, cenizas insolubles en ácido, pH, material extraño y análisis de etiquetas. Resultado y discusión: Después de realizar las pruebas físicas y químicas de las muestras de mate, las propiedades organolépticas mostraron color y olor característicos. Los resultados de pérdida por secado fueron satisfactorios, excepto para las muestras A y D. En las pruebas de ceniza total y ceniza insoluble en ácido, las muestras mostraron resultados satisfactorios para todas las muestras. Conclusión: Existe la necesidad de una mayor fiscalización por parte de la Vigilancia Sanitaria en cuanto a la calidad, inocuidad y eficacia de los productos vegetales vendidos en los supermercados. Introdução: A erva-mate possui diversas propriedades nutricionais e medicinais, atuando como estimulante diurético e facilitador da digestão. Por isso, o uso da erva-mate está sendo modernizado e alternativas para seu uso e inovação estão sendo investigadas. Dentre as atividades farmacológicas atribuídas aos compostos presentes nos extratos de erva-mate, destacam-se: atividade quimiopreventiva (prevenção de danos celulares causados por doenças crônicas), inibição da glicação, inibição do estresse oxidativo, efeito colerético (aumento do fluxo biliar) e propulsão do trato intestinal, efeito vasodilatador e atividade antioxidante. O objetivo deste estudo é analisar as características organolépticas e farmacológicas dos chás mate comercializados em Teresina Piauí, através de um controle físico-químico, e comparando as informações contidas nos rótulos com a Farmacopeia Brasileira, foi realizado um controle físico-químico, através de testes de umidade, cinzas totais, cinzas insolúveis em ácido, pH, material estranho e análise de rótulos. Resultado e discussão: Após a realização dos testes físicos e químicos das amostras de chá mate, as propriedades organolépticas apresentaram cor e cheiro característicos. Os resultados de perda na secagem foram satisfatórios, exceto para as amostras A e D. Nos testes de cinzas totais e cinzas insolúveis em ácido as amostras apresentaram resultados satisfatórios para todas as amostras. Conclusão: É necessária maior fiscalização por parte da Vigilância Sanitária quanto à qualidade, segurança e eficácia dos produtos vegetais comercializados nos supermercados.

Background: Adhesive intestinal obstruction is a common and potentially lethal complication after surgical interventions in the abdomen. Radiologic imaging is the main diagnostic method. Objective: This study aims to analyse the diagnostic value of spiral computed tomography with a novel method (n = 54).Material and Methods: In this multidirectional cohort study, we present the data with non-parallel (historical) control. This study included the analysis of results of patients with a diagnosis of intestinal obstruction (n = 54) who were admitted to the surgical departments of the City Clinical Hospitals (Ufa city) from 2013 to 2019; the patients’ examination methods included computed tomography with conventional enhancement. The proposed novel enhancement method was implemented by ingesting a mixture containing 50 ml of the contrast Unigexol (300 mg) in 1.0 L cold mineral carbonated water, and Computed tomography (CT) was performed during 40 min after ingesting the contrast meal. Further, the patients with suspected obstruction in the colon were administered a pre-prepared contrast enema with a decoction of leaves of smoke-tree (100 g), chamomile flowers (100 g) and calendula flowers (100 g). Additionally, CT was performed. Results: Obstruction was conservatively stopped in 24 (44.4%) patients of the main group. Remaining 30 (55.6%) patients from the main group were operated with minimal surgical access in the early stages. Conclusion: Owing to early diagnosis of intestinal obstruction and application of the phytocomposition during the examination, exerting various effects such as antispasmodic, analgesic, disinfectant, bactericidal, cicatrising, choleretic, tanning and decongestant, unnecessary surgical interventions were prevented.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver pathologies, the prevalence of which is steadily increasing worldwide. Cardiovascular disease (CVD) is another group of common diseases that have similar pathophysiological mechanisms with NAFLD. CVD and NAFLD occur against the background of metabolic syndrome, systemic insulin resistance, oxidative stress, altered lipid metabolism. The course of both diseases predisposes to the development of endothelial dysfunction and formation/instability of atherosclerotic plaques. The progression of NAFLD is associated with an increase of the thickness of intima-media complex and calcification of coronary arteries, which is accompanied by an increased risk of subclinical and clinically significant atherosclerosis development. Patients with NAFLD have a high cardiovascular risk, the maximum increase of which should be expected in patients with severe fibrosis (F3–F4 on the NAFLD Fibrosis Score scale). Ursodeoxycholic acid reduces the severity of systemic inflammatory response and oxidative stress, improves lipid metabolism, increases the hypolipidemic effect of statins, reduces the degree of hyperglycemia and insulin resistance, inhibits the formation of atherosclerotic plaques, has vasodilating effect. The presence of significant pleiotropic properties in combination with apparent cytoprotective, choleretic, antiapoptic, anticholestatic, immunomodulatory activity allows to include ursodeoxycholic acid in NAFLD treatment, non-alcoholic steatohepatitis in order to reduce the clinical manifestations of atherosclerosis and prevent CVD progression.

The aim of the present work was to estimate the choleretic effect of dry extracts derived from Carthamus tinctotius L., Calendula officinalis L. and Tagetes erecta L.Materials and methods: The experiments were carried out on white male rats weighing 180–230 g. The extracts in a single dose were introduced into the duodenum of the rats at the doses of 50, 100 and 200 mg/kg in the form of water solution.Results: The results of the experiments have shown that the extracts from Calendula officinalis and Carthamus tinctorius have the marked choleretic effect due to the presence of biologically active substances, predominantly fl avonoids.

After the discovery of the method of synthesis of ursodeoxycholic acid (UDCA) and the publication of evidence confirming its ability to reduce the lithogenic properties of bile, active clinical use of UDCA began around the world. This drug, in addition to the proven choleretic, cytoprotective, litholytic, anti-apoptotic effects, has a signaling activity that allows UDCA to influence metabolic syndrome components such as hyperglycemia, hypercholesterolemia. Under the influence of UDCA, FXR is activated in the liver, which leads to an increase in the activity of glycogen synthase and decrease in the level of glycaemia. Another mechanism by which UDCA affects glycaemia is mediated by the activation of the TGR5 membrane receptor under the influence of this bile acid, as well as the release of insulin from pancreatic β-cells and decrease in postprandial glycaemia. When taking UDCA, the concentration of glycosylated hemoglobin, insulin in the blood plasma decreases the effects of insulin resistance decrease. UDCA has a beneficial effect on the vascular wall, reducing the severity of atherosclerotic lesions and normalizing the average thickness of the intima-media complex. UDCA improves lipid metabolism by regulating the activity of the AKT/ mTOR-signaling pathway, reduces the synthesis of cholesterol, and decreases the fractional rate of cholesterol synthesis and the fractional rate of triglyceride synthesis. It is proved that UDCA administration is accompanied by a drop in the level of total cholesterol and cholesterol of low-density lipoproteins. Normalization of the metabolism of glucose, triglycerides, cholesterol and the insulin-signaling pathway under the influence of bile acids is the basis for the use of UDCA for the correction of metabolic syndrome, as well as its hepatological manifestations - NAFLD.

After the discovery of the method of ursodeoxycholic acid’s (UDCA) synthesis and the publication of evidence confirming its ability to reduce the lithogenic properties of bile, active clinical use of UDCA began in the world. This drug, which has pleiotropic effect (choleretic, cytoprotective, immunomodulatory, antiapoptic, litholytic, hypocholesterolemic), has proven its effectiveness in the treatment various diseases: primary biliary cholangitis, intrahepatic cholestasis of pregnancy, gallstone disease. Being a tertiary bile acid, UDCA stimulates bile acid synthesis by reducing the circulating fibroblast growth factor 19 and inhibiting the activation of the farnesoid X-receptor (FXR), which leads to the induction of cholesterol-7α-hydroxylase, a key enzyme in the synthesis of bile acid de novo, mediating the conversion of cholesterol into bile acids. Changes in the formation of bile acids and cholesterol while taking UDCA intake is accompanied by activation of the main enzyme of cholesterol synthesis - 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Under the influence of UDCA the activity of stearoyl-Coa desaturase (SCD) in visceral white adipose tissue increases. According to studies conducted in 2019, UDCA improves lipid metabolism by regulating the activity of the ACT/mTOR signaling pathway, reduces the synthesis of cholesterol, decreases the fractional synthesis rate of cholesterol and the fractional synthesis rate of triglycerides. It has been proved that UDCA is accompanied by a decrease in the level of total cholesterol and low density lipoprotein cholesterol.

OBJECTIVE 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. PATIENTS AND METHODS 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 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

The article summarizes the literature data on the expansion of the range of application of ursodeoxycholic acid due to its various mechanisms of action. Almost 50-year history of the study of its properties has proven choleretic, litholytic, antiapoptotic, anti-inflammatory, immunomodulatory, cytoprotective, antifibrotic and hypocholesterolemic effects. In addition to the well-known functions of bile acids, their role has been shown as signa­ling, endocrine molecules that regulate glucose, lipids, and energy metabolism through pathways mediated by the activation of the nuclear receptor of the farnesoid X receptor and the cell surface G protein-coupled receptor, TGR5. The variety of nosological forms in which this substance can be successfully used is substantiated., У статті узагальнено літературні дані щодо розширення спектра застосування урсодезоксихолевої кислоти завдяки різноманітним механізмам її дії. Майже 50-річна історія вивчення її властивостей довела холеретичну, літолітичну, антиапоптичну, протизапальну, імуномодулюючу, цитопротективну, антифібротичну й гіпохолестеринемічну дії. Крім добре відомих функцій жовчних кислот показана їх роль як сигнальних, ендокринних молекул, що регулюють глюкозу, ліпіди й енергетичний метаболізм через шляхи, які опосередковуються активацією ядерного фарнезоїдного X-рецептора і рецептора G-білка клітинної поверхні TGR5. Обґрунтовано різноманітність нозологічних форм, при яких дана речовина може успішно використовуватися.

Intrahepatic cholestasis of pregnancy (IHCP) is of significant practical interest as this pathology is a borderline case between obstetric, infectious and hepatic pathology. The issues of etiology, pathogenesis, risk factors triggering intrahepatic cholestasis, the principles of its treatment and prevention are still an object of debate. At present, ursodeoxycholic acid (UDCA) is considered to be the medicine of choice for the treatment of intrahepatic cholestasis of pregnancy. The peculiarity of this medicine lies in its 4 mechanisms of action: replacement of toxic endogenous bile acids, cytoprotective action for hepatocytes and cholangiocytes, immunomodulation and choleretic action [3]. To test the efficiency of the suggested drug, we selected 71 women who got pregnant owing to ART and who presented a high risk of IHCP at the first prognostication stage. By way of randomization, they were divided into 2 groups: the basic group – 29 patients, who were treated with the recommended complex of therapy and prophylaxis, and the comparison group – 42 pregnant women, whose pregnancy was managed in accordance with the WHO guidelines. The recommended ursodeoxycholic acid has enabled a more effective normalization of biochemical indicators associated with IHCP (reduction of the levels of total bilirubin, bile acids, ALT, AP and total cholesterol in terms of the low-density and the very-low-density lipoprotein fraction) and a significant decrease in the incidence of complications of pregnancy.

Objective — to examine the morpho-functional state of the liver and the processes of free radical oxidation in boys with hypoandrogenism.Materials and methods. The study involved 47 adolescents with hypoandrogenism aged 13—18 years, who underwent a set of standard and special clinical and laboratory examination on the basis of the department of endocrinology SI «Institute of Children and Adolescents Health Care of the NAMS of Ukraine». Patients with hypoandrogenism were divided into groups depending on the index of masculinization. Mathematical processing of the study results was carried out using software packages SPSS Statistics 17.0, Excel.Results and discussion. It was found that complaints of abdominal pain and dyspeptic symptoms were observed in 62 % of cases. The conventional biochemical testing of liver function determined that the average levels of total bilirubin and liver enzymes were within normal range, suggesting that boys with hypoandrogenism probably had no significant violations of the functional state of the liver yet. Analysis of the lipid profile of children and adolescents with hypoandrogenism revealed that 75 % of patients had pathological changes in lipid levels, including 85 % with increased total cholesterol, 34 % with decreased HDL cholesterol and increased TG, 34 % with increased LDL cholesterol, 36 % with increased atherogenic coefficient. Atherogenic­chan­ges in the lipidogram increased with age. The study of indicators of free radical oxidation process revealed that in boys with hypoandrogenism the level of the final product of lipid peroxidation — malondialdehyde remained at the level of the control group, and the level of carbonated proteins tended to decrease with the increasing in the degree of delayed puberty. A significant reduction of the glutathione peroxidase level respectively to the deficiency of androgens was found. Thus, in adolescents with hypoandrogenism, a tendency towards the formation of the state of oxidative stress was revealed, which is confirmed by an increase of the integral coefficient of oxidative stress. Reducing the activity of the most powerful part of antioxidant system, in particular enzymatic, can lead to a «second hit» in the formation of non­alcoholic fatty liver disease and contribute to the transformation of liver steatosis into steatohepatitis. The results of ultrasound examination indicated the presence of functional disorders of the biliary tract in all boys with hypoandrogenism, and in one third of patients there were clear signs of steatohepa­tosis and gallstone disease. Conclusions. The results of the study indicated the formation of comorbid pathology of the hepatobiliary system in boys with hypoandrogenism. In 30 % of patients, ultrasound signs of steatohepatosis, atherogenic dyslipidemia and inhibition of antioxidant defense in the form of a significant decrease in the activity of glutathione peroxidase were detected. The results of the study indicate the necessity of inclusion in the diagnostic algorithm in boys with hypoandrogenism indicators of lipidogram, ultrasound of the liver and biliary tract, as well as the development of protocols for the prevention of hepatobiliary pathology, including the use of dietary correction, the prescription of hepatoprotectors with antioxidant activity, choleretic drugs.

The superior ability of norursodeoxycholic acid (norUDCA) to induce a bicarbonate-rich hypercholeresis has been attributed to its ability to undergo cholehepatic shunting and norUDCA is currently being evaluated as a therapeutic for forms of liver disease. The goal of this study was to use mouse models to investigate contributions of bile acid transporters to the choleretic actions of norUDCA. Here, we show that the apical sodium-dependent bile acid transporter (ASBT) and Organic solute transporter-alpha (OSTα) are dispensable for norUDCA-stimulation of bile flow and biliary bicarbonate secretion in mice. Analysis of the liver transcriptome revealed that norUDCA induced hepatic expression of a limited number of transporter genes, particularly organic anion transporting polypeptide 1a4 (Oatp1a4). However, norUDCA potently stimulated a bicarbonate-rich hypercholeresis in Oatp1a/1b-deficient mice. Blocking intestinal bile acid reabsorption by co-administration of an ASBT inhibitor or bile acid sequestrant did not impact the ability of norUDCA to induce bile flow in wildtype mice. The results support the concept that these major bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions of norUDCA. Additionally, the findings support further investigation of the therapeutic synergy between norUDCA and ASBT inhibitors or bile acid sequestrants for cholestatic liver disease.

Many patients with biliary atresia (BA) continue to suffer from postoperative liver dysfunction, even after undergoing Kasai’s hepatic portoenterostomy. Such patients can experience chronic inflammation with or without jaundice. The oxidative stress may exist in postoperative patients with BA. The prevention of progressive liver fibrosis has, therefore, become an important factor to achieve favorable long-term results. For this purpose, a combination of medications that have hepatocyte protective activity has been used routinely in postoperative patients with BA. Catechin originated from green tea and CoQ10 is commonly used as anti-oxidative supplementary food in Japan. The herbal medicine Inchinkoto (ICKT) has been commonly used in Japan as an anti-inflammatory, antipyretic, choleretic, and diuretic agent for liver disorders and jaundice. In this chapter, we would like to introduce the presence of oxidative stress and the anti-oxidative effects of green tea catechin, CoQ10, herbal medicine ICKT in postoperative patients with BA. After discussing these points, it was shown that all of the oxidative stress markers in the postoperative patients with BA increased in comparison to those in the controls. From these results, green tea catechin, CoQ10, ICKT were experimentally and clinically useful for reducing hepatic fibrosis and injury by controlling stellate cell activation with oxidant stress. Furthermore, it was suggested that these agents described above promote clearance of jaundice.

Kasai hepatic portoenterostomy (HPE) for biliary atresia (BA) has proven acceptable as an initial and standard treatment, with the generally successful outcome. However, about 40% of patients who receive initial Kasai HPE, unfortunately, fail to become jaundice-free after the operation, so medical therapies are administered to maintain the bile flow after the Kasai operation. Postoperative medical therapy with choleretic agents, including intravenous 10% dehydrocholic acid, glucagons, prostaglandin E2, ursodeoxycholic acid (UDCA), and corticosteroids is commonly used with good efficacy.

Since the late 1950s, transport of bile in the liver has been described by the "osmotic concept," according to which bile flows into the canaliculi toward the ducts, countercurrent to the blood flow in the sinusoids. However, because of the small size of canaliculi, it was so far impossible to observe, let alone to quantify this process. Still, "osmotic canalicular flow" was a sufficient and plausible explanation for the clearance characteristics of a wide variety of choleretic compounds excreted in bile. Imaging techniques have now been established that allow direct flux analysis in bile canaliculi of the intact liver in living organisms. In contrast to the prevailing osmotic concept these analyses strongly suggest that the transport of small molecules in canalicular bile is diffusion dominated, while canalicular flow is negligibly small. In contrast, with the same experimental approach, it could be shown that in the interlobular ducts, diffusion is augmented by flow. Thus, bile canaliculi can be compared to a standing water zone that is connected to a river. The seemingly subtle difference between diffusion and flow is of relevance for therapy of a wide range of liver diseases including cholestasis and NAFLD. Here, we incorporated the latest findings on canalicular solute transport, and align them with extant knowledge to present an integrated and explanatory framework of bile flux that will undoubtedly be refined further in the future.

Chronic liver diseases are global health problems representing a significant source of morbidity and mortality worldwide. Cholestasis is one of the most common clinical manifestations of almost all types of liver diseases regardless of etiologies and promotes the pathogenesis of liver. Artemisiae Scopariae Herba (ASH, or Yin Chen) is the most commonly used Traditional Chinese Medicine (TCM) herbal for the treatment of chronic liver diseases, especially cholestatic liver diseases. Various bioactive ingredients have been isolated and identified in ASH, however, most of them were not well characterized for their pharmacological effects. In the current review, we summarize clinical evidence demonstrating the promising therapeutic effects of ASH. We then introduce the profile of bioactive ingredients found in ASH and highlight the change of their abundance during different harvest times of ASH. We further thoroughly review recent advances in the studies of major bioactive ingredients in ASH, including scoparone, capillarisin, chlorogenic acid, and representative flavonoids, for their pharmacological effects, including choleretic, antioxidant, anti-inflammation, anti-fibrosis and other hepatoprotective activities. Underlying molecular targets and signaling networks are also outlined. In conclusion, ASH-based TCM prescriptions are promising strategies for the treatment of cholestatic liver diseases and are more effective than conventional therapies. The future advancement of pharmacology and toxicology researches of ASH and its bioactive ingredients will further contribute to the discovery of novel anti-cholestasis and hepatoprotective drugs.

According to WHO, there are more than 2 billion people in the world using alcohol, and 76,3 million are suffering from alcohol – related diseases, in particular, pathology of the liver. Alcoholic pathology of the liver is manifested in 4 nosological forms: alcoholic steatosis, alcoholic hepatitis, alcoholic liver fibrosis and alcoholic liver cirrhosis. One of the components of liver damage is cholestatic syndrome, due to a violation of the bile formation and outflow into the intestine, the accumulation of its components in the liver and blood. It is manifested by an increase of alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (γ-GTP), transaminases activities, the levels of cholesterol, bilirubin, bile acids, etc. in blood. To correct cholestasis syndrome in alcoholic liver diseases and other liver damages, plant and synthetic hepatoprotective agents with choleretic activity are often used. The aim of the study was to investigate the effect Acorus calamus leaf extract (Acorus calamus L.) on bile formation, bile secretion and cholestasis on the model of ethanol-tetrachloromethane hepatitis in rat. The dealcoholized Acorus calamus leaf extract was obtained at the Department of Botany of the NFaU. The extract is a dark brown liquid substance with a strong spicy specific odor. The standardization of the extract was carried out by the content of flavonoids sum in terms of hyperoside. The anticholestic and choleretic action of the dealcoholized Acorus calamus leaf extract was studied using the model of ethanoltetrachloromethane hepatitis in rats. The dealcoholized Acorus calamus leaf extract and comparison preparations were administered 1 hour before the introduction of pathogenic agents and 2 hours after (treatment and prophylactic regimen). 72 hours after the last use of toxicants in thiopental sodium anesthesia (intraperitoneal, 60 mg/kg), the bile and bile excreton were examined in rats by assessing the rate of bile secretion and its quantitative components: bile acids and cholesterol content. The anticholestatic properties of the dealcoholized Acorus calamus leaf extract and comparison drugs were evaluated by the serum content of indirect bilirubin, direct bilirubin, ALP and γ-GTP activities. It has been established that the use of dealcoholized Acorus calamus leaf extract in the treatment and prophylactic mode of hepatitis in rat significantly reduces the intensity of the cholestasis process, improves bile excretory functions of the liver. The anticholestatic properties of the dealcoholized extract of Acorus calamus leaf extract are confirmed by a significant decrease in the level of indirect and direct bilirubin, a decrease in the activity of ALP and γ-GTP. In terms of normalizing the rate of bile secretion, bile acids and cholesterol content in bile, reducing the processes of cholestasis Acorus calamus leaf extract was not inferior to comparison drugs. The data obtained indicate the expediency for further in-depth studies of dealcoholized Acorus calamus leaf extract for creating effective hepatoprotectors.

Biliary atresia (BA) is an obstructive hepatobiliary disease which manifests during infancy. Kasai portoenterostomy (KPE) is the preferred operation for BA, supplemented with glucocorticoids, antibiotics, and choleretic agents. A great deal of research has been carried out regarding diagnosis, operation, and adjuvant therapies of BA, but no consensus had been reached. To understand the variation in diagnosis and treatment strategies of BA across mainland China and to help achieve a unified treatment strategy in the future, this investigation was carried out.This investigation was conducted via electronic questionnaire. The centres were divided into three groups based on their annual caseload: low (0-20)-, mid (21-40)-, and high (≥ 41)-volume group. Differences in the clinical practice among three groups were analyzed by Chi-square test and considered statistically significant at P 0.05.41 Centres from 26 different administrative regions were involved. The average age at KPE was mainly 51-60 days (39%, 16/41) and 61-70 days (32%, 13/41). The annual caseload was 0-20 patients in 17 centres, 21-40 patients in 11 centres, and 40 patients in 13 centres. Preoperative ultrasound and intraoperative cholangiography were performed in all centres. Low-volume centres had a high proportion of MRI (P = 0.005), while the high-volume group had a high proportion of LSM (P = 0.015). Open KPE without liver mobilisation is the most common surgical procedure (71%, 29/41). Open KPE without liver mobilisation was more commonly used in low-volume group (P = 0.044), and laparoscopic KPE was mainly used in high-volume group (P = 0.011). The spur anti-reflux intestinal valve was performed in more than half of the centres (51%, 21/41). The length of the Roux-en-Y loop was ≥ 30 cm in the majority of centres (78%, 32/41). Glucocorticoids and antibiotics were used in most centres (90%, 37/41; 100%, 41/41) with marked variations in type, administration, dose, and duration. Oral ursodeoxycholic acid (UDCA) was used in 38 centres, in varying doses of 10-20 mg/kg/day. The duration of oral UDCA was over a year in 19 centres.Mainland China has a large number of patients with biliary atresia. Diagnostic and surgical methods vary from centre to centre and are related to its caseload. In most centres, KPE is supplemented with glucocorticoids, antibiotics, and choleretic agents without a standard regimen.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune cholangiopathies characterized by limited treatment options. A more accurate understanding of the several pathways involved in these diseases has fostered the development of novel and promising targeted drugs. For PBC, the characterization of the role of farnesoid X receptor (FXR) and perixosome-proliferator activated receptor (PPAR) has paved the way to several clinical trials including different molecules with choleretic and antinflammatory action. Conversely, different pathogenetic models have been proposed in PSC such as the “leaky gut” hypothesis, a dysbiotic microbiota or a defect in mechanisms protecting against bile acid toxicity. Along these theories, new treatment approaches have been developed, ranging from drugs interfering with trafficking of lymphocytes from the gut to the liver, fecal microbiota transplantation or new biliary acids with possible immunomodulatory potential . Finally, for both diseases, antifibrotic agents are under investigation. In this review, we will illustrate current understanding of molecular mechanisms in PBC and PSC, focusing on actionable biological pathways for which novel treatments are being developed.

The 5-year survival rate of patients with metastatic renal cell carcinoma (mRCC) is

Alcoholic liver disease (ALD), which is recognized as an important health problem worldwide, is a direct consequence of alcohol consumption, which can induce alcoholic fatty liver, alcoholic steatohepatitis, fibrosis and cirrhosis. P-Hydroxyacetophenone (p-HAP) is mainly used as a choleretic and hepatoprotective compound and has anti-hepatitis B, antioxidative and anti-inflammatory effects. However, no experimental report has focused on p-HAP in ALD, and the effect and mechanism of p-HAP in ALD remain unknown. In addition, there is no research on p-HAP in the treatment of ALD. The potential molecular mechanisms of p-HAP against acute alcoholic liver injury remain unknown. In this study, we aimed to investigate whether p-HAP alleviates ALD and to clarify the potential molecular mechanisms. Zebrafish larvae were soaked in 350 mmol/l ethanol for 32 h at 4 days post fertilization (dpf) and then treated with p-HAP for 48 h. We chose various outcome measures, such as liver histomorphological changes, antioxidation and antiapoptosis capability and expression of inflammation-related proteins, to elucidate the essential mechanism of p-HAP in the treatment of alcohol-induced liver damage. Subsequently, we applied pathological hematoxylin and eosin (H&E) staining, Nile red staining and oil red O staining to detect the histomorphological and lipid changes in liver tissues. We also used TUNEL staining, immunochemistry and Western blot analysis to reveal the changes in apoptosis- and inflammation-related proteins. In particular, we used a variety of fluorescent probes to detect the antioxidant capacity of p-HAP in live zebrafish larvae in vivo. In addition, we discovered that p-HAP treatment relieved alcoholic hepatic steatosis in a dose-dependent manner and that the 50 μM dose had the best therapeutic effect. Generally, this research indicated that p-HAP might reduce oxidative stress and cell apoptosis in vivo and in vitro via the NF-κB signaling pathway.

Inchinkoto (ICKT) is a popular choleretic and hepatoprotective herbal medicine that is widely used in Japan. Geniposide, a major ingredient of ICKT, is metabolized to genipin by gut microbiota, which exerts a choleretic effect. This study investigates the relationship between stool genipin-producing activity and diversity of the clinical effect of ICKT in patients with malignant obstructive jaundice. Fifty-two patients with malignant obstructive jaundice who underwent external biliary drainage were included. ICKT was administered as three packets per day (7.5 g/day) for three days and 2.5 g on the morning of the fourth day. Stool samples were collected before ICKT administration and bile flow was monitored on a daily basis. The microbiome, genipin-producing activity, and organic acids in stools were analyzed. The Shannon-Wiener (SW) index was calculated to evaluate gut microbiome diversity. The stool genipin-producing activity showed a significant positive correlation with the SW index. Stool genipin-producing activity positively correlated with the order Clostridia (obligate anaerobes), but negatively correlated with the order Lactobacillales (facultative anaerobes). Moreover, stool genipin-producing activity was positively correlated to the concentration valeric acid, but negatively correlated to the concentration of lactic acid and succinic acid. The change of bile flow at 2 and 3 days after ICKT administration showed significant positive correlation with genipin-producing activity (correlation coefficient, 0.40 and 0.29, respectively, P < 0.05). An analysis of stool profile, including stool genipin-producing activity, may predict the efficacy of ICKT. Modification of the microbiome may be a target to enhance the therapeutic effect of ICKT.

Objectives Gardenia Jasminoides Ellis (Zhizi), belonging to Rubiaceae family, has been traditionally used for treatment cholestasis and jaundice for centuries in Asian countries. In the theory of Traditional Chinese Medicines, Zhizi could dispel dampness and heat via the urine to execute its choleretic effects. However, the potential molecular mechanism has been still poorly clarified. Here, we investigated the effect of different dose of Zhizi aqueous extract powder (0.3 g/kg/d and 0.9 g/kg/d) on urinary excretion of bile acids (BAs), and defined the potential mechanism via renal BAs efflux transporters Mrp2 and Mrp4 in normal rats. Methods Male Wistar rats were orally administrated with 0.3 or 0.9 g/kg/d dose of Zhizi aqueous extract powder for 2 weeks, then body weight, serum aminotransferase, total BAs concentrations in liver, bile, serum, kidney and urine, 1 h bile flow, 12-h urinary volume, biliary and urinary excretion amount of total BAs as well as protein expression of major renal BAs efflux transporter Mrp2 and Mrp4, were all evaluated. Results Zhizi especially the high dose of Zhizi aqueous extract powder could reduce hepatic total BAs concentration. Additionally, bile flow and biliary excretion had no significant difference, but the remarkable increasing urinary excretion of BAs and 2 to 3 folds up-regulated renal Mrp2 expression were observed after administrated with Zhizi as compared with the control group. Conclusion The findings indicate that Zhizi reduces hepatic total BAs level by increasing urinary excretion rather than the biliary excretion of BAs, which, in turn ascribed to elevated protein expression of Mrp2 at apical membrane of renal tubular epithelial cells.

The high prevalence and possibility of transformation of functional disorders into organic pathology determine the relevance of the study of the cluster of functional disorders of the gallbladder and Oddi's sphincter (FD GB and OS) in children. Studies on the properties of ursodeoxycholic acid (UDCA) to alter the activity of generation of some microRNAs in various diseases of the hepatobiliary system have become important in view of the evidential impact on this process. The alm: to determine the effect of choleretic therapy with UDCA drugs addition on the microRNA-4714-3p expression level in functional disorders of the gallbladder and Oddi's sphincter in children. 70 children with FD GB and OS aged 4 to 14 years were examined. Main group included 50 children. They received standard therapy with UDCA combination. The comparison group included 20 patients receiving standard therapy without UDCA. A molecular genetic study was conducted to determine the microRNA-4714-3p expression level in serum before and after treatment by real-time polymerase chain reaction with reverse transcription according to TaqMan Gene Expression Assays. The correlation was established between the main anamnestic data, causative factors of development, clinical and paraclinical parameters of the FD GB and OS and the microRNA-4714-3p expression level in blood serum of children before therapy. The positive relationship of the microRNA-4714-3p expression profile with decrease in gallbladder contractility was determined (r=+0.36; p

In this review article an analysis of literature data on the pharmacological and clinical study of a fixed combination of medicinal substances (artichoke leaf extract, ursodeoxycholic acid, taurine, and Angelica sinensis roots extract), as well a scientific substantiation of the pharmaceutical quality profile of the corresponding finished solid dosage form has been conducted. Chronic diseases of the hepatobiliary system are some of the most common human diseases and inferior only to atherosclerosis . The fact that cholecystectomy is the most common surgical operation in the abdominal organs is evidenced by the widespread distribution of the pathology of the biliary system. The fact that there is an increasing number of diagnoses of cholelithiasis in children and infants is a cause for concern. Diseases of the biliary system are closely related to violations of the functional state of the liver. Synthesis of cholesterol supplemented bile with reduced bile acid content significantly increases the risk of gallstones, as well as gallbladder cholesterol. We have substantiated that the developed preparation is a fixed combination of medicinal substances with well-researched medical applications in the treatment of dyspeptic disorders with functional disorders of the biliary system, biliary dyskinesia of the hypokinetic type, and gastritis with reflux of bile. Each of the components of the fixed combination has an important influence on the human hepatobiliary system. The effect of ursodeoxycholic acid is due to the relative replacement of lipophilic toxic bile acids, improving the secretory capacity of hepatocytes and immunoregulatory processes, which is especially important in liver and cholestatic diseases. Taurine is a synergist of ursodeoxycholic acid, since it forms biliary conjugates in the liver. The artichoke extract has choleretic, hepatoprotective and diuretic effects, while the A. sinensis roots extract demonstrates moderate spasmolytic and anti-inflammatory properties. We conducted a general description of active pharmaceutical ingredients and a review of biopharmaceutical tests, analyzed relevant pharmacokinetic and pharmacodynamic studies, and summarized the results of clinical efficacy and safety trials. Particular attention is paid to the results of clinical studies of the developed fixed combination. It should be noted that artichoke leaf extract, ursodeoxycholic acid, and taurine are widely used throughout the world in official medicine, at the same time, A. sinensis roots extract is more widely used in traditional Chinese medicine. The fixed combination has a favorable safety profile, is investigated in clinical conditions in vivo both in the form of individual components and in the form of a single drug. A fixed combination pharmaceutical profile is based on the general requirements for solid dosage forms, as well as experimentally substantiated specific indicators and research methods.

Andrographolide, a bioactive compound isolated from Andrographis paniculata exhibits multiple pharmacological activities, including anti-HIV, antiplatelet aggregation, hepatic lipid peroxidation protective, hepatoprotective, choleretic, and anticancer effects. Herein, we report the synthesis of diverse analogues of andrographolide along with their β-glucosidase inhibitory activity against sweet almond β-glucosidase. The parent compound, And-1, displayed moderate inhibitory activity against the sweet almond β-glucosidase with IC50 of 142.5 μM. Among the synthesised analogues And-10 showed the best activity, with IC50 of 92.4 μM, whereas the oxidised products (And-4 and And-5) were moderately active against the tested enzyme. Additionally, compounds And-6, And-7, And-8, and And-10 exhibited better β-glucosidase inhibitory activity than the positive control Castanospermine, with IC50 of 100.2, 102.4, 106.5, and 92.4 μM, respectively. These results highlight the importance of an electron-withdrawing NO2 group on the phenyl moiety in attaining the better β-glucosidase inhibition. It is noteworthy that the effect of a particular group plays a significant role in bioactivity. This study thus highlights an important aspect with regard to the most active compounds, which could extend the arsenal of compounds affecting the corresponding enzymes after further polishing and fine tuning.

Water-soluble analogue of quercetin, corvitin is used in patients with myocardial infarction as blocker of 5-lipoxygenase. However, its effects on secretion, lipid content and physico-chemical properties of bile have not been understood yet. We investigated the effect of corvitin, applied in different doses, on the level of bile flow, the content of bile free and esterified cholesterol, phospholipids, triacylglycerols, and free fatty acids. In order to determine stability of the bile colloidal system, we examined the relationship between different lipid components. The rats were injected intraportally with a bolus of corvitin. At doses of 2.5, 5, and 10 mg/kg, the latter increased bile flow and concentration of total cholates, as well as free fatty acids. Corvitin (5 mg/kg) elevated phospholipids and cholesterol content, but at a dose of 10 mg/kg it increased the concentration of bile cholesterol esters and triacylglycerols. Corvitin applied at doses of 2.5 and 10 mg/kg increased total cholates/cholesterol ratio, but at a dose of 10 mg/kg, the drug reduced cholesterol / esterified cholesterol ratio. The results suggest that corvitin exerts choleretic effect and improves stability of bile colloidal system.

Many of the beneficial effects on productive performance observed when vegetable extracts are incorporated as feed additives in intensive farming can be explained by an increase in bile production. An experiment was conducted to study choleretic and cholagogue effect of a Cynara scolymus extract formulation and of silymarin in pigs. Pigs were cannulated with a T-tube catheter in the bile duct. Bile production was continuously measured and re-infused to the duodenum through Oddi’s sphincter at the same production rate. Treatments: Group A (n = 6), commercial feed; Group B (n = 6), C. scolymus extract (300 g/tonne) and Group C (n = 6), silymarin (300 g/tonne). Bile production was recorded hourly for each animal during 24 h. Total bile acids’ concentrations in bile, just before and one hour after meals were evaluated. Average daily bile production for pigs in group B was 66% higher than for pigs in groups A or C (P

Ursodeoxycholate and its taurine conjugate tauroursodeoxycholate (TUDC) promote choleresis by triggering the insertion of transport proteins for bile acids into the canalicular and basolateral membranes of hepatocytes. In addition, TUDC exerts hepatoprotective and anti-apoptotic effects, can counteract the action of toxic bile acids and reduce endoplasmic reticulum stress. TUDC can also initiate the differentiation of multipotent mesenchymal stem cells (MSC) including hepatic stellate cells and promote their development into hepatocyte-like cells. Although the hepatoprotective and choleretic action of TUDC is empirically used in clinical medicine since decades, the underlying molecular mechanisms remained largely unclear. Since TUDC has little or no potency to activate known bile acid receptors, such as farnesoid X receptor and transmembrane G protein-coupled bile acid receptor, other receptors must be involved in TUDC-mediated signaling. Recent research demonstrates that integrins serve as sensors for TUDC. After binding of TUDC to α5β1-integrin, the β1-integrin subunit becomes activated through a conformational change, thereby triggering integrin signaling with the downstream activation of focal adhesion kinase, c-Src, the epidermal growth factor receptor and activation of the mitogen-activated protein kinases, Erks and p38. These events trigger choleresis through a coordinated insertion of the sodium-taurocholate cotransporting polypeptide into the basolateral membrane and of the bile salt export pump into the canalicular membrane. In addition to its choleretic action, TUDC-induced integrin activation triggers a cyclic adenosine monophosphate-dependent protein kinase A activation in hepatocytes, which provides the basis for the anti-apoptotic effect of TUDC. On the other hand, the TUDC-induced stimulation of MSC differentiation appears not to be mediated by integrins. This article gives a brief overview about our work on the signaling network-mediating hepatoprotection by TUDC.

Diabetes becomes a global health burden, affecting almost one third of world population. This figure is self explanatory for its alarming growth and concern to be given for its prevention and management. It is erroneous to treat it as a disease rather it should be treated as a syndrome, because rarely it is presented in its discrete form i.e. only hyperglycemia as a clinical feature. Being a metabolic disease it is almost always accompanied with many other diseases like hypothyroidism, hypertension, fatty liver disease, obesity, dyslipidemia, etc. According to the known pathophysiology of diabetes, hyperglycemia is said to be responsible for dyslipidemia, constant high sugar level in blood produces dreaded effect at micro as well as macro- vascular level. This established pathology of the disease revolves around high glucose level in blood and make it the diagnostic parameter for diabetes. Although the cause of hyperglycemia are also well defined but there is one missing link which is totally neglected by the modern science i.e., role of liver in the pathogenesis of diabetes. Do any way hampered liver functions affect insulin production or its utilization by the cell- the question that required answer. This clinical trial is based on materializing the concept that effective bile secretion improves insulin activity. This is a pilot study carried out on 15 known patient of non insulin dependent diabetes. The study showed that 66.6% patient has diabetes associated with hypothyroidism followed by dyslipidemia (60%). The study drug shows significant (p< 0.001) reduction in both FBS and PPBS and improve the presenting symptoms effectively.

4-methylumbelliferone (4MU) is an inhibitor of hyaluronan deposition and an active substance of hymecromone, a choleretic and antispasmodic drug. 4MU reported to be anti-fibrotic in mouse models, however, precise mechanism of action still requires further investigation. Here we describe the cellular and molecular mechanisms of 4MU action on CCl4-induced liver fibrosis in mice using NGS transcriptome, Q-PCR and immunohistochemical analysis. Collagen and hyaluronan deposition were prevented by 4MU. The CCl4 stimulated expression of Col1a and &alpha, SMA were reduced, while the expression of the ECM catabolic gene Hyal1 was increased in the presence of 4MU. Bioinformatic analysis identified an activation of TGF-beta and Wnt/beta-catenin signaling pathways, and inhibition of the genes associated with lipid metabolism by CCL4 treatment, while 4MU restored key markers of these pathways to the control level. Immunohistochemical analysis reveals the suppression of hepatic stellate cells (HSCs) transdifferentiation to myofibroblasts by 4MU treatment. The drug affected the localization of HSCs and macrophages in the sites of fibrogenesis. CCl4 treatment induced the expression of FSTL1, which was downregulated by 4MU. Our results support the hypothesis that 4MU alleviates CCl4-induced liver fibrosis by reducing hyaluronan deposition and downregulating FSTL1 expression, accompanied by the suppression of HSC trans-differentiation and altered macrophage localization.

Hydrophilic bile salts, ursodeoxycholate and hyodeoxycholate, have choleretic effects. ABCB4, a member of the ABC transporter family, is essential for the secretion of phospholipids from hepatocytes into bile. In this study, we assessed the effects of taurine- or glycine-conjugated cholate, ursodeoxycholate and hyodeoxycholate on the ABCB4-mediated phosphatidylcholine (PC) efflux using Abcb4 knockout mice and HEK293 cells stably expressing ABCB4. To evaluate the effects of bile salts on bile formation in Abcb4+/+ or Abcb4-/- mice, the bile was collected during intravenous infusion of saline or bile salts. The biliary PC secretion in Abcb4+/+ mice was significantly increased by the infusions of all tested bile salts, especially taurohyodeoxycholate. On the other hand, Abcb4-/- mice exhibited extremely low secretion of PC into bile, which was not altered by bile salt infusions. We also showed that the PC efflux from ABCB4-expressing HEK293 cells was stimulated by taurohyodeoxycholate much more strongly than the other tested bile salts. However, taurohyodeoxycholate did not restore the activities of ABCB4 mutants. Furthermore, light scattering measurements demonstrated a remarkable ability of taurohyodeoxycholate to form mixed micelles with PC. Therefore, the enhancing effect of taurohyodeoxycholate on the ABCB4-mediated PC efflux may be due to the strong mixed micelle formation ability.

In folk medicine in the Baikal region, an infusion from the aerial part of the plant Bupleurum scorzonerifolium (Willd) is widely used as a choleretic and anti-inflammatory agent. The choleretic effect of herbal remedies is mainly due to the content of phenylpropanoids and flavonoids. Using high performance liquid chromatography with a diode-matrix detector and 3Q electrospray ionization detector, we studied the metabolic profile of the phenylpropanoids and flavonoids of the aboveground organs of B. scorzonerifolium (Willd.), which grows in the Baikal region. In the aboveground organs of B.scorzonerifolium, 7 phenylpropanoids and 17 flavonoids were identified, of which 15 compounds for the species were identified for the first time. Quantitative determination of individual components was carried out in the aboveground organs of B. scorzonerifolium and dry extract by microcolumn HPLC with UV detection. The predominant components in the aerial part of the plant are 5-O-caffeic quinic acid, 3,5-di-O-caffeic quinic acid, isoquercitrin, isorhamnetin-3-O-glucoside, kaempferol-3-O-rhamnoside and rutin. The dry extract obtained from the aerial part of B. scorzonerifolium contains the entire complex of phenylpropanoids and flavonoids, which are identified in the plant. The content of active ingredients in the extract is 2.5–3.0 times higher than in the aboveground organs. The aboveground organs and dry extract of B. scorzonerifolium can be used as a source of phenylpropanoids and flavonoids., В народной медицине Прибайкалья широко применяется настой из надземной части растения Bupleurum scorzonerifolium (Willd) как желчегонное и противовоспалительное средство. Желчегонный эффект растительных средств обусловлен в основном содержанием фенилпропаноидов и флавоноидов. С помощью высокоэффективной жидкостной хроматографии с диодно-матричным детектором и 3Q детектором с ионизацией электрораспылением изучен метаболомный профиль фенилпропаноидов и флавоноидов надземных органов B.scorzonerifolium (Willd.), произрастающей в Прибайкалье. В надземных органах B.scorzonerifolium идентифицированы 7 фенилпропаноидов и17 флавоноидов, из которых 15 соединений для вида идентифицированы впервые. Количественное определение отдельных компонентов проводили в надземных органах B.scorzonerifolium и экстракте сухом методом микроколоночной ВЭЖХ с УФ-детектированием. Преобладающими компонентами в надземной части растения являются 5-О-кофеилхинная кислота, 3,5-ди-О-кофеилхинная кислота, изокверцитрин, изорамнетин-3-О-глюкозид, кемпферол-3-О-рамнозид и рутин. Экстракт сухой, полученный из надземной части B.scorzonerifolium, содержит весь комплекс фенилпроноидов и флавоноидов, которые идентифицированы в растении. Содержание активных компонентов в экстракте в 2.5–3.0 раза больше, чем в надземных органах. Надземные органы и экстракт сухой B.scorzonerifolium могут быть использованы в качестве источника фенилпропаноидов и флавоноидов.

Turmeric, a rhizome of Curcumin longa L. is widely used as both a spice and an herbal medicine. The traditional use of turmeric in gastroenterology is mainly based on its choleretic activity. The aim of this study is to determine the effects of turmeric on bile flow (BF) and total bile acids (TBAs) excretion in a bile fistula rat model after acute duodenal administration. A significant dose-dependent enhancement in both BF and TBAs was detected after treatment with the turmeric decoctions which suggested the choleretic activity was bile acid-dependent secretion. In order to direct the active group of compounds, aqueous (AE), ethyl acetate (EtOAc), and petroleum ether (PE) extracts were investigated. The EtOAc and PE extracts showing high effects were purified to locate the active ingredients. Three curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) and 2 sesquiterpenes (bisacurone B and ar-turmerone) were isolated. It was found Bisacurone B was the most potent choleretic ingredient followed by ar-turmerone, bisdemethoxycurcumin demethoxycurcumin, and then curcumin. The amounts of the active ingredients were quantitatively analyzed by high-performance liquid chromatography. The EtOAc and PE extracts had high sesquiterpenes and curcuminoids content, while the AE extract had poor content of sesquiterpenes and curcuminoids which affected neither BF nor TBAs. Based on the results of multiple linear regression analysis, the content of BIS and TUR were dominant factors (P < 0.01) of controlling BL and TBAs in EtOAC and PE extracts.

The adenoviral gene transfer of human aquaporin-1 (hAQP1) water channels to the liver of 17α-ethinylestradiol-induced cholestatic rats improves bile flow, in part by enhancing canalicular hAQP1-mediated osmotic water secretion. To gain insight into the mechanisms of 17α-ethinylestradiol cholestasis improvement, we studied the biliary output of bile salts (BS) and the functional expression of the canalicular BS export pump (BSEP; ABCB11). Adenovector encoding hAQP1 (AdhAQP1) or control vector was administered by retrograde intrabiliary infusion. AdhAQP1-transduced cholestatic rats increased the biliary output of major endogenous BS (50%-80%, P < 0.05) as well as that of taurocholate administered in choleretic or trace radiolabel amounts (around 60%, P < 0.05). Moreover, liver transduction with AdhAQP1 normalized serum BS levels, otherwise markedly elevated in cholestatic animals. AdhAQP1 treatment was unable to improve BSEP protein expression in cholestasis; however, its transport activity, assessed by adenosine triphosphate-dependent taurocholate transport in canalicular membrane vesicles, was induced by 90% (P < 0.05). AdhAQP1 administration in noncholestatic rats induced no significant changes in either biliary BS output or BSEP activity. Canalicular BSEP, mostly present in raft (high cholesterol) microdomains in control rats, was largely found in nonraft (low cholesterol) microdomains in cholestasis. Considering that BSEP activity directly depends on canalicular membrane cholesterol content, decreased BSEP presence in rafts may contribute to BSEP activity decline in 17α-ethinylestradiol cholestasis. In AdhAQP1-transduced cholestatic rats, BSEP showed a canalicular microdomain distribution similar to that of control rats, which provides an explanation for the improved BSEP activity. Conclusion: Hepatocyte canalicular expression of hAQP1 through adenoviral gene transfer promotes biliary BS output by modulating BSEP activity in estrogen-induced cholestasis, a novel finding that might help us to better understand and treat cholestatic disorders. (Hepatology 2016;64:535-548). Fil: Marrone, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Soria, Leandro Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Danielli, Mauro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Lehmann Mantaras, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Larocca, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Marinelli, Raul Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina

The hepatoprotective and choleretic activities of three levopimaric acid derivatives were studied experimentally using a CCl4-induced acute hepatitis model in rats. It was established that all investigated levopimaric acid derivatives tended to increase bile secretion whereas (5R,9R,13S,18S)-20-isopropyl-5,9-dimethyl-17-{[(4-methylphenyl)sulfonyl]imino}-14-oxopentacyclo[10.6.2.01, 10.04, 9.013, 18]eicosa-15,19-diene-5-carboxylic acid (I) and dimethyl (4bS,8R)-2-isopropyl-3′-4b,8-trimethyl-2′,4′-dioxo-4,4a,4b,5,6,7,8,8a,9,10-decahydro-3H-spiro[3,10a-ethanophenanthrene-11,5′-[1,3]thiazolidine]-8,12-dicarboxylate (II) reduced transaminase enzyme levels in blood serum.

The development of chronic diseases of gallbladder is closely associated with disorders of its functional state. The objective: to conduct dynamic echosonography (DESG) of gallbladder with choleretic breakfast to evaluate functional state of gallbladder. Patients and methods. There were 124 patients aged 31–55with chronic diseases of the biliary system (CDBS) against the background of obesity. There was performed determination of compositional analysis of the body and functional state of gallbladder. Results. Determination of the gallbladder volume on an empty stomach in healthy persons and patients with CDBS against the background of obesity showed that in patients with both the primary and control groups the gallbladder volume was 1,37 and 1,36 times higher than in healthy individuals (р