Drug therapy of primary biliary diseases: classical and modern strategies

Definition: Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are both cholestatic liver diseases. A common feature of these disorders is the accumulation of bile acids in the liver and blood, presumably because of decreased biliary secretion and reduced bile flow. Etiology: Etiology and pathogenesis of PBC and PSC are still unknown. PBC is considered to be an autoimmune disease. Immunological mechanisms may also be involved in PSC since there is an association with ulcerative colitis and autoantibodies can be detected. Furthermore, genetic factors seem to play an important role in both diseases. Therapy: Since the pathogenesis of both diseases is unclear, there is no definite causal treatment. However, ursodeoxycholic acid (UDCA) was shown to be highly effective. Other drugs which can be used alone or in combination with UDCA are promising and might further improve the outcome of the diseases

Toxicity of ethanol and acetaldehyde in hepatocytes treated with ursodeoxycholic or tauroursodeoxycholic acid

AbstractIn hepatocytes ethanol (EtOH) is metabolized to acetaldehyde and to acetate. Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) are said to protect the liver against alcohol. We investigated the influence of ethanol and acetaldehyde on alcohol dehydrogenase (ADH)-containing human hepatoma cells (SK-Hep-1) and the protective effects of UDCA and TUDCA (0.01 and 0.1 mM). Cells were incubated with 100 and 200 mM ethanol, concentrations in a heavy drinker, or acetaldehyde. Treatment with acetaldehyde or ethanol resulted in a decrease of metabolic activity and viability of hepatocytes and an increase of cell membrane permeability. During simultaneous incubation with bile acids, the metabolic activity was better preserved by UDCA than by TUDCA. Due to its more polar character, acetaldehyde mostly damaged the superficial, more polar domain of the membrane. TUDCA reduced this effect, UDCA was less effective. Damage caused by ethanol was smaller and predominantly at the more apolar site of the cell membrane. In contrast, preincubation with TUDCA or UDCA strongly decreased metabolic activity and cell viability and led to an appreciable increase of membrane permeability. TUDCA and UDCA only in rather high concentrations reduce ethanol and acetaldehyde-induced toxicity in a different way, when incubated simultaneously with hepatocytes. In contrast, preincubation with bile acids intensified cell damage. Therefore, the protective effect of UDCA or TUDCA in alcohol- or acetaldehyde-treated SK-Hep-1 cells remains dubious

Toxicity of ethanol and acetaldehyde in hepatocytes treated with ursodeoxycholic or tauroursodeoxycholic acid

AbstractIn hepatocytes ethanol (EtOH) is metabolized to acetaldehyde and to acetate. Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) are said to protect the liver against alcohol. We investigated the influence of ethanol and acetaldehyde on alcohol dehydrogenase (ADH)-containing human hepatoma cells (SK-Hep-1) and the protective effects of UDCA and TUDCA (0.01 and 0.1 mM). Cells were incubated with 100 and 200 mM ethanol, concentrations in a heavy drinker, or acetaldehyde. Treatment with acetaldehyde or ethanol resulted in a decrease of metabolic activity and viability of hepatocytes and an increase of cell membrane permeability. During simultaneous incubation with bile acids, the metabolic activity was better preserved by UDCA than by TUDCA. Due to its more polar character, acetaldehyde mostly damaged the superficial, more polar domain of the membrane. TUDCA reduced this effect, UDCA was less effective. Damage caused by ethanol was smaller and predominantly at the more apolar site of the cell membrane. In contrast, preincubation with TUDCA or UDCA strongly decreased metabolic activity and cell viability and led to an appreciable increase of membrane permeability. TUDCA and UDCA only in rather high concentrations reduce ethanol and acetaldehyde-induced toxicity in a different way, when incubated simultaneously with hepatocytes. In contrast, preincubation with bile acids intensified cell damage. Therefore, the protective effect of UDCA or TUDCA in alcohol- or acetaldehyde-treated SK-Hep-1 cells remains dubious

Implementing the sterile insect technique with RNA interference – a review

RNA interference (RNAi) of insect pests is reviewed and its potential for implementing Sterile Insect Technique (SIT)-related control is considered. The molecular mechanisms that support RNAi in pest species are reviewed in detail, drawing on literature from a range of species including Drosophila melanogaster and Homo sapiens. The underlying genes that enable RNAi are generally conserved across taxa, although variance exists in both their form and function. RNAi represents a plausible, non-GM system for targeting populations of insects for control purposes, if RNA interference (RNAi) effector molecules can be delivered environmentally (eRNAi). We consider studies of eRNAi from across several insect orders and review to what extent taxonomy, genetics and differing methods of double stranded (ds)RNA synthesis and delivery can influence the efficiency of gene knockdown. Several factors, including the secondary structure of the target mRNA and the specific nucleotide sequence of dsRNA effector molecules, can affect the potency of eRNAi. However, taxonomic relationships between insects cannot be used to reliably forecast the efficiency of an eRNAi response. The mechanisms by which insects acquire dsRNA from their environment require further research, but the evidence to date suggests that endocytosis and transport channels both play key roles. Delivery of RNA molecules packaged in intermediary carriers such as bacteria or nanoparticles may facilitate their entry into and through the gut, and enable the evasion of host defense systems, such as toxic pH, that would otherwise attenuate the potential for RNAi

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9–10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC

Primary biliary cirrhosis in Lithuania: diagnosis and clinical picture

The rising detection and considerable geographical variation of primary biliary cirrhosis (PBC) in some regions demand increased awareness of the disease. The aim was to analyze the clinical, biochemical, immunological, and histological criteria of PBC patients in Lithuania and evaluate the patterns of disease presentation and histological features. One hundred thirty-one PBC patients were examined and followed in the Center of Hepatology, Gastroenterology, and Dietetics, Vilnius University Hospital. Their case records were evaluated in this retrospective record-review study Most of the patients were women (94.6%) older than 50 years with late stages of PBC. Men were significantly older and had a threefold shorter duration from disease presentation to diagnosis (4.0±0.4 vs. 1.4±0.4 years). 29.8% of patients had asymptomatic disease at presentation and at diagnosis, were older than the symptomatic ones, and presented with significantly lower prevalence of jaundice, skin signs, and lower alkaline phosphatase (ALP) activity, but higher frequency of sic-ca syndrome. Antimitochondrial antibody (AMA) positivity was found in 91.7%, bile duct lesions in all patients, while the frequency of histological signs of cholestasis (except copper accumulation) was lower. No significant, differences in these parameters in asymptomatic and symptomatic patients were found. Most PBC patients in Lithuania were at. late histological stages, with a predominance of females older than 50 years and long duration from disease presentation to diagnosis. One third of these PBC patients initially had asymptomatic course, with some differences in clinical slims and their prevalence compared with initially symptomatic patients

Palaeoenvironmental changes in the arid and sub arid belt (Sahara-Sahel-Arabian Peninsula) from 150 kyr to present

The PEP III Arid to Subarid Belt includes the largest hot desert in the world, the Sahara- Arabian desert and the Sahel zone. The region of interest extends south of the Atlas Mountains and south and east of the Mediterranean Sea to approximately 10 °N and shows a broadly zonal pattern with a varying seasonal distribution of precipitation. In the north (ca. 20–23 °N), rainfall results from the southward displacement of the midlatitude westerlies during winter whereas the south is governed by seasonal northward migration of the Intertropical Convergence Zone (ITCZ). Contraction and expansion phases of these presently semi-arid to hyper-arid desert areas result from significant changes in local precipitation. Palaeoenvironmental records from Northern Africa (north of 10 °N) and the surrounding seas document long-term changes in the magnitude and extent of the African monsoon in response to orbitally-forced changes in insolation. However, marine records as well as terrestrial palaeohydrological indicators (e.g., lakes, speleothems, rivers, pollen and charcoal) show that there have been changes in the hydrological cycle superimposed on the long-term waxing and waning of the monsoon which cannot be explained exclusively by changes in insolation. These fluctuations in space, time and magnitude were on a regional to continental scale. Here, we review available data on near-surface palaeohydrological indicators and vegetational changes in arid North Africa and the Arabian Peninsula as well as changes in the intensity of the South Asian Monsoon identified from marine sediments of the Arabian Sea. A comparison of regional environmental changes can clarify relations between the environment and changes in the Earth’s climate system. Each data-set is initially presented independently because they represent heteregeneous records from different regions and time periods and thereby emphasise their potential to provide evidence of continental chronostratigraphic palaeoenvironmental changes. Data-sets of lake status and vegetational change are complementary as they strongly reflect hydrological variation. Deep-sea sediments from the Arabian Sea were used to generate continuous records of oceanic upwelling, continental humidity, and dust and river discharge, that are closely related to palaeoenvironmental changes on the surrounding continents.After presenting the individual data-sets we compare the palaeoclimatic reconstructions derived from the different types of evidence