Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

Background

Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis.

Main body

The major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway.

Short conclusion

Understanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.

     

克隆整合对无芒雀麦(Bromus inermis)忍受沙埋能力的影响

无芒雀麦是浑善达克沙地植物群落中占优势的多年生根茎禾草。研究了克隆整合特性对无芒雀麦忍受沙埋能力的影响。结果表明,克隆整合显著提高了远端完全沙埋分株的存活,耗-益分析表明远端沙埋分株的生物量、分株数、叶片数、根茎节数和根茎总长显著受益于克隆整合,而与之相连的近端非沙埋分株却没有产生显著的损耗,并且随着沙埋程度增加时,远端沙埋分株的收益有增大的趋势。因而,克隆整合特性是无芒雀麦对严酷沙埋环境形成的重要适应对策,它能够缓解沙埋对无芒雀麦存活、生长的胁迫,提高其在半干旱沙化地区的适合度。     

Structure-activity relationships of 3,4-dihydro-1H-quinazolin-2-one derivatives as potential CDK5 inhibitors

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that plays a critical role in the early development of the nervous system. Deregulation of CDK5 is believed to contribute to the abnormal phosphorylation of various cellular substrates associated with neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Acyclic urea 3 was identified as a potent CDK5 inhibitor and co-crystallographic data of urea 3/CDK2 enzyme were used to design a novel series of 3,4-dihydroquinazolin-2(1H)-ones as CDK5 inhibitors. In this investigation we present our synthetic studies toward this series of compounds and discuss their biological relevance as CDK5 inhibitors.     

A HIV-2-based self-inactivating vector for enhanced gene transduction

The employment of HIV-1-based vectors in clinical trials is controversial mainly due to the lethal nature of the virus. HIV-2 is less pathogenic in nature and therefore is likely to be safer for vector design and production. We developed HIV-2-based self-inactivating vectors in which 520 bp out of 554 bp of the viral U3 was deleted. Interestingly, high titers were obtained only when an exogenous promoter was used to drive expression of viral RNA. It was found that the vectors could target a wide range of mammalian cell types including primary neuronal cells and could yield long term expression. It is also noteworthy that the HIV-2 vectors could be effectively cross-packaged into HIV-1 core, which might provide for enhanced safety by reducing the recombination potential of the system.     

Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury

Whether hepatocytes can convert into biliary epithelial cells (BECs) during biliary injury is much debated. To test this concept, we traced the fate of genetically labeled [dipeptidyl peptidase IV (DPPIV)-positive] hepatocytes in hepatocyte transplantation model following acute hepato-biliary injury induced by 4,4’-methylene-dianiline (DAPM) and D-galactosamine (DAPM+D-gal) and in DPPIV-chimeric liver model subjected to acute (DAPM+D-gal) or chronic biliary injury caused by DAPM and bile duct ligation (DAPM+BDL). In both models before biliary injury, BECs are uniformly DPPIV-deficient and proliferation of DPPIV-deficient hepatocytes is restricted by retrorsine. We found that mature hepatocytes underwent a stepwise conversion into BECs after biliary injury. In the hepatocyte transplantation model, DPPIV-positive hepatocytes entrapped periportally proliferated, and formed two-layered plates along portal veins. Within the two-layered plates, the hepatocytes gradually lost their hepatocytic identity, proceeded through an intermediate state, acquired a biliary phenotype, and subsequently formed bile ducts along the hilum-to-periphery axis. In DPPIV-chimeric liver model, periportal hepatocytes expressing hepatocyte nuclear factor-1β (HNF-1β) were exclusively DPPIV-positive and were in continuity to DPPIV-positives bile ducts. Inhibition of hepatocyte proliferation by additional doses of retrorsine in DPPIV-chimeric livers prevented the appearance of DPPIV-positive BECs after biliary injury. Moreover, enriched DPPIV-positive BEC/hepatic oval cell transplantation produced DPPIV-positive BECs or bile ducts in unexpectedly low frequency and in mid-lobular regions. These results together suggest that mature hepatocytes but not contaminating BECs/hepatic oval cells are the sources of periportal DPPIV-positive BECs. We conclude that mature hepatocytes contribute to biliary regeneration in the environment of acute and chronic biliary injury through a ductal plate configuration without the need of exogenously genetic or epigenetic manipulation.     

桑尺蠖的发育起点温度和有效积温

在室内恒温条件下测定了桑尺蠖的发育历期。对试验结果采用 2种方法计算 ,并用变异系数来检验。结果表明 ,对于早春出蛰后的越冬幼虫和非越冬代 ,用直接最优化法计算所得的结果更接近实际 ;越冬幼虫的发育起点温度 (C)为 (3.4± 0 .7)℃ ,有效积温 (K )为 4 97.5日度 ;非越冬代幼虫和全世代发育起点温度 (C)分别为 (4 .2± 1.4 )℃和 (6 .0± 1.3)℃ ,相应的有效积温 (K)分别为 50 5.8日度和 781.7日度。     

FLUTAX法显示纤毛虫微管胞器的改良

在参考Arregui等报道的方法的基础上,对紫杉醇荧光染色(FLUTAX)显示纤毛虫细胞微管胞器的流程进行了改进,对其中一些试剂的配方作了调整,改进了多聚赖氨酸涂布玻片、皂苷孵育、多聚甲醛固定和Triton X-100渗透等步骤。     

长洲水利枢纽建坝后对库区水鸟影响的预测分析

长洲水利枢纽库区分布有41种水鸟,其中38种是涉禽,它们主要栖息于河谷带。环境影响评价分析表明,大坝建成蓄水后将给涉禽带来很不利的影响。由于生境的改变,库区水鸟群落将发生变化,涉禽的种类和数量将减少,而游禽的种类和数量将增多。建议开展受威胁的珍稀水鸟海南鳽(Gorsachius magnificus)的生态生物学研究,以便提出有效的保护措施。