A New Quinolone and Other Constituents from the Fruits of Tetradium ruticarpum: Effects on Neutrophil Pro‐Inflammatory Responses

The fruit of Tetradium ruticarpum is widely used in healthcare products for the improvement of blood circulation, headache, abdominal pain, amenorrhea, chill limbs, migraine, and nausea. A new quinolone, 2‐[(6Z,9Z)‐pentadeca‐6,9‐dienyl]quinolin‐4(1H)‐one ( 1 ), has been isolated from the fruits of T. ruticarpum, together with eleven known compounds. The structure of the new compound was determined by NMR and MS analyses. Rutaecarpine ( 4 ), evodiamine ( 5 ), and skimmianine ( 7 ) exhibited inhibition (IC₅₀≤20.9 μM ) of O$\rm{{_{2}^{{^\cdot} -}}}$ generation by human neutrophils in response to N‐formyl‐L ‐methionyl‐L ‐leucyl‐L ‐phenylalanine/cytochalasin B (fMLP/CB). In addition, 1 , evocarpine ( 2 ), 4, 7 , and evodol ( 8 ) inhibited fMLP/CB‐induced elastase release with IC₅₀ values ≤14.4 μM .     

Evodiamine and rutaecarpine inhibit migration by LIGHT via suppression of NADPH oxidase activation

LIGHT acted as a new player in the atherogenesis. The dried, unripe fruit of Evodia Fructus (EF) has long been used as a traditional Chinese herbal medicine, and is currently widely used for the treatment of headache, abdominal pain, vomiting, colds and reduced blood circulation. Evodiamine and rutaecarpine are active components of EF. In this study, we investigated the inhibitory effect of evodiamine and rutaecarpine on LIGHT‐induced migration in human monocytes. Evodiamine and rutaecarpine decreased the LIGHT‐induced production of ROS, IL‐8, monocyte chemoattractant protein‐1 (MCP‐1), TNF‐α, and IL‐6, as well as the expression of chemokine receptor (CCR) 1, CCR2 and ICAM‐1 and the phosphorylation of the ERK 1/2 and p38 MAPK. Furthermore, NADPH oxidase assembly inhibitor, AEBSF, blocked LIGHT‐induced migration and activation of CCR1, CCR2, ICAM‐1, and MAPK such as ERK and p38 in a manner similar to evodiamine and rutaecarpine. These findings indicate that the inhibitory effects of evodiamine and rutaecarpine on LIGHT‐induced migration and the activation of CCR1, CCR2, ICAM‐1, ERK, and p38 MAPK occurs via decreased ROS production and NADPH oxidase activation. Taken together, these results indicate that evodiamine and rutaecarpine have the potential for use as an anti‐atherosclerosis agent. J. Cell. Biochem. 107: 123–133, 2009. © 2009 Wiley‐Liss, Inc.     

Therapeutic liver repopulation for the treatment of metabolic liver diseases

Orthotopic liver transplantation is the treatment of choice for many inherited and acquired liver diseases. Unfortunately, the supply of donor organs is limiting and therefore many patients cannot benefit from this therapy. In contrast, hepatocyte suspensions can be isolated from a single donor liver can be transplanted into several hosts, and this procedure may help overcome the shortage in donor livers. In classic hepatocyte transplantation, however, only 1% of the liver mass or less can be replaced by donor cells. Recently though, we have used a mouse model of hereditary tyrosinemia to show that > 90% of host hepatocytes can be replaced by a small number of transplanted donor cells in a process we term "therapeutic liver repopulation". This phenomenon is analogous to repopulation of the hematopoietic system after bone marrow transplantation. Liver repopulation occurs when transplanted cells have a growth advantage in the setting of damage to recipient liver cells. Here we will review the current knowledge of this process and discuss the hopeful implications for treatment of liver diseases.     

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.

     

The Biochemical of Tetradium,Euodia and Melicope and their significance in the Rutaceae

From the stem and root barks of Tetradium glabrifolium (Rutaceae) benzophenanthridine alkaloids have been isolated together with furoquinoline alkaloids, coumarins and limonoids. The occurrence of the l-benzyltetrahydroisoquinolinederived benzophenanthridines adds Tetradium to the small group of rutaceous genera (Fagaropsis, Phellodendron, Toddalia, Zanthoxylum) known to produce alkaloids of this type. These findings support Hartley's decision to reassign taxa from Euodia (sensu Engler) into the three genera Tetradium, Euodia s. s. and Melicope and his contention that Tetradium is closely allied to Zanthoxylum and Phellodendron, with which it shares several unusual chemical characters. Hartley's re-alignment of Tetradium, which cuts across Engler's sub-families Rutoideae and Toddalioideae, is therefore sustained by the known distribution of secondary metabolites, whilst available information suggests a wide disparity between the chemical profiles of Tetradium and Melicope. The chemosystematic significance of the addition of Tetradium to the 1-benzyltetrahydroisoquinoline producing genera and the potential of these taxa to have acted as a starting point for biochemical evolution within the Rutaceae is discussed.     

Apoptosis and liver diseases

Regulation of homeostasic balance between cell proliferation and cell death, called apoptosis, is essential for development and maintenance of multicellular organisms. Recent research into the molecular mechanisms of apoptosis has revealed that apoptosis is a genetically and evolutionarily conserved process that can become deranged when the components of the cellular apoptotic machinery are mutated, perturbated by viral gene products or present in inappropriated quantities. Analysis of the regulatory apoptotic pathways has led to a better understanding of the etiology and pathogenesis of many human diseases, notably cancers, infectious diseases or autoimmune diseases. Our understanding of the regulation of apoptosis in health and disease is far from complete and the use of understanding into new therapeutic modalities has only begun to be approached.     

Advances on liver cell-derived exosomes in liver diseases

Exosomes are extracellular vesicles with diameters ranging from 30 to 150 nm, which contain several donor cell-associated proteins as well as mRNA, miRNA, and lipids and coordinate multiple physiological and pathological functions through horizontal communication between cells. Almost all types of liver cells, such as hepatocytes and Kupffer cells, are exosome-releasing and/or exosome-targeted cells. Exosomes secreted by liver cells play an important role in regulating general physiological functions and also participate in the onset and development of liver diseases, including liver cancer, liver injury, liver fibrosis and viral hepatitis. Liver cell-derived exosomes carry liver cell-specific proteins and miRNAs, which can be used as diagnostic biomarkers and treatment targets of liver disease. This review discusses the functions of exosomes derived from different liver cells and provides novel insights based on the latest developments regarding the roles of exosomes in the diagnosis and treatment of liver diseases.     

Tissue remodelling in liver diseases

Tissue remodelling is a dynamic process that occurs during fetal or adult life and involves a modification of the original organization and function of a tissue. Tissue remodelling is observed in physiological and pathological conditions such as during wound healing or in the mammary gland during the course of pregnancy. In this review we will discuss the remodelling occurring in the liver as a consequence of chronic inflammation, as observed in chronic hepatitis, or as a consequence of hepatocellular carcinoma (HCC) progression in more detail. We will consider how altered deposition and turn-over of extracellular matrix (ECM) proteins could lead to development of liver fibrosis, and how the exacerbation of fibrosis could underlie the development of cirrhosis. The involvement of inflammatory and anti-inflammatory cytokines commonly used as therapeutic agents, such as Interferon-a, is then evaluated with a particular focus on modulation of ECM proteolysis. Finally, we analyze the role of alterations of the surrounding microenvironment including ECM, growth factors, cytokines and membrane receptors for ECM ligands in the development of HCC and in its invasive behaviour.     

Biological affinity, phenotypic variation and palaeoecology of Tetradium Dana, 1846

Comparisons of morphologies and modes of life of the Ordovician fossil Tetradium Dana, 1846, with chaetetid sponges, tabulate corals, and Recent rhodophytes show that several defining Tetradium characteristics are incompatible with its chaetetid and tabulate classifications. All Tetradium characteristics fit a rhodophyte identification, however, as a calcified uniaxial corticated florideophyte. It is argued from functional morphology that the fundamental subsquare cross-section of the Tetradium tube is an adaptation for close packing, which implies that the basic growth form is compact and should have developed where conditions were optimal. More open forms are derived from it and probably occupied less-favourable environments.
Palaeoecological studies from the Ottawa Valley, Canada, show that the Tetradium growth form is correlated with environmental stress and became more open as salinity increased: i.e. the compact T. fibratum form lived in normal marine conditions, radiating bundles of T. cellulosum tubes in low to middle hypersalinity and single T. syringoporoides tubes in high hypersalinity. Different Tetradium growth forms from the study area are phenotypic variants of a single species, rather than different species and genera. Therefore, classifications that divide Tetradium into different species and genera based only on growth form have no biological basis. There is little evidence of interspecific interactions with Tetradium .