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Natali Abeywickrama-Samarakoon, Jean-Claude Cortay, Paul Dény
PURPOSE OF REVIEW: To highlight new concepts and therapeutic approaches concerning hepatitis D virus (HDV) infection. RECENT FINDINGS: Common receptor for hepatitis B virus (HBV) and HDV has been elucidated, deciphering of HDV replication is still in progress, preliminary results of phase II proof-of-concept clinical assays for entry inhibitors and cellular farnesyl transferase inhibitors are now available. SUMMARY: Hepatitis D infection remains a severe acute and chronic liver illness with the only currently approved therapy (Peg-αIFN) achieving disappointingly low rates of sustained viral response and clinical improvement...
October 7, 2016: Current Opinion in Infectious Diseases
Jinxin Li, Shujie Liu, Juan Wang, Jing Li, Dahui Liu, Jianli Li, Wenyuan Gao
In this work, we selected three fungi strains (Aspergillus niger, Aspergillus flavus and Aspergillus oryzae) as elicitors prepared from mycelium or fermentation broth to improve ginsenosides production in adventitious roots culture. The results showed that ginsenosides production (29.90±4.67mgg(-1)) was significantly enhanced upon elicitation with 200mgL(-1)A. niger elicitor prepared from mycelium, which was 3.52-fold of untreated group. HPLC-ESI-MS(n) analysis was performed, showing that ginsenoside Rb3 was present after treatment with the A...
October 13, 2016: Journal of Biotechnology
Nagendra Yaluri, Shalem Modi, Tarja Kokkola
Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor widely used for the treatment of hypercholesterolemia. Recent data indicates that simvastatin increases the risk of new-onset diabetes by impairing both insulin secretion and insulin sensitivity. However, systematic evaluation of mechanistic pathways is lacking. We aimed to explore the effects of simvastatin on glucose uptake and underlying mechanisms using L6 skeletal muscle myotubes. We performed our experiments at basal and insulin-stimulated conditions, at normal (5...
October 12, 2016: Biochemical and Biophysical Research Communications
Ming Gu, Ping Zhao, Jinwen Huang, Yuanyuan Zhao, Yahui Wang, Yin Li, Yifei Li, Shengjie Fan, Yue-Ming Ma, Qingchun Tong, Li Yang, Guang Ji, Cheng Huang
Background and purpose: Silymarin, a standardized extract of the milk thistle seeds, has been widely used to treat chronic hepatitis, cirrhosis, and other types of toxic liver damage. Despite increasing studies on the action of silymarin and its major active constituent, silybin in their therapeutic properties against insulin resistance, diabetes and hyperlipidaemia in vitro and in vivo, the mechanism underlying silymarin action remains unclear. Experimental approach: C57BL/6 mice were fed high-fat diet (HFD) for 3 months to induce obesity, insulin resistance, hyperlipidaemia, and fatty liver...
2016: Frontiers in Pharmacology
Sapan J Patel, Costel C Darie, Bayard D Clarkson
Tumors contain heterogeneous cell populations and achieve dominance by functioning as collective systems. The mechanisms underlying the aberrant growth and interactions between cells are not very well understood. The pre-B acute lymphoblastic leukemia cells we studied were obtained directly from a patient with Ph+ ALL. A new Ph+ ALL cell line (ALL3) was established from the leukemic cells growing as ascitic cells in his pleural fluid. The patient died of his disease shortly after the cells were obtained. ALL3 cells grow well at high cell densities (HD), but not at low cell densities...
2016: American Journal of Translational Research
Chun-Tang Chiou, Chien-Chang Shen, Tung-Hu Tsai, Yu-Jen Chen, Lie-Chwen Lin
Six new meroterpenoids, diplomeroterpenoids A-F (1-6), two new chalcone-lignoids, diplochalcolins A and B (7, 8), and 13 known compounds were isolated from the root extract of Mimosa diplotricha. Diplomeroterpenoids A-F consist of a 4H-chromen-4-one and a diterpenoid unit, and their absolute configurations were determined by X-ray crystallographic analysis. Compounds 1-3 and 5 showed potent inhibitory activity on protein farnesyl transferase, with IC50 values from 5.0 to 8.5 μM. Compound 1 showed antiproliferative activity against human hepatoblastoma HepG2 cells with a GI50 value of approximately 8...
October 7, 2016: Journal of Natural Products
Christian Schem, Robert J Tower, Philipp Kneissl, Anna-Christina Rambow, Graeme M Campbell, Christine Desel, Timo Damm, Thorsten Heilmann, Sabine Fuchs, Maaz Zuharya, Anna Trauzold, Claus C Glüer, Sarah Schott, Sanjay Tiwari
Bisphosphonates have effects which are anti-resorptive, anti-tumor and anti-apoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolite-bisphosphonate conjugates have potential for improved performance as a class of bone specific anti-neoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with anti-resorptive and anti-tumor activity...
October 7, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Trinh-Don Nguyen, Juan A Faraldos, Maria Vardakou, Melissa Salmon, Paul E O'Maille, Dae-Kyun Ro
The Andes-endemic Barnadesioideae lineage is the oldest surviving and phylogenetically basal subfamily of the Asteraceae (Compositae), a prolific group of flowering plants with world-wide distribution (∼24,000 species) marked by a rich diversity of sesquiterpene lactones (STLs). Intriguingly, there is no evidence that members of the Barnadesioideae produce STLs, specialized metabolites thought to have contributed to the adaptive success of the Asteraceae family outside South America. The biosynthesis of STLs requires the intimate expression and functional integration of germacrene A synthase (GAS) and germacrene A oxidase (GAO) to sequentially cyclize and oxidize farnesyl diphosphate into the advanced intermediate germacrene A acid leading to diverse STLs...
October 28, 2016: Biochemical and Biophysical Research Communications
Mathew J Wong, Crystal Kantores, Julijana Ivanovska, Amish Jain, Robert P Jankov
Chronic neonatal pulmonary hypertension (PHT) frequently results in early death. Systemically administered Rho-kinase (ROCK) inhibitors prevent and reverse chronic PHT in neonatal rats, but at the cost of severe adverse effects, including systemic hypotension and growth restriction. Simvastatin has pleiotropic inhibitory effects on isoprenoid intermediates that may limit activity of RhoA, which signals upstream of ROCK. We therefore hypothesized that statin treatment would safely limit pulmonary vascular RhoA activity and prevent and reverse experimental chronic neonatal PHT via downstream inhibitory effects on pathological ROCK activity...
September 30, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Sun Young Choi, Hyun Jeong Lee, Jaeyeon Choi, Jiye Kim, Sang Jun Sim, Youngsoon Um, Yunje Kim, Taek Soon Lee, Jay D Keasling, Han Min Woo
BACKGROUND: Metabolic engineering of cyanobacteria has enabled photosynthetic conversion of CO2 to value-added chemicals as bio-solar cell factories. However, the production levels of isoprenoids in engineered cyanobacteria were quite low, compared to other microbial hosts. Therefore, modular optimization of multiple gene expressions for metabolic engineering of cyanobacteria is required for the production of farnesyl diphosphate-derived isoprenoids from CO2. RESULTS: Here, we engineered Synechococcus elongatus PCC 7942 with modular metabolic pathways consisting of the methylerythritol phosphate pathway enzymes and the amorphadiene synthase for production of amorpha-4,11-diene, resulting in significantly increased levels (23-fold) of amorpha-4,11-diene (19...
2016: Biotechnology for Biofuels
Vivek Asati, Debarshi Kar Mahapatra, Sanjay Kumar Bharti
The discovery of genetic, genomic and clinical biomarkers have revolutionized the treatment option in the form of personalized medicine which allows to accurately predict a person's susceptibility/progression of disease, the patient's response to therapy, and maximize the therapeutic outcome in terms of low/no toxicity for a particular patient. Recently, the U.S. Food and Drug Administration has realized the contribution of pharmacogenomics in better healthcare and advocated the consideration of pharmacogenomic principles in making safer and more effective drug...
September 16, 2016: European Journal of Medicinal Chemistry
Jia-Rong Wu, Lian-Chin Wang, Yu-Ru Lin, Chi-Pei Weng, Ching-Hui Yeh, Shaw-Jye Wu
Protein farnesylation is a post-translational modification known to regulate abscisic acid (ABA)-mediated drought tolerance in plants. However, it is unclear whether and to what extent protein farnesylation affects plant tolerance to high-temperature conditions. The Arabidopsis heat-intolerant 5 (hit5) mutant was isolated because it was thermosensitive to prolonged heat incubation at 37°C for 4 d but thermotolerant to sudden heat shock at 44°C for 40 min. Map-based cloning revealed that HIT5 encodes the β-subunit of the protein farnesyltransferase...
September 27, 2016: New Phytologist
Ingy I Abdallah, Magdalena Czepnik, Ronald van Merkerk, Wim J Quax
Amorphadiene synthase (ADS) is known for its vital role as a key enzyme in the biosynthesis of the antimalarial drug artemisinin. Despite the vast research targeting this enzyme, an X-ray crystal structure of the enzyme has not yet been reported. In spite of the remarkable difference in product profile among various sesquiterpene synthases, they all share a common α-helical fold with many highly conserved regions especially the bivalent metal ion binding motifs. Hence, to better understand the structural basis of the mechanism of ADS, a reliable 3D homology model representing the conformation of the ADS enzyme and the position of its substrate, farnesyl diphosphate, in the active site was constructed...
September 27, 2016: Journal of Natural Products
Nobutaka Suzuki, Tatsuo Ito, Hisanori Matsui, Masayuki Takizawa
TAK-475 (lapaquistat acetate) and its active metabolite-I (TAK-475 M-I) inhibit squalene synthase, which catalyzes the conversion of farnesyl diphosphate (FPP) to squalene. FPP is a substrate for synthesis of other mevalonate-derived isoprenoids (MDIs) such as farnesol (FOH), geranlygeranyl diphosphate (GGPP), and geranylgeraniol. In patients with MKD, a rare autosomal recessive disorder, defective activity of mevalonate kinase leads to a shortage of MDIs. MDIs especially GGPP are required for prenylation of proteins, which is a posttranslation modification necessary for proper functioning of proteins like small guanosine triphosphatases...
2016: SpringerPlus
Panpan Zhang, Xiaoying Cao, Changgen Li, Zhujun Zheng, Sun Yong, Ji-Hong Jiang
Squalene synthase catalyzes the condensation of 2 molecules of farnesyl diphosphate to produce squalene, the first committed precursor for sterol, brassinosteroid, and triterpene biosynthesis. A squalene synthase gene, designated IoSQS, was isolated from Inonotus obliquus, a medicinal mushroom that produces a plethora of bioactive triterpenes. IoSQS complementary DNA was found to contain an open reading frame of 1476 bp, encoding a protein of 491 amino acids with a calculated molecular mass of 55.85 kDa. The IoSQS genomic DNA sequence consisted of 1813 bp and contained 4 exons and 3 introns...
2016: International Journal of Medicinal Mushrooms
Gennadii A Grabovyi, Justin T Mohr
A novel synthetic approach for the synthesis of bioactive phenolic natural products is reported. This strategy highlights the power of halogenative aromatization reactions recently developed in our group for preparing densely functionalized arenes in a controlled fashion. Five natural products related by an aromatic core and a farnesyl side chain are synthesized. In contrast to prior methods, this synthesis features high efficiency and generality that permits preparation of targets in gram-scale quantities.
October 7, 2016: Organic Letters
Jianli Li, Shujie Liu, Juan Wang, Jing Li, Jinxin Li, Wenyuan Gao
This study reports the best culture conditions for roots growth and accumulation of active components by optimizing the parameters. Glycyrrhiza uralensis adventitious roots metabolites were significantly increased after adding Saccharomyces cerevisiae and Meyerozyma guilliermondii. The highest contents of polysaccharide, glycyrrhizic acid, glycyrrhetinic acid and total flavonoids were obtained in Meyerozyma guilliermondii group, the content of glycyrrhizic acid was 5.3-fold higher than the control. In control and treatment groups, twelve compounds were identified by high performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS),among which, some new compounds have been detected in elicitor groups including 5,7-Dihydroxyflavanone, glycyrrhisoflavanone, licorice saponin J2, uralsaponin B, (3R)-vestitol, uralenol...
September 20, 2016: Biotechnology and Applied Biochemistry
Wei Xie, Alexandre Chojnowski, Thomas Boudier, John S Y Lim, Sohail Ahmed, Zheng Ser, Colin Stewart, Brian Burke
The nuclear lamina is a universal feature of metazoan nuclear envelopes (NEs) [1]. In mammalian cells, it appears as a 10-30 nm filamentous layer at the nuclear face of the inner nuclear membrane (INM) and is composed primarily of A- and B-type lamins, members of the intermediate filament family [2]. While providing structural integrity to the NE, the lamina also represents an important signaling and regulatory platform [3]. Two A-type lamin isoforms, lamins A and C (LaA and LaC), are expressed in most adult human cells...
October 10, 2016: Current Biology: CB
Yasutomo Shinohara, Shunji Takahashi, Hiroyuki Osada, Yasuji Koyama
Esterified drimane-type sesquiterpene lactones such as astellolides display various biological activities and are widely produced by plants and fungi. Given their low homology to known sesquiterpene cyclases, the genes responsible for their biosynthesis have not been uncovered yet. Here, we identified the astellolide gene cluster from Aspergillus oryzae and discovered a novel sesquiterpene biosynthetic machinery consisting of AstC, AstI, and AstK. All these enzymes are annotated as haloacid dehalogenase-like hydrolases, whereas AstC also contains a DxDTT motif conserved in class II diterpene cyclases...
2016: Scientific Reports
Xiangjian Luo, Namei Li, Juanfang Zhong, Zheqiong Tan, Ying Liu, Xin Dong, Can Cheng, Zhijie Xu, Hongde Li, Lifang Yang, Min Tang, Xinxian Weng, Wei Yi, Jikai Liu, Ya Cao
Grifolin, a farnesyl phenolic compound isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens, exhibits effective antitumor bioactivity in previous study of our group and other lab. In this study, we observed that grifolin inhibited tumor cells adhesion and migration. Moreover, grifolin reduced reactive oxygen species (ROS) production and caused cellular ATP depletion in high-metastatic tumor cells. PGC1α (Peroxisome proliferator-activated receptor γ, coactivator 1α) encodes a transcriptional co-activator involved in mitochondrial biogenesis and respiration and play a critical role in the maintenance of energy homeostasis...
September 10, 2016: Oncotarget
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