Light calcium carbonate improves pullulan biosynthesis by Aureobasidium pullulans under high concentration of sugar.

The effects of light calcium carbonate (CaCO3) on pullulan biosynthesis by Aureobasidium pullulans NCPS2016 were investigated. Light CaCO3 enhanced pullulan production by 12.4 % when added to the low concentration of fructose broth compared with K2HPO4. Pullulan production was further improved when increasing both the concentrations of light CaCO3 and fructose. Compared to K2HPO4, light CaCO3 improved the activities of UDP-glucose pyrophosphorylase, α-phosphoglucose mutase, UDP-glucosyltransferase, and glucosyltransferase relevant to pullulan biosynthesis, and the gene transcriptional levels of UDP-glucose pyrophosphorylase, α-phosphoglucose mutase, UDP-glucosyltransferase, and glucose kinase were enhanced. During 30-liter fermentation, 144.3 g/L of purified pullulan was produced from 200 g/L of fructose and 15 g/L of light CaCO3 within 168 h, with the yield and productivity of 0.72 g/g and 0.86 g/L/h respectively. This is the first report that light CaCO3 improves pullulan production significantly.

High-level production of pullulan from high concentration of glucose by mutagenesis and adaptive laboratory evolution of Aureobasidium pullulans.

The cost of carbon sources and the low efficiency of the fermentation titer limit the industrial application of pullulan. In this study, a hypertonic-tolerant strain with efficient utilization of glucose was obtained using a double strategy. Initially, a strain for efficient synthesis of pullulan from glucose was generated by mutagenesis. Subsequently, the mutant was directionally evolved on the plate containing a high glucose concentration to enhance high osmotic resistance. The enzyme activities and the transcriptional levels involved in pullulan biosynthesis and high osmotic tolerance in mutants were increased. Nitrogen source and inorganic salts also significantly affected the production of pullulan by M233-20 from high concentration of glucose. The pullulan titer of 162.1 g/L was obtained using the response surface methodology in the flask. The strain M233-20 produced 162.3 g/L pullulan in a 30-L bioreactor with a yield of 0.82 g/g glucose. Hence, this work provides a potential industrial pullulan producer M233-20 and a strategy to develop excellent strain.

Dual-target Inhibitors Based on BRD4: Novel Therapeutic Approaches for Cancer.

BACKGROUND: Currently, cancer continues being a dramatically increasing and serious threat to public health. Although many anti-tumor agents have been developed in recent years, the survival rate of patients is not satisfactory. The poor prognosis of cancer patients is closely related to the occurrence of drug resistance. Therefore, it is urgent to develop new strategies for cancer treatment. Multi-target therapies aim to have additive or synergistic effects and reduce the potential for the development of resistance by integrating different pharmacophores into a single drug molecule. Given the fact that majority of diseases are multifactorial in nature, multi-target therapies are being exploited with increasing intensity, which has brought improved outcomes in disease models and obtained several compounds that have entered clinical trials. Thus, it is potential to utilize this strategy for the treatment of BRD4 related cancers. This review focuses on the recent research advances of dual-target inhibitors based on BRD4 in the aspect of anti-tumor. METHODS: We have searched the recent literatures about BRD4 inhibitors from the online resources and databases, such as pubmed, elsevier and google scholar. RESULTS: In the recent years, many efforts have been taken to develop dual-target inhibitors based on BRD4 as anti-cancer agents, such as HDAC/BRD4 dual inhibitors, PLK1/BRD4 dual inhibitors and PI3K/BRD4 dual inhibitors and so on. Most compounds display good anti-tumor activities. CONCLUSION: Developing new anti-cancer agents with new scaffolds and high efficiency is a big challenge for researchers. Dual-target inhibitors based on BRD4 are a class of important bioactive compounds. Making structural modifications on the active dual-target inhibitors according to the corresponding structure-activity relationships is of benefit to obtain more potent anti-cancer leads or clinical drugs. This review will be useful for further development of new dual-target inhibitors based on BRD4 as anti-cancer agents.

Discovery of Small-Molecule Inhibitors of the HSP90-Calcineurin-NFAT Pathway against Glioblastoma.

Glioblastoma (GBM) is among the most common and malignant types of primary brain tumors in adults, with a dismal prognosis. Although alkylating agents such as temozolomide are widely applied as the first-line treatment for GBM, they often cause chemoresistance and remain ineffective with recurrent GBM. Alternative therapeutics against GBM are urgently needed in the clinic. We report herein the discovery of a class of inhibitors (YZ129 and its derivatives) of the calcineurin-NFAT pathway that exhibited potent anti-tumor activity against GBM. YZ129-induced GBM cell-cycle arrest at the G2/M phase promoted apoptosis and inhibited tumor cell proliferation and migration. At the molecular level, YZ129 directly engaged HSP90 to antagonize its chaperoning effect on calcineurin to abrogate NFAT nuclear translocation, and also suppressed other proto-oncogenic pathways including hypoxia, glycolysis, and the PI3K/AKT/mTOR signaling axis. Our data highlight the potential for targeting the cancer-promoting HSP90 chaperone network to treat GBM.

Bioluminescent Probe for Tumor Hypoxia Detection via CYP450 Reductase in Living Animals.

Hypoxia is a pathogenic characteristic of solid tumors owing to absent or abnormal vasculature in the tumor microenvironment and essential in tumor progression, angiogenesis, metastasis, invasion and resistance to immune system and therapy. In hypoxic environments, CYP450 enzymes are more efficient than in normoxia. Herein, based on the reductive capacity of CYP450 enzymes/NADPH system, we managed to cage aminoluciferin developing a reaction-based bioluminescent probe as well as an imaging method for the hypoxia detection. Exhibiting enhanced about 3-fold total flux in big (1.2 cm-diameter) tumors, Hypoxia BioLuminescent probe (HBL) can afford potential utility for in cellulo and in vivo hypoxia imaging in tumor model mice.

Discovery of the First Environment-Sensitive Fluorescent Probe for GPR120 (FFA4) Imaging.

GPR120, which is activated by long-chain free fatty acids (FFAs), has been recognized as a new attractive target for the treatment of type 2 diabetes and metabolic disease. The visualization and location of GPR120 in native cells can provide powerful information for guiding the physiological and pathological studies of GPR120. We report herein the first potent fluorescent probes that sensitively detect GPR120. We designed and synthesized a series of novel environment-sensitive probes with suitable fluorescence property, high biological activity on the GPR120, and acceptable cytotoxicity. These fluorescent probes targeting GPR120 are expected to expand the toolkit for further studies on GPR120.

A practical synthesis of chiral tricyclic cyclopenta[b]benzofuran, a key intermediate of Beraprost.

A novel formal synthesis of Beraprost (1) is described. The tricyclic cyclopent[b]benzofuran core is efficiently prepared from (-)-Corey lactone diol in 12 steps with an overall yield of 37.4%. Key features of the strategy include a ring-closing metathesis reaction and aromatization to form the tricyclic cyclopenta[b]benzofuran framework, and selective halogenation/formylation to install the butyrate side-chain.

Store-operated CRAC channel inhibitors: opportunities and challenges.

Aberrant Ca(2+) release-activated Ca(2+) (CRAC) channel activity has been implicated in a number of human disorders, including immunodeficiency, autoimmunity, occlusive vascular diseases and cancer, thus placing CRAC channels among the important targets for the treatment of these disorders. We briefly summarize herein the molecular basis and activation mechanism of CRAC channel and focus on discussing several pharmacological inhibitors of CRAC channels with respect to their biological activity, mechanisms of action and selectivity over other types of Ca(2+) channel in different types of cells.

Total synthesis of (+/-)-4-demethylenglerin A.

Racemic 4-demethylenglerin A (1'), a simplified analog of the guaiane-type sesquiterpene englerin A (1), has been synthesized. The cyclic hydrocarbon core structure was built through modified Metz approach using epoxynitrile cyclization and direct Aldol reaction to prepare the precursor of RCM. The primary cytotoxicity test summarized that C4 methyl has marked impacts on the bioactivity.