Synthesis of Some New Pyrazoline-Based Thiazole Derivatives and Evaluation of Their Antimicrobial,Antifungal, and Anticancer Activities

Russian Journal of Bioorganic Chemistry - 3-(2-Thienyl)-5-aryl-1-thiocarbamoyl-2-pyrazolines were reacted with chloroacetone derivatives and hydrazonyl chloride derivatives in ethanol to afford the...     

Synthesis and biological evaluation of 2-amino-7,7-dimethyl 4-substituted-5-oxo-1-(3,4,5-trimethoxy)-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile derivatives as potential cytotoxic agents

A large number of antimitotic drugs, derived from natural sources or chemically synthesized, have been identified and shown to interfere with the tubulin system. Inhibition of tubulin polymerization is among the important targets useful in the cancer therapy.The present work reports the synthesis of some novel quinoline derivatives bearing a trimethoxyphenyl moiety. The trimethoxybenzene moiety has been reported to be crucial to obtain relevant cytotoxic and antitubulin responses. All the newly synthesized compounds were evaluated for their in vitro anticancer activity. Several compounds showed interesting cytotoxic activities compared to the used reference drug.     

Independent of Calorie Intake,Short-term Alternate-day Fasting Alleviates NASH,With Modulation of Markers of Lipogenesis,Autophagy, Apoptosis,and Inflammation in Rats

Non-alcoholic steatohepatitis (NASH) is a worldwide health problem. Alternate-day fasting (ADF), although thought to be aggressive, has proven safety and efficacy. We aimed to evaluate the effect of short-term ADF against already established high-fat-fructose (HFF)-induced NASH, independent of the amount of calorie intake, and to study the effect of ADF on lipogenesis, apoptosis, and hepatic inflammation. Male Sprague Dawley rats were divided into two groups: (1) negative control and (2) NASH group fed on HFF for 9 weeks, and then randomized into two subgroups of either HFF alone or with ADF protocol for 3 weeks. The ADF could improve HFF-related elevation in serum lactate dehydrogenase and could decrease the mRNA expression of lipogenesis genes; acetyl CoA carboxylase, peroxisome proliferator-activated receptor γ, and peroxisome proliferator-activated receptor α; apoptotic genes caspase-3, p53, and inflammatory cyclo-oxygenase 2; and immunohistochemical staining for their proteins in liver with upregulation of LC3 and downregulation of P62 immunoexpression. Moreover, ADF ameliorated HFF-induced steatosis, inflammation, ballooning, and fibrosis through hematoxylin and eosin, Oil Red O, and Sirius Red staining, confirmed by morphometric analysis, without significant weight loss. Significant correlation of morphometric parameters with levels of gene expression was found. These findings suggest ADF to be a safe effective therapeutic agent in the management of NASH     

Use of Humanised Rat Basophilic Leukaemia Cell Line RS-ATL8 for the Assessment of Allergenicity of Schistosoma mansoni Proteins

Background

Parasite-specific IgE is thought to correlate with protection against Schistosoma mansoni infection or re-infection. Only a few molecular targets of the IgE response in S. mansoni infection have been characterised. A better insight into the basic mechanisms of anti-parasite immunity could be gained from a genome-wide characterisation of such S. mansoni allergens. This would have repercussions on our understanding of allergy and the development of safe and efficacious vaccinations against helminthic parasites.

Methodology/Principal Findings

A complete medium- to high-throughput amenable workflow, including important quality controls, is described, which enables the rapid translation of S. mansoni proteins using wheat germ lysate and subsequent assessment of potential allergenicity with a humanised Rat Basophilic Leukemia (RBL) reporter cell line. Cell-free translation is completed within 90 minutes, generating sufficient amounts of parasitic protein for rapid screening of allergenicity without any need for purification. Antigenic integrity is demonstrated using Western Blotting. After overnight incubation with infected individuals'' serum, the RS-ATL8 reporter cell line is challenged with the complete wheat germ translation mixture and Luciferase activity measured, reporting cellular activation by the suspected allergen. The suitability of this system for characterization of novel S. mansoni allergens is demonstrated using well characterised plant and parasitic allergens such as Par j 2, SmTAL-1 and the IgE binding factor IPSE/alpha-1, expressed in wheat germ lysates and/or E. coli. SmTAL-1, but not SmTAL2 (used as a negative control), was able to activate the basophil reporter cell line.

Conclusion/Significance

This method offers an accessible way for assessment of potential allergenicity of anti-helminthic vaccine candidates and is suitable for medium- to high-throughput studies using infected individual sera. It is also suitable for the study of the basis of allergenicity of helminthic proteins.     

Purification of toxic protease from Brevibacterium otitidis KB76 with both metal and hydrosulfuryl at the active site

An extracellular toxic protease, KB76 from Brevibacterium otitidis was successfully purified to 31.3-fold by anion-exchange and gel filtration chromatography. The molecular mass was determined to be 47 kDa using SDS-PAGE. The optimum temperature and pH of the protease were 7.4 and 40°C, respectively. Ethylenediaminetetraacetic acid and phenylmethylsulfonyl fluoride inhibited the activity of the enzyme but soybean trypsin inhibitor and aprotinin had no obvious inhibition, which suggested the presence of both metal and hydrosulfuryl at or near the active site. Additionally, the isoelectric point of this protein was 5.5 ± 0.2. Its apparent K _m and V _max for the synthetic substrate N-succinyl-L-phenylalanine p-nitroanilide were 2.41 mM and 21.74 μM/min, respectively. Further, studying the lethality of the protease on mice by intraperitoneal injection, it exhibited 48-h LD₅₀ value of 9.6 mg/kg body weight. Gross and electron microscopic study in mice revealed that purified protease was capable of eliciting a variety of tissue responses resulted in liver necrosis. In conclusion, this protease produced by B. otitidis represents a potential toxic agent.     

New quinoxaline 1,4-di-N-oxides. Part 1: Hypoxia-selective cytotoxins and anticancer agents derived from quinoxaline 1,4-di-N-oxides

Hypoxic cells which are common feature of solid tumors are resistant to both anticancer drugs and radiation therapy. Thus, the identification of drugs with the selective toxicity toward hypoxic cells is an important target in anticancer chemotherapy. Tirapazamine has been shown to be an efficient and selective cytotoxin after bioreductive activation in hypoxic cells which is thought to be due to the presence of the 1,4-di-N-oxide. A new series of quinoxaline 1,4-di-N-oxides and fused quinoxaline di-N-oxides were synthesized and evaluated for hypoxic-cytotoxic activity on EAC cell line. Compound 10a was the most potent cytotoxin IC(50) 0.9 microg/mL, potency 75 microg/mL, and was approximately 15 times more selective cytotoxin (HCR>111) than 3-aminoquinoxaline-2-carbonitrile which has been used as a standard (HCR>7.5). Compounds 4 and 3a,b were more selective than the standard. In addition, antitumor activity against Hepg2 (liver) and U251 (brain) human cell lines was evaluated, compounds 9c and 8a were the most active against Hepg2 with IC(50) values 1.9 and 2.9 microg/mL, respectively, however, all the tested compounds were nontoxic against U251 cell line.     

The anti-tumour effect of induced pluripotent stem cells against submandibular gland carcinoma in rats is achieved via modulation of the apoptotic response and the expression of Sirt-1, TGF-β, and MALAT-1 in cancer cells

Molecular and Cellular Biochemistry - The era of induced pluripotent stem cells (iPSCs) was used as novel biotechnology to replace embryonic stem cells bypassing the ethical concerns and problems...     

Strengthening desert plant biotechnology research in the United Arab Emirates: a viewpoint

The biotechnology of desert plants is a vast subject. The main applications in this broad field of study comprises of plant tissue culture, genetic engineering, molecular markers and others. Biotechnology applications have the potential to address biodiversity conservation as well as agricultural, medicinal, and environmental issues. There is a need to increase our knowledge of the genetic diversity through the use of molecular genetics and biotechnological approaches in desert plants in the Arabian Gulf region including those in the United Arab Emirates (UAE). This article provides a prospective research for the study of UAE desert plant diversity through DNA fingerprinting as well as understanding the mechanisms of both abiotic stress resistance (including salinity, drought and heat stresses) and biotic stress resistance (including disease and insect resistance). Special attention is given to the desert halophytes and their utilization to alleviate the salinity stress, which is one of the major challenges in agriculture. In addition, symbioses with microorganisms are thought to be hypothesized as important components of desert plant survival under stressful environmental conditions. Thus, factors shaping the diversity and functionality of plant microbiomes in desert ecosystems are also emphasized in this article. It is important to establish a critical mass for biotechnology research and applications while strengthening the channels for collaboration among research/academic institutions in the area of desert plant biotechnology.     

USP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin

Mutations in the Park2 gene, encoding the E3 ubiquitin‐ligase parkin, are responsible for a familial form of Parkinson's disease (PD). Parkin‐mediated ubiquitination is critical for the efficient elimination of depolarized dysfunctional mitochondria by autophagy (mitophagy). As damaged mitochondria are a major source of toxic reactive oxygen species within the cell, this pathway is believed to be highly relevant to the pathogenesis of PD. Little is known about how parkin‐mediated ubiquitination is regulated during mitophagy or about the nature of the ubiquitin conjugates involved. We report here that USP8/UBPY, a deubiquitinating enzyme not previously implicated in mitochondrial quality control, is critical for parkin‐mediated mitophagy. USP8 preferentially removes non‐canonical K6‐linked ubiquitin chains from parkin, a process required for the efficient recruitment of parkin to depolarized mitochondria and for their subsequent elimination by mitophagy. This work uncovers a novel role for USP8‐mediated deubiquitination of K6‐linked ubiquitin conjugates from parkin in mitochondrial quality control.