Hormonal requirements for the induction of cytochrome P-450 in hepatocytes cultured in a serum-free medium

Drug mediated induction of cytochrome P450 was studied in cultures of hepatocytes that had never been cultured in the presence of serum. Propylisopropylacetamide induced a five-fold increase in cytochrome P450, approximating $\text{in ovo}$ induced levels, when triiodothyronine and/or dexamethasone were included in the culture medium. Insulin was apparently not required for this induction. Cytochrome P450, free of cytochrome oxidase, could be fully recovered from cell homogenates in a 8700g supernatant, by use of a buffer containing 0.2% Emulgen.     

Exploring structural features of EGFR–HER2 dual inhibitors as anti-cancer agents using G-QSAR approach

Abstract

Simultaneous inhibition of EGFR and HER2 by dual-targeting inhibitors is an established anti-cancer strategy. Therefore, a recent trend in drug discovery involves understanding the features of such dual inhibitors. In this study, three different G-QSAR models were developed corresponding to individual EGFR, HER2 and the dual-model for both receptors. The dual-model provided site-specific information wherein (i) increasing electronegative character and higher index of saturated carbon at R4 position; (ii) presence of chlorine atom at R2 position; (iii) decreasing alpha modified shape index at R1 and R3 positions; and (iv) less electronegativity at R2 position; were found important for enhancing the dual activity. Also, comparison of dual-model with the EGFR/HER2 individual models revealed that it incorporates the properties of both models and, thus, represents a combination of EGFR/HER2. Further, fragment analysis revealed that R2 and R4 are important for imparting high potency while specificity is decided by R1/R3 fragment. We also checked the predictive ability of the dual-model by determining applicability domain using William’s plot. Also, analysis of active molecules showed they show favorable substitutions that agree with the constructed dual-model. Thus, we have been successful in developing a single dual-response QSAR model to get an insight into various structural features influencing EGFR/HER2 activity.     

Sizeable acquired subglottic cyst in a baby with Williams–Beuren syndrome: Association or coincidence?

We describe a case of an acquired subglottic cyst presented with persistent stridor and voice hoarsening in a baby diagnosed with Williams–Beuren syndrome that was born premature and required intubation during neonatal period. We also comment on whether this is a coincidence or there can be an association between impaired elastogenesis, a feature of patients with the syndrome and the formation of a subglottic cyst.     

A novel indirubin derivative that increases somatic cell plasticity and inhibits tumorigenicity

Indirubin-based compounds affect diverse biological processes, such as inflammation and angiogenesis. In this study, we tested a novel indirubin derivative, LDD-1819 (2-((((2Z,3E)-5-hydroxy-5′-nitro-2′-oxo-[2,3′-biindolinylidene]-3-ylidene)amino)oxy)ethan-1-aminium chloride) for two major biological activities: cell plasticity and anti-cancer activity. Biological assays indicated that LDD-1819 induced somatic cell plasticity. LDD-1819 potentiated myoblast reprogramming into osteogenic cells and fibroblast reprogramming into adipogenic cells. Interestingly, in an assay of skeletal muscle dedifferentiation, LDD-1819 induced human muscle cellularization and blocked residual proliferative activity to produce a population of mononuclear refractory cells, which is also observed in the early stages of limb regeneration in urodele amphibians. In cancer cell lines, LDD-1819 treatment inhibited cell invasion and selectively induced apoptosis compared to normal cells. In an animal tumor xenograft model, LDD-1819 reduced human cancer cell metastasis in vivo at doses that did not produce toxicity. Biochemical assays showed that LDD-1819 possessed inhibitory activity against glycogen synthase kinase-3β, which is linked to cell plasticity, and aurora kinase, which regulates carcinogenesis. These results indicate that novel indirubin derivative LDD-1819 is a dual inhibitor of glycogen synthase kinase-3β and aurora A kinase, and has potential for development as an anti-cancer drug or as a reprogramming agent for cell-therapy based approaches to treat degenerative diseases.     

Gene-targeted and site-directed mutagenesis of photosynthesis genes in cyanobacteria

This historical minireview traces the development and application of methods for gene-targeted and site-directed mutagenesis of photosynthesis genes in cyanobacteria (mainly Synechocystis sp. PCC 6803). This approach allowed important data to be obtained on the structure and function of Photosystem I and Photosystem II complexes. I describe some of the major contributions of molecular genetics and subsequent mutant analysis in the 1980s and early 1990s that led to substantial advances in our knowledge of basic principles regarding the organization of the photosynthetic apparatus. This molecular-genetic research on cyanobacteria has initiated a fresh wave of photosynthesis research and created a solid foundation for rapid progress at the threshold of the twenty-first century. This revised version was published online in June 2006 with corrections to the Cover Date.     

Composition of volatiles of banana cultivars from Madeira Island

The composition of the volatiles of banana fruit from various cultivars grown on Madeira Island has been determined. Using GC-MS, the volatiles were shown to be complex mixtures of several classes of components, mainly esters, alcohols, aldehydes, ketones and acids. The average contents of the total volatiles from cultivars "Dwarf Cavendish", "Giant Cavendish", "Robusta" and "Williams" were 93.0, 116.5, 157.3 and 157.0 mg/kg, respectively. The ester and alcoholic fractions appear to play a decisive role in the organoleptic characteristics of banana fruit, presenting a substantial content ranging from 57.2 to 89.8 mg/ kg and 19.0 to 47.7 mg/kg, respectively, in all cultivars from Madeira Island studied. 3-Methyl butyl butanoate ester was the major constituent.