Targeting Prostate Tumor Low-Molecular Weight Tyrosine Phosphatase for Oxidation-Sensitizing Therapy

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the ACP1 gene-is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr270. PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2-mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress

Hyperglycemia and Diabetes Downregulate the Functional Expression of TRPV4 Channels in Retinal Microvascular Endothelium

Retinal endothelial cell dysfunction is believed to play a key role in the etiology and pathogenesis of diabetic retinopathy. Numerous studies have shown that TRPV4 channels are critically involved in maintaining normal endothelial cell function. In the current paper, we demonstrate that TRPV4 is functionally expressed in the endothelium of the retinal microcirculation and that both channel expression and activity is downregulated by hyperglycaemia. Quantitative PCR and immunostaining demonstrated molecular expression of TRPV4 in cultured bovine retinal microvascular endothelial cells (RMECs). Functional TRPV4 activity was assessed in cultured RMECs from endothelial Ca2+-responses recorded using fura-2 microfluorimetry and electrophysiological recordings of membrane currents. The TRPV4 agonist 4α-phorbol 12,13-didecanoate (4-αPDD) increased [Ca2+]i in RMECs and this response was largely abolished using siRNA targeted against TRPV4. These Ca2+-signals were completely inhibited by removal of extracellular Ca2+, confirming their dependence on influx of extracellular Ca2+. The 4-αPDD Ca2+-response recorded in the presence of cyclopiazonic acid (CPA), which depletes the intracellular stores preventing any signal amplification through store release, was used as a measure of Ca2+-influx across the cell membrane. This response was blocked by HC067047, a TRPV4 antagonist. Under voltage clamp conditions, the TRPV4 agonist GSK1016790A stimulated a membrane current, which was again inhibited by HC067047. Following incubation with 25 mM D-glucose TRPV4 expression was reduced in comparison with RMECs cultured under control conditions, as were 4αPDD-induced Ca2+-responses in the presence of CPA and ion currents evoked by GSK1016790A. Molecular expression of TRPV4 in the retinal vascular endothelium of 3 months' streptozotocin-induced diabetic rats was also reduced in comparison with that in age-matched controls. We conclude that hyperglycaemia and diabetes reduce the molecular and functional expression of TRPV4 channels in retinal microvascular endothelial cells. These changes may contribute to diabetes induced endothelial dysfunction and retinopathy

Cotton in the new millennium: advances, economics, perceptions and problems

Cotton is the most significant natural fibre and has been a preferred choice of the textile industry and consumers since the industrial revolution began. The share of man-made fibres, both regenerated and synthetic fibres, has grown considerably in recent times but cotton production has also been on the rise and accounts for about half of the fibres used for apparel and textile goods. To cotton’s advantage, the premium attached to the presence of cotton fibre and the general positive consumer perception is well established, however, compared to commodity man-made fibres and high performance fibres, cotton has limitations in terms of its mechanical properties but can help to overcome moisture management issues that arise with performance apparel during active wear. This issue of Textile Progress aims to: i. Report on advances in cotton cultivation and processing as well as improvements to conventional cotton cultivation and ginning. The processing of cotton in the textile industry from fibre to finished fabric, cotton and its blends, and their applications in technical textiles are also covered. ii. Explore the economic impact of cotton in different parts of the world including an overview of global cotton trade. iii. Examine the environmental perception of cotton fibre and efforts in organic and genetically-modified (GM) cotton production. The topic of naturally-coloured cotton, post-consumer waste is covered and the environmental impacts of cotton cultivation and processing are discussed. Hazardous effects of cultivation, such as the extensive use of pesticides, insecticides and irrigation with fresh water, and consequences of the use of GM cotton and cotton fibres in general on the climate are summarised and the effects of cotton processing on workers are addressed. The potential hazards during cotton cultivation, processing and use are also included. iv. Examine how the properties of cotton textiles can be enhanced, for example, by improving wrinkle recovery and reducing the flammability of cotton fibre

Computational design of self-assembling cyclic protein homo-oligomers

Self-assembling cyclic protein homo-oligomers play important roles in biology, and the ability to generate custom homo-oligomeric structures could enable new approaches to probe biological function. Here we report a general approach to design cyclic homo-oligomers that employs a new residue-pair-transform method to assess the designability of a protein-protein interface. This method is sufficiently rapid to enable the systematic enumeration of cyclically docked arrangements of a monomer followed by sequence design of the newly formed interfaces. We use this method to design interfaces onto idealized repeat proteins that direct their assembly into complexes that possess cyclic symmetry. Of 96 designs that were characterized experimentally, 21 were found to form stable monodisperse homo-oligomers in solution, and 15 (four homodimers, six homotrimers, six homotetramers and one homopentamer) had solution small-angle X-ray scattering data consistent with the design models. X-ray crystal structures were obtained for five of the designs and each is very close to their corresponding computational model

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Polyethelene Glycol-Anthranilic Acid Composite as Corrosion Inhibitor for Mild Steel in Acid Medium

The polymer PGA composite was prepared by chemical oxidative method of polyethylene glycol, anthranilic acid with ammonium persulphate in oxalic acid medium. The resulted polymer was characterized by FTIR spectroscopy. The performance of the polymer polyglycol anthranilic acid composite (PGA) as corrosion inhibitor for mild steel in 1 M HCl has been studied by weight loss, potentiodynamic and impedance spectroscopy methods. The maximum IE was found to be 97%. Experimental results were fitted to Langmuir adsorption isotherm. Electrochemical studies confirmed the inhibitive nature of the PGA composite and also the mixed nature of the inhibitor. The polymer is found to be highly efficient non-toxic and environmentally safe

Polyethelene Glycol-Anthranilic Acid Composite as Corrosion Inhibitor for Mild Steel in Acid Medium

The polymer PGA composite was prepared by chemical oxidative method of polyethylene glycol, anthranilic acid with ammonium persulphate in oxalic acid medium. The resulted polymer was characterized by FTIR spectroscopy. The performance of the polymer polyglycol anthranilic acid composite (PGA) as corrosion inhibitor for mild steel in 1 M HCl has been studied by weight loss, potentiodynamic and impedance spectroscopy methods. The maximum IE was found to be 97%. Experimental results were fitted to Langmuir adsorption isotherm. Electrochemical studies confirmed the inhibitive nature of the PGA composite and also the mixed nature of the inhibitor. The polymer is found to be highly efficient non-toxic and environmentally safe

Rhodium(I) and ruthenium(II) complexes with monothio-β-diketones and (mono-, di-scleno)bis(β-diketone)

885-888The treatment of the rhodium carbonylated species with monothio-β-diketonesleads to the formation of monomeric complexes of general formula [Rh(CO)2(tβdk)] (H-tβdk = mono-thio- β -diketone). The carbon monoxide group can be replaced in part by triphenylphosphine, triphenylphosphite and triphenylarsine to form complexes of the type [Rh(CO) (tβdt)L] (L = PPh3, OPPh3 and AsPh3). Further, bridged binuclear rhodium(I) and ruthenium(II) complexes of (mono- and di-seleno)bis(β-diketones) have also been prepared. All the complexes obtained have been characterised by means of analytical and spectroscopic data