Chemical Proteomics-Based Analysis of Off-target Binding Profiles for Rosiglitazone and Pioglitazone: Clues for Assessing Potential for Cardiotoxicity

Drugs exert desired and undesired effects based on their binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug selective for a given target—in this case, PPARγ. Herein, we report a retrospective analysis of two variants of the glitazone scaffold, pioglitazone and rosiglitazone, in an effort to identify off-target binding events in the rat heart to explain recently reported cardiovascular risk associated with these drugs. Our results suggest that glitazone has affinity for dehydrogenases, consistent with known binding preferences for related rhodanine cores. Both drugs bound ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additional proteins involved in glucose homeostasis, synaptic transduction, and mitochondrial energy production were detected and potentially contribute to drug efficacy and cardiotoxicity

Links Between Hydrothermal Environments, Pyrophosphate, Na+, and Early Evolution

The discovery that photosynthetic bacterial membrane-bound inorganic pyrophosphatase (PPase) catalyzed light-induced phosphorylation of orthophosphate (Pi) to pyrophosphate (PPi) and the capability of PPi to drive energy requiring dark reactions supported PPi as a possible early alternative to ATP. Like the proton-pumping ATPase, the corresponding membrane-bound PPase also is a H+-pump, and like the Na+-pumping ATPase, it can be a Na+-pump, both in archaeal and bacterial membranes. We suggest that PPi and Na+ transport preceded ATP and H+ transport in association with geochemistry of the Earth at the time of the origin and early evolution of life. Life may have started in connection with early plate tectonic processes coupled to alkaline hydrothermal activity. A hydrothermal environment in which Na+ is abundant exists in sediment-starved subduction zones, like the Mariana forearc in the W Pacific Ocean. It is considered to mimic the Archean Earth. The forearc pore fluids have a pH up to 12.6, a Na+-concentration of 0.7 mol/kg seawater. PPi could have been formed during early subduction of oceanic lithosphere by dehydration of protonated orthophosphates. A key to PPi formation in these geological environments is a low local activity of water

The role of MgBr2 to enhance the ionic conductivity of PVA/PEDOT:PSS polymer composite

A solid polymer electrolyte system based on poly(vinyl alcohol) (PVA) and poly(3,4-Etylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) complexed with magnesium bromide (MgBr2) salt was prepared using solution cast technique. The ionic conductivity is observed to increase with increasing MgBr2 concentration. The maximum conductivity was found to be 9.89 × 10−6 S/cm for optimum polymer composite film (30 wt.% MgBr2) at room temperature. The increase in the conductivity is attributed to the increase in the number of ions as the salt concentration is increased. This has been proven by dielectric studies. The increase in conductivity is also attributable to the increase in the fraction of amorphous region in the electrolyte films as confirmed by their structural, thermal, electrical and optical properties

Experimental identification of the actinosporean stage of Sphaerospora renicola Dykova & Lom 1982 (Myxosporea: Sphaerosporidae) in oligochaete alternate hosts

The extrapiscine development of Sphaerospora renicola, a myxosporean parasite of the kidney of common carp, Cyprinus carpio L., was studied in the experimentally infected oligochaetes Tubifex tubifex (Muller) and Branchiura sowerbyi (Beddard). After the infection of these tubificids with homogenized common carp kidneys containing myxospores of S. renicola, the development of actinosporean stages was first observed under light microscopy 8 days after infection in pathogen-free T. tubifex. Infection of B, sowerbyi with mature actinosporean stages was first observed 91 days after infection. At that stage of development, pansporocysts containing neoactinospores filled the intestinal epithelium of the worm. Ninety-five days after infection, pansporocysts containing actinospores and free actinospores were found in the gut lumen of B. sowerbyi. Actinospores of S. renicola emerged from B. sowerbyi after 98 days of intraoligochaete development. These were floating in the water and showed the typical form of neoactinospores. The shape of the spores was triangular in apical view and elliptical in lateral view. The prevalence of infection reached 37%. Control specimens of B. sowerbyi proved to be free of neoactinospores. Except for a single specimen of B. sowerbyi, the only early developmental stages (pansporocysts) were found in T. tubifex

The role of copepods (Cyclops spp.) in eliminating the actinospore stages of fish-parasitic myxozoans

The actinospore consumption of copepods ( Cyclops spp.) was demonstrated by laboratory observations. It was observed that in experimental dishes the number of actinospores floating in the water decreased, or such actinospores were completely eliminated, in the presence of copepods. The ingestion of actinospores by copepods and their further fate were monitored by fluorescent staining and by conventional histological techniques. The actinospores were observed to have got caught on the filters of Cyclops spp. Two and a half hours after the copepods had been placed into water containing actinospores, their digestive tract was found to contain spores that had extruded their filaments from the polar capsules. After copepods having ingested the actinospores of the species Myxobolus pseudodispar had been fed to roaches, no muscle infection developed in the fish host. It is likely that Cyclops spp. can filter out actinospores floating in the water also from natural waters, thus decreasing the chance of development of myxosporean infections