Accelerating the clearance of mutant huntingtin protein aggregates through autophagy induction by europium hydroxide nanorods

Autophagy is one of the well-known pathways to accelerate the clearance of protein aggregates, which contributes to the therapy of neurodegenerative diseases. Although there are numerous reports that demonstrate the induction of autophagy with small molecules including rapamycin, trehalose and lithium, however, there are few reports mentioning the clearance of aggregate-prone proteins through autophagy induction by nanoparticles. In the present article, we have demonstrated that europium hydroxide [Eu^III(OH)₃] nanorods can reduce huntingtin protein aggregation (EGFP-tagged huntingtin protein with 74 polyQ repeats), responsible for neurodegenerative diseases. Again, we have found that these nanorods induce authentic autophagy flux in different cell lines (Neuro 2a, PC12 and HeLa cells) through the expression of higher levels of characteristic autophagy marker protein LC3-II and degradation of selective autophagy substrate/cargo receptor p62/SQSTM1. Furthermore, depression of protein aggregation clearance through the autophagy blockade has also been observed by using specific inhibitors (wortmannin and chloroquine), indicating that autophagy is involved in the degradation of huntingtin protein aggregation. Since [Eu^III(OH)₃] nanorods can enhance the degradation of huntingtin protein aggregation via autophagy induction, we strongly believe that these nanorods would be useful for the development of therapeutic treatment strategies for various neurodegenerative diseases in near future using nanomedicine approach.     

Hematological and plasma biochemistry in Cirrhinus mrigala (Hamilton 1822)

Hematological and plasma chemistry indices are important parameters for the evaluation of fish physiological status. In this study, we determined the results of selected hematological and plasma biochemical profiles in Cirrhinus mrigala captured from the wild in a tropical climate of India. Blood was analyzed using standard techniques, and differences in hematological parameters including hemoglobin concentration, erythrocyte count, total leukocyte count, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) of fish were compared according to sex and different seasons. Analysis of variance showed that there were significant differences (p?<?0.05) between sexes, and the results indicated that blood parameters levels between the sexes in summer were significantly different than that measure in other seasons except MCH and MCHC value. The number of total leukocyte levels was found to be higher in female fish especially in reproductive seasons (summer), but the levels of hemoglobin, hematocrit, and MCV values were high in male fish in an annual period. However, there was no difference in MCH and MCHC values between the sexes and seasons throughout the study period. These may be related to season of sampling and changing physiological cycles during these months. Differences were noted in plasma lipid, cholesterol, and glucose level in the summer season, but the higher amount of plasma protein was found in spring and winter in male and female fish, respectively. In conclusion, monitoring fish hematological and biochemical parameters essentially can be a way to evaluate the physiological and health status of their populations, which may be a useful indicator of the environmental status.     

A magnetically separable and recyclable g-C3N4/Fe3O4/porous ruthenium nanocatalyst for the photocatalytic degradation of water-soluble aromatic amines and azo dyes

Herein, we present the development of a visible-light-driven magnetically retrievable nanophotocatalyst made of porous ruthenium nanoparticles supported on magnetic carbon nitride (g-C₃N₄/Fe₃O₄/p-RuNP) for the facile removal/degradation of aromatic amines and azo dyes from wastewater. Aromatic amines and azo-based dyes in water bodies are highly toxic and carcinogenic even at very low concentrations and are difficult to separate because of their high solubility. Our nanocatalyst can efficiently degrade/decompose the aromatic amines and azo dyes under visible light (LED/sunlight) at room temperature and in a wide pH range (pH 5.0–9.0) without using any external chemicals. The magnetic property of the nanocatalyst facilitates its efficient and facile separation from the reaction mixture for reuse in multiple photocatalytic cycles. The nanocatalyst-based degradation of azo dyes and aromatic amines presented here is simple and convenient in terms of efficiency, energy, reusability and cost. The process also does not require any external chemicals and forms gaseous/less harmful end products.

A magnetically separable and recyclable g-C₃N₄/Fe₃O₄/porous ruthenium nanocatalyst display excellent photocatalytic degradation of water-soluble aromatic amines and azo dyes at ambient condition.     

Achieving highly efficient and selective cesium extraction using 1,3-di-octyloxycalix[4]arene-crown-6 in n-octanol based solvent system: experimental and DFT investigation

Due to the long half-life of ¹³⁷Cs (t_1/2 ∼ 30 years), the selective extraction of cesium (Cs) from high level liquid waste is of paramount importance in the back end of the nuclear fuel cycle to avoid long term surveillance of high radiotoxic waste. As 1,3-di-octyloxycalix[4]arene-crown-6 (CC6) is suggested to be a promising candidate for selective Cs extraction, the improvement in the Cs extraction efficiency by CC6 has been investigated through the optimization of the effect of dielectric media on the extraction process. The effects of the feed acid (HNO₃, HCl, and HClO₄) and the composition of the diluents for the ligand in the organic phase on the extraction efficiency of Cs have been investigated systematically. In 100% n-octanol medium, Cs is found to form a 1 : 1 ion-pair complex with CC6 (0.03 M) providing a very high distribution ratio of D_Cs ∼ 22, suggesting n-octanol as the most suitable diluent for Cs extraction. No significant interference of other relevant cations such as Na, Mg and Sr was observed on the D_Cs value in the optimized solvent system. Density functional theory (DFT) based calculations have been carried out to elucidate the reason of ionic selectivity and enhanced Cs extraction efficiency of CC6 in the studied diluent systems. In addition to the ionic size-based selectivity of the crown-6 cavity, the polarity of the organic solvent system, the hydration energy of the ion, and the relative reorganization of CC6 upon complexation with Cs are understood to have roles in achieving the enhanced efficiency for the extraction of Cs by the CC6 extractant in nitrobenzene medium.

Separation scheme was developed for selective extraction of long-lived fission product ¹³⁷Cs using substituted calix crown 6 ether from aqueous acidic solution.     

Isolation and study of insulin activated nitric oxide synthase inhibitory protein in acute myocardial infarction subjects

Insulin inhibits platelet aggregation through nitric oxide synthesis by stimulating platelet insulin activated nitric oxide synthase. Impaired platelet insulin activated nitric oxide synthase in acute myocardial infarction (AMI) patients had been reported and thus our aim was to identify and isolate the factors impairing insulin activated nitric oxide in acute myocardial infarction patients’ plasma and study its effect on platelets aggregation in vitro. The insulin activated nitric oxide synthase inhibitor was identified as a protein and was purified from the plasma of AMI subjects using DEAE cellulose and Sephadex G-50 column, molecular weight determined by SDS-PAGE, nitric oxide quantified by methaemoglobin method, inhibitor protein quantified in plasma by immunoblot and ELISA, platelet aggregation studies done using an aggregometer, thromboxane-A2 in the platelets determined by radioimmunoassay, ¹²⁵I-insulin radioligand binding studies done using normal subject platelets. The purified nitric oxide synthase inhibitor protein was ~66 kDa, concentration in AMI subjects’ plasma varied from 114 to 9,090 μM and was undetected in normal subjects’ plasma. The inhibitor protein competes with insulin for insulin receptor binding sites. The Incubation of the normal subject PRP with 5.0 μM inhibitor for 30 min followed by 0.4 μM ADP addition caused platelet aggregation in vitro, 130 μM aspirin or 400 μU insulin/ml addition was able to abrogate 0.4 μM ADP induced platelet aggregation even in the presence of 5.0 μM inhibitor. A potent inhibitory protein against insulin activated nitric oxide synthase in platelets appears in circulation of AMI subjects impairing nitric oxide production, potentiating ADP induced platelet aggregation and increasing the thromboxane-A2 level in platelets.     

An endogenous glycosylphosphatidylinositol-specific phospholipase D releases basic fibroblast growth factor-heparan sulfate proteoglycan complexes from human bone marrow cultures

Basic fibroblast growth factor (bFGF) is a hematopoietic cytokine that stimulates stromal and stem cell growth. It binds to a glycosylphosphatidylinositol (GPI)-anchored heparan sulfate proteoglycan on human bone marrow (BM) stromal cells. The bFGF- proteoglycan complex is biologically active and is released by addition of exogenous phosphatidylinositol-specific phospholipase C. In this study, we show the presence of an endogenous GPI-specific phospholipase D (GPI-PLD) that releases the bFGF-binding heparan sulfate proteoglycan and the variant surface glycoprotein (a model GPI-anchored protein) from BM cultures. An involvement of proteases in this process is unlikely, because released proteoglycan contained the GPI anchor component, ethanol-amine, and protease inhibitors did not diminish the release. The mechanism of release is likely to involve a GPI-PLD and not a GPI-specific phospholipase C, because the release of variant surface glycoprotein did not reveal an epitope called the cross- reacting determinant that is exposed by phospholipase C-catalyzed GPI anchor cleavage. In addition, phosphatidic acid (which is specifically a product of GPI-PLD-catalyzed anchor cleavage) was generated during the spontaneous release of the GPI-anchored variant surface glycoprotein. We also detected GPI-PLD-specific enzyme activity and mRNA in BM cells. Therefore, we conclude that an endogenous GPI-PLD releases bFGF-heparan sulfate proteoglycan complexes from human BM cultures. This mechanism of GPI anchor cleavage could be relevant for mobilizing biologically active bFGF in BM. An endogenous GPI-PLD could also release other GPI-anchored proteins important for hematopoiesis and other physiologic processes.     

Targeted specific inhibition of bacterial and Candida species by mesoporous Ag/Sn–SnO2 composite nanoparticles: in silico and in vitro investigation

Invasive bacterial and fungal infections have notably increased the burden on the health care system and especially in immune compromised patients. These invasive bacterial and fungal species mimic and interact with the host extracellular matrix and increase the adhesion and internalization into the host system. Further, increased resistance of traditional antibiotics/antifungal drugs led to the demand for other therapeutics and preventive measures. Presently, metallic nanoparticles have wide applications in health care sectors. The present study has been designed to evaluate the advantage of Ag/Sn–SnO₂ composite nanoparticles over the single oxide/metallic nanoparticles. By using in silico molecular docking approaches, herein we have evaluated the effects of Ag/Sn–SnO₂ nanoparticles on adhesion and invasion responsible molecular targets such as LpfD (E. coli), Als3 (C. albicans) and on virulence/resistance causing PqsR (P. aeruginosa), RstA (Bmfr) (A. baumannii), FoxA (K. pneumonia), Hsp90 and Cyp51 (C. albicans). These Ag/Sn–SnO₂ nanoparticles exhibited higher antimicrobial activities, especially against the C. albicans, which are the highest ever reported results. Further, Ag/Sn–SnO₂ NPs exhibited interaction with the heme proionate residues such as Lys143, His468, Tyr132, Arg381, Phe105, Gly465, Gly464, Ile471 and Ile304 by forming hydrogen bonds with the Arg 381 residue of lanosterol 1 4α-demethylase and increased the inhibition of the Candida strains. Additionally, the Ag/Sn–SnO₂ nanoparticles exhibited extraordinary inhibitory properties by targeting different proteins of bacteria and Candida species followed by several molecular pathways which indicated that it can be used to eliminate the resistance to traditional antibiotics.

Mesoporous Ag/Sn–SnO₂ composite nanoparticles exhibits extraordinary inhibitory properties by targeting different proteins of bacteria and Candida species which can be used to eliminate the resistance of traditional antibiotics.     

Modulation of in vitro eosinophil progenitors by hydrocortisone: role of accessory cells and interleukins

The growth of human eosinophil progenitors (CFU-Eo) and the modulation of growth by hydrocortisone were studied as functions of the presence of lymphocytes and monocytes in marrow cells under study; and the source of colony-stimulating factors, specifically, media conditioned by macrophage-like cell line, GCT; phytohemagglutinin-stimulated mononuclear cells (PHA-LCM); or the T cell line, MO. CFU-Eo growth was greatest in marrow containing accessory cells as compared to marrow depleted of accessory cells; and in marrow treated with phytohemagglutinin-stimulated leukocyte conditioned media (PHA-LCM) or MO (T cell line)-conditioned medium (MO-CM) as compared with GCT cell- conditioned medium (GCT-CM). Hydrocortisone reproducibly inhibited eosinophil progenitor growth in unfractionated marrow stimulated by GCT- CM. This effect was abrogated by admixing irradiated mononuclear cells or T lymphocytes with the target marrow or by adding interleukin 1 or interleukin 2 (IL-1, IL-2). Inhibition by hydrocortisone did not occur when monocyte and T lymphocyte depleted marrow was studied. Unlike GCT- CM, MO-CM and PHA-LCM stimulated equal proportions of eosinophil progenitors in nondepleted and accessory cell-depleted marrow and demonstrated less hydrocortisone inhibition. However, both GCT-CM and PHA-LCM produced in the presence of hydrocortisone stimulated significantly fewer CFU-Eos in both unfractionated and accessory cell- depleted marrow target populations. These results indicate that the growth of CFU-Eo and inhibition of growth by hydrocortisone is a direct function of a monocyte-T cell interaction and probably is mediated through effects on the production/release of eosinophil colony stimulating factor (Eo-CSF).