- Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT [BOOK]
- BOOKNIHR Journals Library: Southampton (UK)
- CONCLUSIONS: Using a novel adaptive design, we demonstrated that there was no significant effect of telmisartan (80 mg) on the primary outcome measure of HOMA-IR and some secondary outcomes (plasma lipids and adipokines). Telmisartan did lead to favourable, and biologically plausible, changes of the secondary longitudinal outcome measures: revised QUICKI, hs-CRP, hepatic fat accumulation and urinary albumin excretion. Taken collectively, our findings showed that telmisartan did not reduce insulin resistance in patients infected with HIV on antiretrovirals.
- From early adversities to immune activation in psychiatric disorders: the role of the sympathetic nervous system. [Review]
- CEClin Exp Immunol 2019 Jul 18
- Increased peripheral levels of cytokines and central microglial activation have been reported in patients with psychiatric disorders. The degree of both innate and adaptive immune activation is also …
Increased peripheral levels of cytokines and central microglial activation have been reported in patients with psychiatric disorders. The degree of both innate and adaptive immune activation is also associated with worse clinical outcomes and poor treatment response in these patients. Understanding the possible causes and mechanisms leading to this immune activation is therefore an important and necessary step for the development of novel and more effective treatment strategies for these patients. In this manuscript, we review the evidence of literature pointing to childhood trauma as one of the main causes behind the increased immune activation in patients with psychiatric disorders. We then discuss the potential mechanisms linking the experience of early-life adversity (ELA) to innate immune activation. Specifically, we focus on the innervation of the bone marrow from sympathetic nervous system (SNS) as new and emerging mechanism that has the potential to bridge the observed increases in both central and peripheral inflammatory markers in patients exposed to ELA. Experimental studies in laboratory rodents suggest that SNS activation following early-life stress exposure causes a shift in the profile of innate immune cells, with an increase in pro-inflammatory monocytes. In turn, these cells traffic to the brain and influence neural circuitry, which manifests as increased anxiety and other relevant-behavioral phenotypes. To date however, very few studies have been conducted to explore this candidate mechanism in humans. Future research is also needed to clarify whether these pathways could be partially reversible to improve prevention and treatment strategies in the future. This article is protected by copyright. All rights reserved.
- Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury. [Journal Article]
- EJEur J Endocrinol 2019 Jul 01
- CONCLUSIONS: Fatigue and depression were common 8-10 years post childhood TBI. One individual had GHD (1/22) using rigorous diagnostic criteria. A single ITT potentially over-diagnosed GHD in 25% (6/25) without clear correlation with symptoms underlying the importance of using two diagnostic tests in TBI survivors.
- Male-biased zebrafish sex differentiation and metabolomics profile changes caused by dydrogesterone. [Journal Article]
- ATAquat Toxicol 2019 Jul 11; 214:105242
- Some progestins, including the widely used dydrogesterone (DDG), have been shown to cause male-biased sex ratio in teleost. However, there is a gap to fully understand the mechanisms of the sex diffe…
Some progestins, including the widely used dydrogesterone (DDG), have been shown to cause male-biased sex ratio in teleost. However, there is a gap to fully understand the mechanisms of the sex differentiation disturbance by progestins, particularly from the metabolic aspect. We thus aimed to examine the sex changes by exposing zebrafish embryos to 4.4 (L), 44 (M) and 440 (H) ng/L DDG for up to 140 days, and investigated metabolomic profile changes during the critical period of sex differentiation at fry stage (35 dpf). DDG increased the percentage of male zebrafish in a dose-dependent manner, with 98% male fish in the high concentration group. In zebrafish fry, DDG increased the levels of some free fatty acids, monoglycerides, acylcarnitines, organic acids, free amino acids, while decreased lysophospholipids, uric acid and bile acids. DDG exposure also decreased the nucleoside monophosphates and UDP-sugars while increased nucleosides and their bases. These metabolite changes, namely increase in n-3 PUFAs (polyunsaturated fatty acids), myo-inositol, taurine, palmitoleic acid, oleic acid, lactic acid, fumaric acid, and uracil, and decrease in uric acid and bile acids, might account for the male-biased sex ratio in zebrafish. It appears that many of these metabolites could inhibit several pathways that regulate zebrafish gonad differentiation, including NF-κB/COX-2 and Wnt/β-catenin pathways, and activate p53 pathway. Thus we proposed a hypothesis that DDG might induce oocytes apoptosis through the above pathways and finally lead to female-to-male sex reversal. The results from this study suggest that DDG at environmentally relevant concentrations could affect zebrafish metabolomic profiles and finally disturb fish sex differentiation.
- A network approach to investigate the bi-hemispheric synchrony in absence epilepsy. [Journal Article]
- CNClin Neurophysiol 2019 Jul 01; 130(9):1611-1619
- CONCLUSIONS: The transition from the interictal to the ictal state is for some of the children characterized by dominant LoC at either the parietal/occipital and for others at the frontal/temporal region.The focal onset of the SWDs varies in location among the children with a clinical similar profile, who, however, seemingly are differing with regard to seizure control.
- Discovery of new potent dual sigma receptor/GluN2b ligands with antioxidant property as neuroprotective agents. [Journal Article]
- EJEur J Med Chem 2019 Jul 08; 180:268-282
- Among several potential applications, sigma receptors (σRs) can be used as neuroprotective agents, antiamnesic, antipsychotics and against other neurodegenerative disorders. On the other hands, antag…
Among several potential applications, sigma receptors (σRs) can be used as neuroprotective agents, antiamnesic, antipsychotics and against other neurodegenerative disorders. On the other hands, antagonists of the GluN2b-subunit-containing-N-methyl-D-aspartate (NMDA) receptors are of major interest for the same purpose, being this subunit expressed in specific areas of the central nervous system and responsible for the excitatory regulation of nerve cells. Under these premises, we have synthesized and biologically tested novel hybrid derivatives obtained from the combination of phenyloxadiazolone and dihydroquinolinone scaffolds with different amine moieties, peculiar of σ2R ligands. Most of the new ligands exhibited a pan-affinity towards both σR subtypes and high affinity against GluN2b subunit. The most promising compounds belong to the dihydroquinolinone series, with the best affinity profile for the cyclohexylpiperazine derivative 28. Investigation on their biological activity showed that the new compounds were able to protect SH-SY5Y cells against oxidative stress induced by hydrogen peroxide treatment. These results proved that our dual σR/GluN2b ligands have beneficial effects in a model of neuronal oxidative stress and can represent strong candidate pharmacotherapeutic agents for minimizing oxidative stress-induced neuronal injuries.
- PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy. [Journal Article]
- CSColloids Surf B Biointerfaces 2019 Jul 13; 182:110356
- A novel triblock amphiphilic copolymer (PAL-PEG-Birinapant) was designed and synthesized as a dual-functional micellar carrier utilizing birinapant (an inhibitor of inhibitor-of-apoptosis proteins) a…
A novel triblock amphiphilic copolymer (PAL-PEG-Birinapant) was designed and synthesized as a dual-functional micellar carrier utilizing birinapant (an inhibitor of inhibitor-of-apoptosis proteins) as a pH-sensitive segment and inhibitor-of-apoptosis proteins-targeting ligand. The mixed micelles comprised of PAL-PEG-Birinapant (PPB) and mPEG2k-PDLLA2k (MPP), named as PPB/MPP (2/1,w/w) micelles were developed for enhanced solubility and antitumor potency of hydrophobic drugs as paclitaxel (PTX). In vitro cell viability and cytotoxicity studies revealed that the PTX-loaded PPB/MPP micelles were more potent than the commercial PTX formulation (Taxol®), as well as the in vitro cell apoptosis study. Clear differences in the intracellular uptake of free coumarin-6 (C6) solution and C6-loaded PPB/MPP micelles were observed and indicated that the PPB/MPP micelles could efficiently deliver chemical compound into tumor cells. PPB copolymer and PTX-loaded PPB/MPP micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of above 1.2 g copolymer/kg and above 100 mg PTX/kg in mice respectively in contrast to 20˜24 mg/kg of Taxol®. The near infrared (NIR) fluorescence imaging showed that PPB/MPP micelles persisted for a relatively long time in the circulation and accumulated preferentially in tumor tissue. Moreover, PTX loaded PPB/MPP micelles significantly inhibited the tumor growth both in MDA-MB-231 and Ramos cancer xenograft mice models without obvious toxicity. Collectively, our study presents a new dual-functional micelles that improve the therapeutic efficacy of PTX in vitro and in vivo.
- TRANSPLANTATION IN CHILDREN AND ADOLESCENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA FROM A MATCHED DONOR VERSUS AN HLA-IDENTICAL SIBLING: IS THE OUTCOME COMPARABLE? RESULTS FROM THE INTERNATIONAL BFM ALL SCT 2007 STUDY. [Journal Article]
- BBBiol Blood Marrow Transplant 2019 Jul 15
- CONCLUSIONS: Since the outcome of transplantation from a matched donor was not inferior to transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and, possibly, in other malignancies. Bone marrow should be the preferred stem cell source and the addition of MTX should be considered in MSD recipients.
- Fatty acid content and profile of the novel strain of Coccomyxa elongata (Trebouxiophyceae, Chlorophyta) cultivated at reduced nitrogen and phosphorus concentrations. [Journal Article]
- JPJ Phycol 2019 Jul 18
- A novel freshwater strain of Coccomyxa elongata (MZ-Ch64) was isolated from the Zaporizhia region, Ukraine. The identification is based on the phylogenetic analysis of SSU rDNA gene and ITS1-5.8S rDN…
A novel freshwater strain of Coccomyxa elongata (MZ-Ch64) was isolated from the Zaporizhia region, Ukraine. The identification is based on the phylogenetic analysis of SSU rDNA gene and ITS1-5.8S rDNA-ITS2 region and predicted secondary structure of the ITS2. Phylogenetic analysis places this strain in the Coccomyxa group, within the class Trebouxiophyceae. The novel strain MZ-Ch64 formed a strongly supported lineage closest with C. elongata. The MZ-Ch64 strain differed from the morphological description of the species by the size of vegetative cells and absence of small mucilaginous caps at one end of the cell. A number of experiments with different concentrations of phosphate and nitrate were conducted to evaluate changes in the resulting fatty acid profiles and biomass productivity. The fatty acid profile and total fatty acids varied significantly under different nutrient deficiencies. The dominant fatty acid during cultivation on standard BBM medium, as well as in phosphorus-depleted conditions, was oleic acid (to 48.0-54.6% of total fatty acids). Absence of nitrogen alone, and absence of both nitrogen and phosphorus, led to an increase of palmitic acid (to 24.7-25.6%), cis-7-hexadecenoic acid (to 14.8%) and α-linolenic acid (to 9.1-10.1%) in comparison with the control sample. The greatest variation was found for oleic acid (31.9-54.6%). Thus, this strain can be considered as a potential producer of oleic acid or cis-7-hexadecenoic and α-linolenic acids for biotechnological applications. This article is protected by copyright. All rights reserved.
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- Luciferase-based reporting of suicide gene activity in murine mesenchymal stem cells. [Journal Article]
- PlosPLoS One 2019; 14(7):e0220013
- Due to their ease of isolation, gene modification and tumor-homing properties, mesenchymal stem cells (MSCs) are an attractive cellular vehicle for the delivery of toxic suicide genes to a variety of…
Due to their ease of isolation, gene modification and tumor-homing properties, mesenchymal stem cells (MSCs) are an attractive cellular vehicle for the delivery of toxic suicide genes to a variety of cancers in pre-clinical models. In addition, the incorporation of suicide genes in stem cell-derived cell replacement therapies improves their safety profile by permitting graft destruction in the event of unexpected tumorigeneses or unwanted differentiation. Due to the functional requirement of ATP for the Firefly luciferase gene Luc2 to produce light, luciferase-based reporting of cytotoxicity can be engineered into potential cell therapies. Consequently, we nucleofected mammalian expression plasmids containing both the Luc2 and the yeast fusion cytosine deaminase uracil phosphoribosyltransferase (CDUPRT) genes for expression in murine MSCs to assess luciferase as a reporter of suicide gene cytotoxicity, and MSC as vehicles of suicide gene therapy. In vitro bioluminescence imaging (BLI) showed that following the addition of the non-toxic prodrug fluorocytosine (5-FC), CDUPRT-expressing MSCs displayed enhanced cytotoxicity in comparison to Luc2 reporter MSC controls. This study demonstrates the utility of luciferase as a reporter of CDUPRT-mediated cytotoxicity in murine MSC using BLI.