Effect of C-2 substitution on the stability of non-traditional cephalosporins in mouse plasma.
Ontology highlight
ABSTRACT:
SUBMITTER: Zimmerman M
PROVIDER: S-EPMC7255492 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:In this work, a novel total non-ionic polystyrene-polyurethane (PS-PU) composite latex was synthesized with polymerizable polyethylene glycol ether. Contrary to traditional styrene-butyl acrylate latex (St-BA), PS-PU has a smaller size and superior dispersion stability, and it is stable in saturated Ca(OH)2 even after 72 h. In fresh-mixed mortars, PS-PU showed a little adverse effect on workability and insignificant air entrainment, with little defoamer consumption. The retardation effect of PS-PU is also much milder than traditional St-BA. As for strength, PS-PU showed a less adverse effect on early and late age compressive strength, but its effect on flexural strength is not as pronounced as St-BA at high dosages (4% and 6%). The different behavior in cementitious materials between PS-PU and St-BA can be reasoned from their different adsorption behavior and surface charge properties, as the results from characterizations suggest. The non-ionic nature of PS-PU made it less prone to destabilization and adsorption, which turned out as the aforementioned behavior in cementitious systems. The difference can further be ascribed to the difference in their polymeric structure and properties.
| S-EPMC9458191 | biostudies-literature
Project description:Classically, β-lactams need an ionizable group to potentiate antibacterial activity. Sets of cephalosporins and penicillins featuring different substituted hydroxamates in place of the traditional carboxylate group have been synthesized and tested for antibiotic activity. Many of the compounds exhibited anti-bacterial activities with notable MIC values in the range of 6-0.2 μM.
| S-EPMC5329033 | biostudies-literature
Project description:Pim-1 kinase, a serine/threonine protein kinase encoded by the pim proto-oncogene, is involved in several signalling pathways such as the regulation of cell cycle progression and apoptosis. Many cancer types show high expression levels of Pim kinases and particularly Pim-1 has been linked to the initiation and progression of the malignant phenotype. In several cancer tissues somatic Pim-1 mutants have been identified. These natural variants are nonsynonymous single nucleotide polymorphisms, variations of a single nucleotide occurring in the coding region and leading to amino acid substitutions. In this study we investigated the effect of amino acid substitution on the structural stability and on the activity of Pim-1 kinase. We expressed and purified some of the mutants of Pim-1 kinase that are expressed in cancer tissues and reported in the single nucleotide polymorphisms database. The point mutations in the variants significantly affect the conformation of the native state of Pim-1. All the mutants, expressed as soluble recombinant proteins, show a decreased thermal and thermodynamic stability and a lower activation energy values for kinase activity. The decreased stability accompanied by an increased flexibility suggests that Pim-1 variants may be involved in a wider network of protein interactions. All mutants bound ATP and ATP mimetic inhibitors with comparable IC50 values suggesting that the studied Pim-1 kinase mutants can be efficiently targeted with inhibitors developed for the wild type protein.
| S-EPMC3673989 | biostudies-literature
Project description:BackgroundPatients with chronic kidney disease (CKD) experience high rates of atherosclerotic cardiovascular disease and death that are not fully explained by traditional risk factors. In animal studies, defective cellular cholesterol efflux pathways which are mediated by the ATP binding cassette transporters ABCA1 and ABCG1 are associated with accelerated atherosclerosis. We hypothesized that cholesterol efflux in humans would vary in terms of cellular components, with potential implications for cardiovascular disease.MethodsWe recruited 120 CKD patients (eGFR<30mL/min/1.73m2) and 120 control subjects (eGFR ≥60mL/min/1.73m2) in order to measure cholesterol efflux using either patients' HDL and THP-1 macrophages or patients' monocytes and a flow cytometry based cholesterol efflux assay. We also measured cell-surface levels of the common β subunit of the IL-3/GM-CSF receptor (IL-3Rβ) which has been linked to defective cholesterol homeostasis and may promote monocytosis. In addition, we measured plasma inflammatory cytokines and plasma metabolite profiles.ResultsThere was a strong positive correlation between cell-surface IL-3Rβ levels and monocyte counts in CKD (P<0.001). ABCA1 mRNA was reduced in CKD vs. control monocytes (P<0.05), across various etiologies of CKD. Cholesterol efflux to apolipoprotein A1 was impaired in monocytes from CKD patients with diabetic nephropathy (P<0.05), but we found no evidence for a circulating HDL-mediated defect in cholesterol efflux in CKD. Profiling of plasma metabolites showed that medium-chain acylcarnitines were both independently associated with lower levels of cholesterol transporter mRNA in CKD monocytes at baseline (P<0.05), and with cardiovascular events in CKD patients after median 2.6years of follow-up.ConclusionsCholesterol efflux in humans varies in terms of cellular components. We report a cellular defect in ABCA1-mediated cholesterol efflux in monocytes from CKD patients with diabetic nephropathy. Unlike several traditional risk factors for atherosclerotic cardiovascular disease, plasma metabolites inversely associated with endogenous cholesterol transporters predicted cardiovascular events in CKD patients. (Funded by the National Institute of Diabetes and Digestive and Kidney DiseasesK23DK097288 and others.).
| S-EPMC5708851 | biostudies-literature
Project description:Non-thermal plasma (NTP) has been studied as a novel therapeutic tool for cancer that does not damage healthy cells. In this study, we show that NTP-treated solutions (NTS) can induce death in various leukemia cells through mechanistic target of rapamycin (mTOR) ubiquitination. Previously, we manufactured and demonstrated the efficacy of NTS in solid cancers. NTS did not exhibit any deleterious side effects, such as acute death or weight loss in nude mice. In the present study, NTS induced cell death in myeloid leukemia cells, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). We found that mTOR was downregulated in NTS-treated cells via the ubiquitin-proteasome system (UPS). We also identified 'really interesting new gene' finger protein 126 (RNF126) as a novel binding protein for mTOR through protein arrays and determined the role of E3 ligase in NTS-induced mTOR ubiquitination. NTS-derived reactive oxygen species (ROS) affected RNF126 expression and lysosomal dysfunction. These findings suggest that NTS has potential antileukemic effects through RNF126-mediated mTOR ubiquitination with no deleterious side effects. Thus, NTS may represent a new therapeutic method for chemotherapy-resistant leukemia.
| S-EPMC7140413 | biostudies-literature
Project description:We have performed selective plasma exchange (SePE) as apheresis before ABO-incompatible kidney transplantation since 2015. In this study, we divided the SePE sessions into two groups, those using albumin alone (Group A) and those partially using fresh frozen plasma (FFP) (Group F), and compared their clinical efficacies. A total of 58 sessions of SePE (Group A: n?=?41, Group F: n?=?17) were performed in 30 recipients of ABOi kidney transplantation during the study period and the decrease in isoagglutinin titers, changes in the levels of serum IgG and IgM as well as coagulation factors (fibrinogen, factor XIII), and incidence of side effects were retrospectively compared. There was a more significant decrease of isoagglutinin titers in Group F compared to Group A. Immunoglobulins and coagulants were replenished in Group F. Meanwhile, the incidence of side effects was significantly higher in Group F. SePE using FFP, which can effectively decrease isoagglutinins titers and replenish immunoglobulin and coagulation factors, may be a beneficial treatment modality as apheresis before ABO-incompatible kidney transplantation, in spite of a disadvantage that there are many side effects.
| S-EPMC6989510 | biostudies-literature
Project description:Dystrophic epidermolysis bullosa, a severely disabling hereditary skin fragility disorder, is caused by mutations in the gene coding for collagen VII, a specialized adhesion component of the dermal-epidermal junction zone. Both recessive and dominant forms are known; the latter account for about 40% of cases. Patients with dominant dystrophic epidermolysis bullosa exhibit a spectrum of symptoms ranging from mild localized to generalized skin manifestations. Individuals with the same mutation can display substantial phenotypic variance, emphasizing the role of modifying genes in this disorder. The etiology of dystrophic epidermolysis bullosa has been known for around two decades; however, important pathogenetic questions such as involvement of modifier genes remain unanswered and a causative therapy has yet to be developed. Much of the failure to make progress in these areas is due to the lack of suitable animal models that capture all aspects of this complex monogenetic disorder. Here, we report the first rat model of dominant dystrophic epidermolysis bullosa. Affected rats carry a spontaneous glycine to aspartic acid substitution, p.G1867D, within the main structural domain of collagen VII. This confers dominant-negative interference of protein folding and decreases the stability of mutant collagen VII molecules and their polymers, the anchoring fibrils. The phenotype comprises fragile and blister-prone skin, scarring and nail dystrophy. The model recapitulates all signs of the human disease with complete penetrance. Homozygous carriers of the mutation are more severely affected than heterozygous ones, demonstrating for the first time a gene-dosage effect of mutated alleles in dystrophic epidermolysis bullosa. This novel viable and workable animal model for dominant dystrophic epidermolysis bullosa will be valuable for addressing molecular disease mechanisms, effects of modifying genes, and development of novel molecular therapies for patients with dominantly transmitted skin disease.
| S-EPMC3662756 | biostudies-literature
Project description:The stability of host–guest complexes of two NSAID drugs with similar physicochemical properties, fenbufen and fenoprofen, was investigated by comparing induced circular dichroism and 1H nuclear magnetic resonance methods using eight cyclodextrins of different degrees of substitution and isomeric purity as guest compounds. These cyclodextrins include native β-cyclodextrin (BCyD), 2,6-dimethyl-β-cyclodextrin 50 (DIMEB50), 80 (DIMEB80) and 95% (DIMEB95) isomerically pure versions, low-methylated CRYSMEB, randomly methylated β-cyclodextrin (RAMEB) and 4.5 and 6.3 average substitution grade hydroxypropyl-β-cyclodextrin (HPBCyD). The stability constants obtained by the two methods show good agreement in most cases. For fenbufen complexes, there is a clear trend that the stability constant increases with the degree of substitution while isomer purity has a smaller effect on the magnitude of stability constants. A significant difference was found in the case of DIMEB50 when compared to DIMEB80/DIMEB95, while the latter two are similar. In the fenbufen–fenoprofen comparison, fenbufen, with its linear axis, gives a more stable complex, while fenoprofen shows lower constants and poorly defined trends.
| S-EPMC10139022 | biostudies-literature
Project description:The study investigates the antitumor effect of two cationic peptides, R-DIM-P-LF11-215 (RDP215) and the D-amino acid variant 9D-R-DIM-P-LF11-215 (9D-RDP215), targeting the negatively charged lipid phosphatidylserine (PS) exposed by cancer cells, such as of melanoma and glioblastoma. Model studies mimicking cancer and non-cancer membranes revealed the specificity for the cancer-mimic PS by both peptides with a slightly stronger impact by the D-peptide. Accordingly, membrane effects studied by DSC, leakage and quenching experiments were solely induced by the peptides when the cancer mimic PS was present. Circular dichroism revealed a sole increase in β-sheet conformation in the presence of the cancer mimic for both peptides; only 9D-RDP215 showed increased structure already in the buffer. Ex vitro stability studies by SDS-PAGE as well as in vitro with melanoma A375 revealed a stabilizing effect of D-amino acids in the presence of serum, which was also confirmed in 2D and 3D in vitro experiments on glioblastoma LN-229. 9D-RDP215 was additionally able to pass a BBB model, whereupon it induced significant levels of cell death in LN-229 spheroids. Summarized, the study encourages the introduction of D-amino acids in the design of antitumor peptides for the improvement of their stable antitumor activity.
| S-EPMC8395111 | biostudies-literature
Project description:This study investigates the effect of substitution with different functional groups and of molecular flexibility by changing within the axle from a single C-C bond to a double C=C bond. Therefore, we present static quantum chemical calculations at the dispersion-corrected density functional level (DFT-D3) for several Leigh-type rotaxanes. The calculated crystal structure is in close agreement with the experimental X-ray data. Compared to a stiffer axle, a more flexible one results in a stronger binding by 1-3 kcal/mol. Alterations of the binding energy in the range of 5 kcal/mol could be achieved by substitution with different functional groups. The hydrogen bond geometry between the isophtalic unit and the carbonyl oxygen atoms of the axle exhibited distances in the range of 2.1 to 2.4 Å for six contact points, which shows that not solely but to a large amount the circumstances in the investigated rotaxanes are governed by hydrogen bonding. Moreover, the complex with the more flexible axle is usually more unsymmetrical than the one with the stiff axle. The opposite is observed for the experimentally investigated axle with the four phenyl stoppers. Furthermore, we considered an implicit continuum solvation model and found that the complex binding is weakened by approximately 10 kcal/mol, and hydrogen bonds are slightly shortened (by up to 0.2 Å).
| S-EPMC4077404 | biostudies-literature