According to the "membrane sensor" hypothesis, the membrane's physical properties and microdomain organization play an initiating role in the heat shock response. Clinical conditions such as cancer, diabetes and neurodegenerative diseases are all coupled with specific changes in the physical state and lipid composition of cellular membranes and characterized by altered heat shock protein levels in cells suggesting that these "membrane defects" can cause suboptimal hsp-gene expression. Such observations provide a new rationale for the introduction of novel, heat shock protein modulating drug candidates. Intercalating compounds can be used to alter membrane properties and by doing so normalize dysregulated expression of heat shock proteins, resulting in a beneficial therapeutic effect for reversing the pathological impact of disease. The membrane (and lipid) interacting hydroximic acid (HA) derivatives discussed in this review physiologically restore the heat shock protein stress response, creating a new class of "membrane-lipid therapy" pharmaceuticals. The diseases that HA derivatives potentially target are diverse and include, among others, insulin resistance and diabetes, neuropathy, atrial fibrillation, and amyotrophic lateral sclerosis. At a molecular level HA derivatives are broad spectrum, multi-target compounds as they fluidize yet stabilize membranes and remodel their lipid rafts while otherwise acting as PARP inhibitors. The HA derivatives have the potential to ameliorate disparate conditions, whether of acute or chronic nature. Many of these diseases presently are either untreatable or inadequately treated with currently available pharmaceuticals. Ultimately, the HA derivatives promise to play a major role in future pharmacotherapy.
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The invention relates to a novel class of [1,4]-benzodiazepine derivatives, processes for their preparation, intermediates usable in these processes, and pharmaceutical compositions containing the compounds. Other aspects of the invention are directed to the use of said [1,4]-benzodiazepine derivatives in therapy based on the capability of said compounds to interfere with the binding of the peptide hormone, vasopressin, to its receptors. In particular as vasopressin V2 receptor antagonists and therefore useful for treating involving increased vascular resistance, cardiac insufficiency, and water retention.
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A series of new, easily synthesized C60-fullerene derivatives is introduced that allow for optimization of the interactions between rr-P3HT and the fullerene by systematic variation of the size of the ester group. Two compounds gave overall cell efficiencies of 4.8%, clearly outperforming [60]PCBM which gives 4.3% under identical conditions.
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Using the reversed phase high performance liquid chromatography with diode-array and massspectrometric (in ESI mode) detection, a composition of Catharanthus roseum petals was established. After the acid hydrolysis, all five anthocyanidins were found to be different comparing to the ordinary anthocyanidins from Vitis vinifera fruits. The anthocyanins were elucidated to be 7-O-methyl derivatives of delphinidin, cyanidin, petunidin, peonidin and malvidin by the analysis of retention in RP HPLC, mass- and UV-visible spectra.The anthocyanins were characterized with UV-visible spectra, having the same fixtures as the set of nonmethylated (in position 7) anthocyanin with hypsochromic (4 nm) of spectral maxima. The absorption bands for 7-methylcyanidin and 7-methylpeonidin aglycons and derivatives were indistinguishable while for the set of 7-methydelphinidin, 7-methypetunidin and 7-methylmalvidine (hirsutidin) a consecutive shift of absorption maximaby approximately 1 – 1.5 nm was found. The same was true for non-methylates at position 7 derivatives. The analysis of retention of anthocyanins of the flowers including the comparison with the retention of Mangifera indica skin anthocyanins, mass- and UV-visible spectra indicated that a minor set of anthocyanins included two sets of derivatives. The minor compounds were found to be 3-galactosides for samples under investigation, while the set of the major anthocyanins was represented by 3-rhamnosylgalactosides. Indeed, though through mass-spectra it was not possible to differentiate 3-rhamnosylgalatosides and 3-(p-coumaroylgalactosides) because of m/z coincidence, the retention difference between the two found anthocyanins sets as well as UV-visible spectra excluded the latter type of derivatives.
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ABSTRACT Background: We investigated if the addition of an inter-professional student-led medication review team (ISP-team) to standard care can increase the number of detected ADRs and reduce the number of ADRs 3 months after an outpatient visit. Research design and methods: In this controlled clinical trial, patients were allocated to standard care (control group) or standard care plus the ISP team (intervention group). The ISP team consisted of medical and pharmacy students and student nurse practitioners. The team performed a structured medication review and adjusted medication to reduce the number of ADRs. Three months after the outpatient visit, a clinical pharmacologist who was blinded for allocation performed a follow-up telephone interview to determine whether patients experienced ADRs. Results: During the outpatient clinic visit, significantly more (p < 0.001) ADRs were detected in the intervention group (n = 48) than in the control group (n = 10). In both groups, 60–63% of all detected ADRs were managed. Three months after the outpatient visit, significantly fewer (predominantly mild and moderately severe) ADRs related to benzodiazepine derivatives and antihypertensive causing dizziness were detected in the patients of the intervention group. Conclusions: An ISP team in addition to standard care increases the detection and management of ADRs in elderly patients resulting in fewer mild and moderately severe ADRs
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The complex amino acid (l-threo)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (l-TFB-TBOA) and its derivatives are privileged compounds for studying the roles of excitatory amino acid transporters (EAATs) in regulation of glutamatergic neurotransmission, animal behavior, and in the pathogenesis of neurological diseases. The wide-spread use of l-TFB-TBOA stems from its high potency of EAAT inhibition and the lack of off-target binding to glutamate receptors. However, one of the main challenges in the evaluation of l-TFB-TBOA and its derivatives is the laborious synthesis of these compounds in stereoisomerically pure form. Here, we report an efficient and step-economic chemoenzymatic route that gives access to enantio- and diastereopure l-TFB-TBOA and its derivatives at multigram scale.
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Injuries of runners reduce the ability to train and hinder competing. Literature shows that the relation between potential risk factors and injuries are not definitive, limited, and inconsistent. In team sports, workload derivatives were identified as risk factors. However, there is an absence of literature in running on workload derivatives. This study used the workload derivatives acute workload, chronic workload, and acute: chronic workload ratios to investigate the relation between workload and injury risk in running. Twenty-three competitive runners kept a daily training log for 24 months. The runners reported training duration, training intensity and injuries. One-week (acute) and 4-week (chronic) workloads were calculated as the average of training duration multiplied by training intensity. The acute:chronic workload ratio was determined dividing the acute and chronic workloads. Results show that a fortnightly low increase of the acute:chronic workload ratio (0.10-0.78) led to an increased risk of sustaining an injury (p<0.001). Besides, a low increase of the acute:chronic workload ratio (0.05-0.62) between the second week and third week before an injury showed an association with increased injury risk (p=0.013). These findings demonstrate that the acute:chronic workload ratio relates to injury risk.
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Seven new 1,3,5-cyclohexyltricarboxamide-phenylalanine derivatives were synthesized in order to investigate the effect of the amino acid chirality on the gelating properties of these small molecules in water. Gelation tests have shown that enantiomerically pure homochiral 1,3,5-cyclohexyltricarboxamide-L-phenylalanine is a non-hydrogelator as it crystallizes from water, whereas the heterochiral derivatives with either two L-phenylalanine moieties and one D-phenylalanine (LLD), or vice versa (DDL), are very good hydrogelators. Concentration-dependent gel-to-sol transition-temperature (T(gs)) curves for LLD or DDL gels show a sigmoidal behaviour, which is in contrast to the logarithmic curves generally observed for gels derived from low molecular weight gelators (LMWGs). Such sigmoidal behaviour can be related to interactions between fibre bundles, which give rise to intertwined bundles of fibres. Transmission electron microscopy (TEM) images of LLD and DDL gels show a network of thin, unbranched, fibre bundles with diameters of 20 nm. Right-handed twisted fibre bundles are present in the LLD gel, whereas left-handed structures can be found in the DDL gel. Each bundle of fibres consists of a finite number of primary fibres. Gels consisting of mixtures of gelators, LLD and DDL, and nongelators (LLL or DDD) were investigated by means of T(gs) measurements, CD spectroscopy and TEM. Results show that the incorporation of nongelator molecules into gel fibres occurs; this leads to higher T(gs) values and to changes in the helicity of the fibre bundles. Furthermore, it was found that peripheral functionalization of the homochiral derivatives LLL or DDD by means of a second amino acid or a hydrophilic moiety can overcome the effect of chirality; this process in turn leads to good hydrogelators.
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The copper(II) catalyzed enantioselective 1,4-addition reactions of diethylzinc to cyclic enones in the presence of novel phosphorus amidite ligands, easily prepared from α,α,α',α'-tetraphenyl-2,2'-dimethyl-1,3- dioxolane-4,5-dimethanol (TADDOL) derivatives, resulted in e.e.s up to 71% for cyclohexenone and up to 62% for cyclopentenone. A remarkable enhancement of enantioselectivity was observed upon the addition of powdered molecular sieves to the reaction mixture.
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Probiotic bacteria harbor effector molecules that confer health benefits, but also adaptation factors that enable them to persist in the gastrointestinal tract of the consumer. To study these adaptation factors, an antibiotic-resistant derivative of the probiotic model organism Lactobacillus plantarum WCFS1 was repeatedly exposed to the mouse digestive tract by three consecutive rounds of (re)feeding of the longest persisting colonies. This exposure to the murine intestine allowed the isolation of intestine-adapted derivatives of the original strain that displayed prolonged digestive tract residence time. Re-sequencing of the genomes of these adapted derivatives revealed single nucleotide polymorphisms as well as a single nucleotide insertion in comparison with the genome of the original WCFS1 strain. Detailed in silico analysis of the identified genomic modifications pinpointed that alterations in the coding regions of genes encoding cell envelope associated functions and energy metabolism appeared to be beneficial for the gastrointestinal tract survival of L. plantarum WCFS1. This work demonstrates the feasibility of experimental evolution for the enhancement of the gastrointestinal residence time of probiotic strains, while full-genome resequencing of the adapted isolates provided clues towards the bacterial functions involved. Enhanced gastrointestinal residence is industrially relevant because it enhances the efficacy of the delivery of viable probiotics in situ.
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