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The stereoselectivity of phosphonylation of serine hydrolases by the ROR'P(O)X group of compounds is governed by the electronic properties of X and the size of RO. The electronic properties of ligands attached to P are decisive in...
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The stereoselectivity of phosphonylation of serine hydrolases by the ROR'P(O)X group of compounds is governed by the electronic properties of X and the size of RO. The electronic properties of ligands attached to P are decisive in whether C-O or P-O bond cleavage occurs in phosphonate diesters of serine hydrolases. Phenolate ions leave readily with P-O cleavage from chymotrypsin and the cholinesterases. The architecture and electrostatic character of the active site governs the fate of a covalently attached phosphonyl fragment. Strong negative electrostatic and hydrophobic forces in the cholinesterases preferentially promote C-O bond cleavage with occasional methyl migration whereas this route of dealkylation is nearly absent in phosphonate esters of serine proteases.
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Despite tremendous advances in radiotherapy techniques, allowing dose escalation to tumour tissues and sparing of organs at risk, cure rates from radiotherapy or chemoradiotherapy remain suboptimal for most cancers. In tandem with...
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Despite tremendous advances in radiotherapy techniques, allowing dose escalation to tumour tissues and sparing of organs at risk, cure rates from radiotherapy or chemoradiotherapy remain suboptimal for most cancers. In tandem with our growing understanding of tumour biology, we are beginning to appreciate that targeting the molecular response to radiation-induced DNA damage holds great promise for selective tumour radiosensitisation. In particular, approaches that inhibit cell cycle checkpoint controls offer a means of exploiting molecular differences between tumour and normal cells, thereby inducing so-called cancer-specific synthetic lethality. In this overview, we discuss cellular responses to radiation-induced damage and discuss the potential of using G2/M cell cycle checkpoint inhibitors as a means of enhancing tumour control rates.
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? 2022 International Federation of Clinical NeurophysiologyObjective: To assess the relationship between spinal reflexes and motor function in sub-acute (SAS) and chronic stroke (CS) patients. Methods: Twelve SAS and 16 CS patient...
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? 2022 International Federation of Clinical NeurophysiologyObjective: To assess the relationship between spinal reflexes and motor function in sub-acute (SAS) and chronic stroke (CS) patients. Methods: Twelve SAS and 16 CS patients underwent electrophysiological assessment of heteronymous facilitation (HF), heteronymous inhibition (HI), disynaptic reciprocal inhibition (DRI), and D1 inhibition (D1). The Fugl-Meyer Assessment Lower Extremity (FMA-LE) and modified Ashworth scale (MAS) were assessed. The relationship between spinal reflexes and motor function was examined in a cross-sectional manner. SAS patients were also longitudinally evaluated before and after intensive rehabilitation for approximately 2 months. Results: SAS patients with triceps surae muscle spasticity (MAS ≥ 1) showed higher HF values (p = 0.03) than those without spasticity. SAS patients with quadriceps muscle spasticity showed higher HF values (p < 0.01); patients with hamstring muscle spasticity showed higher DRI value (disinhibition) (p < 0.01) than those without spasticity. CS patients showed no significant correlation between spinal reflexes and motor function. The longitudinal study revealed a significant correlation between increase in D1 inhibition and FMA-LE improvement in SAS patients (r = 0.69). Conclusions: The association between impaired spinal reflexes varies with the stage of stroke; HF and DRI may be spasticity indicators in SAS patients. Significance: Spinal reflexes as potential biomarkers may facilitate tailor-made rehabilitation of stroke patients.
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The objective was to analyze the phenolic composition, antioxidant capacity, and physical characteristics of 10 blackcurrant cultivars, their juices, and the enzymatic inhibition of dipeptidyl peptidase-IV, alpha-amylase, alpha-gl...
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The objective was to analyze the phenolic composition, antioxidant capacity, and physical characteristics of 10 blackcurrant cultivars, their juices, and the enzymatic inhibition of dipeptidyl peptidase-IV, alpha-amylase, alpha-glucosidase, nitric oxide synthase, and cyclooxygenase-2. Fruit masses ranged from 0.47 to 1.22 g and diameters from 7.42 to 14.42 mm. For the juices, pH ranged from 2.80 to 2.96, soluble solids from 11.33% to 17.5%, total acidity from 3.17 to 4.26 g/100 mL, and viscosity from 1.28 to 273.83 mPa.s. Total anthocyanins (TA) ranged from 1.81 to 5.48 mg eq cyanidin 3-O-glucoside/100 g, total polyphenols (TP) from 7.67 to 39.70 mg eq gallic acid/100 g, total condensed tannins from 3.24 to 7.76 g eq catechin/100 g, and antioxidant capacity from 219.24 to 499.26 mu mol eq Trolox/100 g. Juices of the cultivars Coronet and Consort contained the highest levels of TA, TP, and antioxidants. Whistler cultivar contained high concentrations of major anthocyanins. Juices from all cultivars favorably inhibited the activities of enzymes used as surrogate biochemical markers for T2 diabetes and inflammation.
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Sodium salts of four n-alkyl xanthate compounds, C2H5OCS2Na (I), C3H7OCS2Na (II), C4H9OCS2Na (III), and C6H13OCS2Na (IV) were synthesized and examined for inhibition of both cresolase and catecholase activities of mushroom tyrosin...
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Sodium salts of four n-alkyl xanthate compounds, C2H5OCS2Na (I), C3H7OCS2Na (II), C4H9OCS2Na (III), and C6H13OCS2Na (IV) were synthesized and examined for inhibition of both cresolase and catecholase activities of mushroom tyrosinase (MT) in 10 mM sodium phosphate buffer, pH 6.8, at 293 K using UV spectrophotemetry. 4-[(4-methylbenzo)azo]-1,2-benzendiol (MeBACat) and 4-[(4-methylphenyl)azo]-phenol (MePAPh) were used as synthetic substrates for the enzyme for catecholase and cresolase reactions, respectively. Lineweaver-Burk plots showed different patterns of mixed, competitive or uncompetitive inhibition for the four xanthates. For the cresolase activity, I and II showed uncompetitive inhibition but III and IV showed competitive inhibition pattern. For the catecholase activity, I and II showed mixed inhibition but III and IV showed competitive inhibition. The synthesized compounds can be classified as potent inhibitors of MT due to their Ki values of 13.8, 11, 8 and 5 μM for the cresolase activity, and 1.4, 5, 13 and 25 μM for the catecholase activity for I, II, III and IV, respectively. For the catecholase activity both substrate and inhibitor can be bound to the enzyme with negative cooperativity between the binding sites (α > 1) and this negative cooperativity increases with increasing length of the aliphatic tail of these compounds. The length of the hydrophobic tail of the xanthates has a stronger effect on the Ki values for catecholase inhibition than for cresolase inhibition. Increasing the length of the hydrophobic tail leads to a decrease of the Ki values for cresolase inhibition and an increase of the Ki values for catecholase inhibition.
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Around 70% of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth, survival and disease progression. The presence of hormone sensitivity is usually associated with a favorable prognosis. Use of adju...
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Around 70% of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth, survival and disease progression. The presence of hormone sensitivity is usually associated with a favorable prognosis. Use of adjuvant anti-endocrine therapy has significantly decreased breast cancer mortality in patients with early-stage disease, and anti-endocrine therapy also plays a central role in the treatment of advanced stages. However a subset of hormone receptor-positive breast cancers do not benefit from anti-endocrine therapy, and nearly all hormone receptor-positive metastatic breast cancers ultimately develop resistance to anti-hormonal therapies. Despite new insights into mechanisms of anti-endocrine therapy resistance, e.g., crosstalk between ER and Her2/neu, the management of advanced hormone-receptor-positive breast cancers that are resistant to anti-endocrine agents remains a significant challenge. In the present study, we demonstrate that the proteasome inhibitor Bortezomib strongly inhibits ER and HER2/neu expression, increases expression of cyclin-dependent kinase inhibitors, inhibits expression of multiple genes associated with poor prognosis in ER+ breast cancer patients and induces cell death in ER+ breast cancer cells in both the presence and absence of functional p53. Although Bortezomib increased the levels of p53 and increased the expression of pro-apoptotic target genes in ER+ breast cancer cells harboring wild-type p53, Bortezomib also exerts anti-tumoral effects on ER+ breast cancer cells through suppression of ER expression and inhibition of PI3K/Akt/mammalian target of rapamycin (mTOR) and ERK signaling independently of functional p53. These findings suggest that Bortezomib might have the potential to improve the management of anti-endocrine therapy resistant ER+ breast cancers independently of their p53 status.
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Age-related features of spinal inhibition were studied in males at relative muscle rest. Main developmental stages were identified for spinal inhibition, including the periods when the relevant processes grow weaker or more intens...
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Age-related features of spinal inhibition were studied in males at relative muscle rest. Main developmental stages were identified for spinal inhibition, including the periods when the relevant processes grow weaker or more intense. Heterochrony was observed for the development of particular spinal inhibition types, i.e., their definitive developmental stages were achieved at different ages: 9-12 years of age for presynaptic inhibition of heteronymous Ia afferents and reciprocal inhibition of homonymous α motoneurons, 17-18 years of age for recurrent inhibition of heteronymous α motoneurons, and 14-15 years of age for nonre-ciprocal inhibition of heteronymous and homonymous α motoneurons. Teenage age was identified as a critical period in the development of presynaptic inhibition of heteronymous and homonymous Ia afferents and recurrent inhibition of α motoneurons. The physiological mechanisms underlying the above age-related regularities are discussed.
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The formal mechanism of linear mixed and non-competitive enzyme inhibition implies the binding of inhibitors to both the active site of the free enzyme in competition with the substrate, and to an allosteric site on the enzyme-sub...
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The formal mechanism of linear mixed and non-competitive enzyme inhibition implies the binding of inhibitors to both the active site of the free enzyme in competition with the substrate, and to an allosteric site on the enzyme-substrate complex. However, it is evident from a review of the scientific literature that the two-site mechanism is frequently mistaken as the actual underlying mechanism of mixed inhibition. In this study, we conducted a comprehensive assessment of the mechanistic relevance of this type of inhibition using a statistical approach. By combining a statistical analysis of the inhibition cases documented in the BRENDA database with a theoretical investigation of inhibition models, we conclude that mixed inhibitors exclusively bind to the active site of enzymes. Hence ruling out any implication of allosteric sites and depriving the two-site model of any mechanistic relevance.
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Psoriatic arthritis (PsA) is an inflammatory disease characterised by the clinical domains of arthritis, enthesitis, dactylitis, spondylitis, and psoriasis, often causing significant functional disability, loss of quality of life,...
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Psoriatic arthritis (PsA) is an inflammatory disease characterised by the clinical domains of arthritis, enthesitis, dactylitis, spondylitis, and psoriasis, often causing significant functional disability, loss of quality of life, and premature mortality. Prior to the introduction of targeted biologic medications, such as TNF inhibitors, the capacity to control disease activity was limited, with only modest effects noted in most patients with traditional oral medications such as methotrexate and sulfasalazine. The introduction of TNF inhibitors substantially changed the outlook of PsA patients, yielding significant response in all relevant clinical domains and demonstrating the capacity to inhibit progressive structural damage of joints. However, not all patients responded to these agents and many patients displayed initial response which waned over time, partly due to immunogenicity (development of antibodies which blocked full therapeutic effect of the biologic protein), or because of poor tolerability and/or adverse events. Thus, it has been important to develop new medicines which target other key cytokines and immunologic pathways, including ustekinumab which inhibits both IL12 and IL23 and thus is felt to work in both the TH1 and TH7 pathways of inflammation, has been approved for the treatment of PsA as well as psoriasis. IL17 inhibitors, including secukinumab and ixekizumab have demonstrated significant effectiveness in psoriasis and PsA; abatacept, which modulates T cell activity via inhibition the second signal of T cell activation is under study. This article provides an historical overview of this revolution; details of specific biological therapies will be provided in adjacent articles in this supplement.
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? 2022 Elsevier B.V.The present study aimed to examine whether impairments in reactive (outright stopping) and proactive (preparation for stopping) response inhibition are affected by negative emotions in individuals with high sch...
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? 2022 Elsevier B.V.The present study aimed to examine whether impairments in reactive (outright stopping) and proactive (preparation for stopping) response inhibition are affected by negative emotions in individuals with high schizotypy, a subclinical group at risk for schizophrenia, as well as the neural mechanisms underlying these processes. Twenty-seven participants with high schizotypy and 28 matched low-schizotypy individuals completed an emotional stop-signal task in which they responded to facial emotions (neutral or angry) or inhibited their responses (when the frame of the picture turned red). Electroencephalogram (EEG) data were also recorded during the task. At the neural level, analysis of go trials revealed that viewing angry faces impaired proactive inhibition. In addition, the high-schizotypy group exhibited a greater P3 amplitude in go trials in the neutral condition than the low-schizotypy group; however, no group difference was found in the angry condition. For stop trials (reactive inhibition), a smaller P3 amplitude was found in the angry condition than in the neutral condition. Moreover, high-schizotypy individuals showed smaller P3 amplitudes than low-schizotypy individuals. The current findings suggest that, at the neural level, viewing negative emotions impaired both proactive and reactive response inhibition. Individuals with high schizotypy exhibited impairments in proactive response inhibition in the neutral condition but not in the angry condition; they exhibited impaired reactive response inhibition in both emotion conditions. The present findings deepen our understanding of emotional response inhibition in individuals on the schizophrenia spectrum.
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