Synthesis and Characterization of Azole Isoflavone Inhibitors of Aromatase

The synthesis and biological evaluation of a series of 2-azole and 2-thioazole isoflavones as potential aromatase inhibitors are described. Differences in inhibitory activity of triazole and imidazole inhibitors are rationalized with density functional theory to expose a key difference in the electronic structure of these molecules. In addition, difference binding spectra of inhibitors to immunoaffinity-purified aromatase produces classical Type II spectra consistent with coordination of the nitrogen lone pair electrons to the aromatase P450 heme

Synthesis and Characterization of Azole Isoflavone Inhibitors of Aromatase

The synthesis and biological evaluation of a series of 2-azole and 2-thioazole isoflavones as potential aromatase inhibitors are described. Differences in inhibitory activity of triazole and imidazole inhibitors are rationalized with density functional theory to expose a key difference in the electronic structure of these molecules. In addition, difference binding spectra of inhibitors to immunoaffinity-purified aromatase produces classical Type II spectra consistent with coordination of the nitrogen lone pair electrons to the aromatase P450 heme

Lead Optimization of 7-benzyloxy 2-(4′-pyridylmethyl)Thio Isoflavone Aromatase Inhibitors

Aromatase, the enzyme responsible for estrogen biosynthesis, is a particularly attractive target in the treatment of hormone-dependent breast cancer. The synthesis and biological evaluation of a series of 2-(4′-pyridylmethyl)thio, 7-alkyl- or aryl-substituted isoflavones as potential aromatase inhibitors are described. The isoflavone derivatives demonstrate IC50 values from 79 to 553 nM and compete with the endogenous substrate, androstenedione. Data supporting the ability of these analogs to suppress aromatase enzyme activity in the SK-BR-3 breast cancer cell line are also presented

Involvement of Heme Oxygenase-1 Induction in the Cytoprotective and Immunomodulatory Activities of Viola patrinii in Murine Hippocampal and Microglia Cells

A number of diseases that lead to injury of the central nervous system are caused by oxidative stress and inflammation in the brain. In this study, NNMBS275, consisting of the ethanol extract of Viola patrinii, showed potent antioxidative and anti-inflammatory activity in murine hippocampal HT22 cells and BV2 microglia. NNMBS275 increased cellular resistance to oxidative injury caused by glutamate-induced neurotoxicity and reactive oxygen species generation in HT22 cells. In addition, the anti-inflammatory effects of NNMBS275 were demonstrated by the suppression of proinflammatory mediators, including proinflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase-2) and cytokines (tumor necrosis factor-α and interleukin-1β). Furthermore, we found that the neuroprotective and anti-inflammatory effects of NNMBS275 were linked to the upregulation of nuclear transcription factor-E2-related factor 2-dependent expression of heme oxygenase-1 in HT22 and BV2 cells. These results suggest that NNMBS275 possesses therapeutic potential against neurodegenerative diseases that are induced by oxidative stress and neuroinflammation

A CRY-BIC negative-feedback circuitry regulating blue light sensitivity of Arabidopsis.

Cryptochromes are blue light receptors that regulate various light responses in plants. Arabidopsis cryptochrome 1 (CRY1) and cryptochrome 2 (CRY2) mediate blue light inhibition of hypocotyl elongation and long-day (LD) promotion of floral initiation. It has been reported recently that two negative regulators of Arabidopsis cryptochromes, Blue light Inhibitors of Cryptochromes 1 and 2 (BIC1 and BIC2), inhibit cryptochrome function by blocking blue light-dependent cryptochrome dimerization. However, it remained unclear how cryptochromes regulate the BIC gene activity. Here we show that cryptochromes mediate light activation of transcription of the BIC genes, by suppressing the activity of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), resulting in activation of the transcription activator ELONGATED HYPOCOTYL 5 (HY5) that is associated with chromatins of the BIC promoters. These results demonstrate a CRY-BIC negative-feedback circuitry that regulates the activity of each other. Surprisingly, phytochromes also mediate light activation of BIC transcription, suggesting a novel photoreceptor co-action mechanism to sustain blue light sensitivity of plants under the broad spectra of solar radiation in nature

Prediction of renal recovery following sepsis-associated acute kidney injury requiring renal replacement therapy using contrast-enhanced ultrasonography

Background Microcirculatory dysfunction plays a critical role in sepsis-associated acute kidney injury (S-AKI) development; however, its impact on renal recovery remains uncertain. We investigated the association between cortical microcirculatory function assessed using contrast-enhanced ultrasonography (CEUS) and renal recovery after S-AKI needing renal replacement therapy (RRT). Methods This retrospective study included 23 patients who underwent CEUS among those who underwent acute RRT for S-AKI. In addition, we acquired data from 17 healthy individuals and 18 patients with chronic kidney disease. Renal recovery was defined as sustained independence from RRT for at least 14 days. Results Of the CEUS-derived parameters, rise time, time to peak, and fall time were longer in patients with S-AKI than in healthy individuals (p = 0.045, 0.01, and 0.096, respectively). Fourteen patients (60.9%) with S-AKI receiving RRT experienced renal recovery; and these patients had higher values of peak enhancement, wash-in area under the curve (AUC), wash-in perfusion index, and wash-out AUC than those without recovery (p = 0.03, 0.01, 0.03, and 0.046, respectively). We evaluated the receiver operating characteristic curve and found that the peak enhancement, wash-in AUC, wash-in perfusion index, and wash-out AUC of CEUS derivatives estimated the probability of renal recovery after S-AKI requiring RRT (p = 0.03, 0.01, 0.03, and 0.04, respectively). Conclusion CEUS-assessed cortical microvascular perfusion may predict renal recovery following S-AKI that requires RRT. Further studies are essential to validate the clinical utility of microcirculatory parameters obtained from CEUS to estimate renal outcomes in various etiologies and severities of kidney disease

Psychometric properties of the readiness for return to work scale in occupational rehabilitation in South Korea

This study validated the Korean version of the Readiness to Return to Work (RRTW) scale, as an assessment measure, following a musculoskeletal, work-related injury and as a measure of following return to work. The participants of this study were workers with experience in rehabilitation programs at the Workers Compensation and Welfare Service (KCOMWEL) Hospital in Korea. Factor analyses were employed to ensure the validity and reliability of the RRTW scale in claimants who were in treatment without working (the not-working group) or who had already returned to work (the working group). To test structural validity, we analyzed exploratory factor analysis (EFA) respectively for the not working group (exploratory factor analysis (EFA) (n= 200), confirmatory factor analysis (CFA) (n= 109), and the working group (n= 123). To verify concurrent validity (multidimensional and assignment approach), the variables that were identified as relevant variables in previous studies were analyzed. The not working group EFA, as shown in the original scale, had four dimensions, and one item was deleted: (1) Precontemplation (PC), (2) Contemplation (C), (3) Prepared for Action-Self-evaluative (PAS), and (4) Prepared for Action-Behavioral (PAB). The CFA revealed that a good model fit and reliability were suitable. Regarding the working group of EFA, it appeared in two dimensions as in the original scale, one item was modified from the UM scale to the PM scale, and the reliability was appropriate. Concurrent validity was satisfied based on the correlation between the RRTW factor and related variables. RRTW in the Korean version of the instrument was similar to those reported for the original scale, indicating that it may be used in research and clinical settings

The assessment of efficacy of porcine reproductive respiratory syndrome virus inactivated vaccine based on the viral quantity and inactivation methods

<p>Abstract</p> <p>Background</p> <p>There have been many efforts to develop efficient vaccines for the control of porcine reproductive and respiratory syndrome virus (PRRSV). Although inactivated PRRSV vaccines are preferred for their safety, they are weak at inducing humoral immune responses and controlling field PRRSV infection, especially when heterologous viruses are involved.</p> <p>Results</p> <p>In all groups, the sample to positive (S/P) ratio of IDEXX ELISA and the virus neutralization (VN) titer remained negative until challenge. While viremia did not reduce in the vaccinated groups, the IDEXX-ELISA-specific immunoglobulin G increased more rapidly and to significantly greater levels 7 days after the challenge in all the vaccinated groups compared to the non-vaccinated groups (<it>p </it>< 0.05). VN titer was significantly different in the 10⁶PFU/mL PRRSV vaccine-inoculated and binary ethylenimine (BEI)-inactivated groups 22 days after challenge (<it>p </it>< 0.05). Consequently, the inactivated vaccines tested in this study provided weak memory responses with sequential challenge without any obvious active immune responses in the vaccinated pigs.</p> <p>Conclusions</p> <p>The inactivated vaccine failed to show the humoral immunity, but it showed different immune response after the challenge compared to mock group. Although the 10⁶PFU/mL-vaccinated and BEI-inactivated groups showed significantly greater VN titers 22 days after challenge, all the groups were already negative for viremia.</p

Clinical importance of F-waves as a prognostic factor in Guillain-Barré syndrome in children

PurposeA limited number of studies have examined the link between F-wave abnormalities and clinical presentation in pediatric Guillain-Barré syndrome (GBS). Therefore, this study examined the importance of F-wave abnormalities as a prognostic factor in pediatric GBS patients.MethodsThe records and electrodiagnostic studies (EDS) of 70 GBS patients were retrospectively evaluated, and divided into 2 groups according to the results of EDS. Group A (n=33) presented with F-wave abnormalities, and group B (n=26) exhibited normal findings. We compared laboratory reports, clinical features, response to treatment, and prognosis between the 2 groups.ResultsMotor weakness was the most frequently observed symptom for either group. Clinically, the incidence of fever and upper respiratory symptoms differed between the 2 groups, while the prevalence of abnormal deep tendon reflex (DTR) was significantly higher in group A than B (P<0.05). Patients diagnosed with GBS had received intravenous immunoglobulin treatment: 94% in group A and 58% in group B. Furthermore, significantly greater numbers of patients in group A showed H-reflex abnormalities and poor prognosis compared with group B (P<0.05).ConclusionThis study demonstrated that F-waves are a clinically important prognostic factor in GBS. F-wave abnormalities were associated with abnormal DTR and poor prognosis in patients. Limited studies have examined the link between F-wave abnormalities and clinical results; therefore, further randomized controlled studies are needed to confirm the clinical characteristics and efficacy of treatments

Incidence of Atazanavir-associated Hyperbilirubinemia in Korean HIV Patients: 30 Months Follow-up Results in a Population with Low UDP-glucuronosyltransferase1A1*28 Allele Frequency

Hyperbilirubinemia is frequently observed in Caucasian HIV patients treated with atazanavir. UDP-glucuronosyltransferase 1A1 polymorphism, UGT1A1*28, which is associated with atazanavir-induced hyperbilirubinemia, is less common in Asians than in Caucasians. However, little is known about the incidence of atazanavir-associated hyperbilirubinemia in Asian populations. Our objective was to investigate the incidence of and tolerability of atazanavir-associated hyperbilirubinemia in Korean HIV patients. The prevalence and cumulative incidence of atazanavir-associated hyperbilirubinemia and UGT1A1*28 allele frequency was investigated in 190 Korean HIV-infected patients treated with atazanavir 400 mg per day. The UGT1A1*28 were examined by direct sequencing of DNA from peripheral whole blood. The UGT1A1*28 allele frequency was 11%. The cumulative incidence of any grade of hyperbilirubinemia was 77%, 89%, 98%, and 100%, at 3, 12, 24, and 30 months, respectively. The cumulative incidence of severe (grade 3-4) hyperbilirubinemia was 21%, 41%, 66%, and 75%, at 3, 12, 24, and 30 months, respectively. However, the point prevalence of severe hyperbilirubinemia did not increase with time and remained around 25%. Our data suggest that atazanavir-associated hyperbilirubinemia is common but transient in a population with low UGT1A1*28 allele frequency