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Determination and validation of mycophenolic acid by a UPLC-MS/MS method: Applications to pharmacokinetics and tongue tissue distribution studies in rats
No full textMycophenolic acid (MPA) has being used clinically for organ rejection prophylaxis. Recent studies have revealed that MPA can also act as a chemo-sensitizing agent when used in combination with various chemotherapeutic agents in a cancer type-specific manner, including with oxaliplatin on oral squamous cell carcinoma (OSCC) cells. To prepare for the analysis of a novel drug delivery route for MPA absorption via oral mucosa as a potential therapeutic product, it is essential to develop and validate a highly sensitive analytical method for the quantification of MPA in biological samples for pharmacokinetic and tissue distribution studies. Herein, we report a sensitive, specific and reproducible UPLC-MS/MS method to do so. Blank rat plasma or tongue tissue homogenates coupled with griseofulvin, as internal standard, was used for generating standard curves ranging from 0.5 to 1000 ng/mL (r \u3e 0.9990) for both plasma and tongue tissue homogenates. The chromatographic separation was achieved by a reverse phase ACE Excel 2 Super C18 column with a flow rate of 0.4 mL/min under gradient elution. Mass detection was performed under positive ionization electrospray. Inter- and intra-day accuracy and precision of the assay were ≤15% in both plasma and tongue tissue homogenates. The matrix effect was non-significant and extraction recovery rates were within 87.99% and 109.69% in plasma and tongue homogenates, respectively. The validity of this assay has been confirmed by measuring MPA in rat plasma for pharmacokinetics following intravenous administration of 0.5 mg/kg of mycophenolate sodium, as well as monitoring MPA in rat tongues for tissue distribution and detecting MPA that diffused into systemic circulation following a 4-h transmucosal delivery of 357 μg/cm2 of mycophenolate sodium
Development and validation of ultra-high-performance liquid chromatography–mass spectrometry method for the determination of raloxifene and its phase II metabolites in plasma: Application to pharmacokinetic studies in rats
No full textThe aim of this study is to establish a reliable liquid chromatography–mass spectrometry method to simultaneously quantitate raloxifene, and its major metabolites, raloxifene-6-glucuronide, raloxifene-4′-glucuronide, and raloxifene-6-sulfate in rat plasma samples for pharmacokinetic studies. The separation of the analytes was achieved on a Waters BEH C18 column. Water (0.1% formic acid) and acetonitrile were used as the mobile phases for elution. A one-step protein precipitation using a mixture solvent was applied for plasma sample preparation. The method was validated following the FDA guidance. The results showed that the linear range were 1.95–1000 nM for raloxifene-6-glucuronide, and raloxifene-4′-glucuronide, 0.195–100 nM for raloxifene-6-sulfate, and 0.195–200 nM for raloxifene, respectively. The lower limit of quantification was 1.95, 1.95, 0.195, and 0.195 nM for raloxifene-6-glucuronide, raloxifene-4′-glucuronide, raloxifene-6-sulfate, and raloxifene, respectively. Only 20 µl of plasma sample was required since the method is sensitive. The intra- and interday variance is \u3c15% and the accuracy is within 85–115%. The variance of matrix effect and recovery were \u3c15%. The method was successfully applied in a pharmacokinetic study in rats with oral administration of raloxifene
A discrete hidden Markov model for SMS spam detection
Get PDFMany machine learning methods have been applied for short messaging service (SMS) spam detection, including traditional methods such as naive Bayes (NB), vector space model (VSM), and support vector machine (SVM), and novel methods such as long short-term memory (LSTM) and the convolutional neural network (CNN). These methods are based on the well-known bag of words (BoW) model, which assumes documents are unordered collection of words. This assumption overlooks an important piece of information, i.e., word order. Moreover, the term frequency, which counts the number of occurrences of each word in SMS, is unable to distinguish the importance of words, due to the length limitation of SMS. This paper proposes a new method based on the discrete hidden Markov model (HMM) to use the word order information and to solve the low term frequency issue in SMS spam detection. The popularly adopted SMS spam dataset from the UCI machine learning repository is used for performance analysis of the proposed HMM method. The overall performance is compatible with deep learning by employing CNN and LSTM models. A Chinese SMS spam dataset with 2000 messages is used for further performance evaluation. Experiments show that the proposed HMM method is not language-sensitive and can identify spam with high accuracy on both datasets
Methanol leaf extract of Momordica charantia protects alloxan-induced hepatopathy through modulation of caspase-9 and interleukin-1β signaling pathways in rats
Get PDFBackground and Aim: Momordica charantia is a highly valued plant, widely distributed in the tropical and subtropical regions. The plant is reported to have a wide range of medicinal uses. This study was designed to explore the ameliorative potential of M. charantia methanol leaf extract in alloxan-induced diabetic animal model with a particular focus on the liver. Materials and Methods: Hepatoprotective effect of methanol leaf extract of M. charantia was assessed in alloxan-induced toxicity in 50 rats divided into five groups (A-E) (n=10). Group A normal control, Group B was toxicant group, and Group C animals received glibenclamide treatment while Groups D and E received extracts at 200 and 400 mg/kg doses, respectively. The experiment lasted for 28 days. Histopathological changes, blood glucose level, and serum enzymes such as aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, oxidative status and caspase-9, and interleukin-1β (IL-1β) were evaluated. Results: Extract-treatment caused a decreased blood glucose level, markers of oxidative stress such as malondialdehyde and hydrogen peroxide (H2O2). Treatment of rats with leaf extract of M. charantia resulted in increased levels and activities of protein thiols, non-protein thiols, glutathione (GSH), glutathione peroxidase, glutathione S-transferase, and superoxide dismutase indicating its antioxidant potential. The liver section revealed mild distortion of the hepatic architecture compared to the toxicant group, while decreased expressions of caspase-9 and IL-1β in extract-treated groups was observed. Conclusion: The plant extract exhibited antioxidant, anti-apoptotic, and anti-inflammatory effects, thus showing its hepatoprotective property
Effect of cocoa powder on hypertension and antioxidant status in uninephrectomized hypertensive rats
Get PDFBackground and Aim: High salt diet and uninephrectomy are associated with high blood pressure with attendant cardiovascular disease conditions such as hypertension, renal damage, myocardial infarction, and stroke. The aim of this study was to investigate the beneficial effects of consumption of cocoa and cocoa-containing products in the management of high blood pressure in uninephrectomized hypertensive rats. Materials and Methods: The effect of cocoa powder on blood pressure, markers of inflammation, oxidative stress, and histopathology were investigated in uninephrectomized animals fed with cocoa feed alone or in combination with a high salt diet. Male rats were randomly divided into five groups: Group A was the control group and fed with normal feed alone, Group B was fed with cocoa feed alone, Group C was fed with high salt diet (8% salt), Group D was fed with cocoa-feed compounded with 8% salt for 4 weeks after uninephrectomy, and Group E was uninephrectomized rats on a normal diet. The left kidneys of animals in Groups C, D, and E were removed by surgery. After 4 weeks of treatment, the systolic, diastolic, and mean arterial blood pressure was measured. The serum markers of renal damage and oxidative stress were determined. Histological examination was also performed on renal and cardiac tissues. Results: Results showed significant increases in biomarkers of oxidative stress, inflammation, and renal damage with a concomitant decrease in antioxidant status in hypertensive uninephrectomized rats. Cocoa feed, however, significantly improved blood pressure and nitric oxide bioavailability, antioxidant status and reduced markers of inflammation and oxidative stress. Conclusion: These findings show that cocoa powder could be used to maintain blood pressure levels in hypertensive rats through its antioxidant capacity
Knock down of Fas-Associated Protein with Death Domain (FADD) Sensitizes Osteosarcoma to TNFα-induced Cell Death
Get PDFFas-associated protein with death domain (FADD) was first identified for its role in linking death receptors to the apoptotic signaling pathway with subsequent cell death. Later studies reported non-apoptotic functions for FADD in normal cells and cancer cells. Non-apoptotic functions for FADD in osteosarcoma (OS) have not been reported. In this study, FADD protein expression was knocked down in human CCHOSD, LM7, and SaOS2 OS cell lines followed by assessment of sensitivity to TNFα- or TRAIL-induced cell death. Knock down of FADD significantly increased TNFα-induced cell death in LM7 and SaOS2 cell lines. The mode of TNFα-induced cell death was apoptosis and not necroptosis. Inhibition of nuclear factor kappa B (NFκB) in wildtype cells increased TNFα-induced cell death to similar levels observed in FADD knockdown cells, suggesting a role for FADD in NFκB pro-survival cell signaling. In addition, knock down of FADD increased SMAC mimetic-mediated TNFα-induced cell death in all cell lines studied. The results of this study indicate that FADD has a pro-survival function in OS following TNFα treatment that involves NFκB signaling. The results also indicate that the pro-survival function of FADD is associated with XIAP activity
Deficiency of splicing factor 1 (Sf1) reduces intestinal polyp incidence in apc\u3csup\u3emin/+\u3c/sup\u3e mice
Get PDFBackground: Splicing factor 1 (SF1) is a conserved alternative splicing factor expressed in many different mammalian cell types. The genetically modified Sf1+/− (or Sf1β-geo/+ ) mice express reduced levels of SF1 protein in mouse tissues, including in cells of the intestines. Mutational inactivation of human adenomatous polyposis coli (APC) gene deregulates the Wnt signaling pathway and is a frequent genetic event in colon cancers. Mice with a point mutation in the Apc gene (ApcMin/+ ) also develop numerous intestinal polyps at a young age. Our aim was to determine the effect of reduced SF1 levels on polyp development due to the strong driver ApcMin/+ mutation. Methods: We utilized mice genetically deficient for expression of SF1 to assess how SF1 levels affect intestinal tumorigenesis. We crossed ApcMin/+ to Sf1+/− mice to generate a cohort of heterozygous mutant ApcMin/+;Sf1+/− mice and compared intestinal polyp development in these mice to that in a control cohort of sibling ApcMin/+ mice. We compared total polyp numbers, sizes of polyps and gender differences in polyp numbers between ApcMin/+;Sf1+/− and ApcMin/+ mice. Results: Our results showed that ApcMin/+ mice with lower SF1 expression developed 25–30% fewer intestinal polyps compared to their ApcMin/+ siblings with normal SF1 levels. Interestingly, this difference was most significant for females (ApcMin/+;Sf1+/− and ApcMin/+ females developed 39 and 55 median number of polyps, respectively). Furthermore, the difference in polyp numbers between ApcMin/+;Sf1+/− and ApcMin/+ mice was significant for smaller polyps with a size of 2 mm or less, whereas both groups developed similar numbers of larger polyps. Conclusions: Our results suggest that lower SF1 levels likely inhibit the rate of initiation of polyp development due to ApcMin/+ driver mutation in the mouse intestine. Thus, therapeutic lowering of SF1 levels in the intestine could attenuate intestinal polyp development
Assessing Risk Among Correctional Community Probation Populations: Predicting Reoffense With Mobile Neurocognitive Assessment Software
No full textWe seek to address current limitations of forensic risk assessments by introducing the first mobile, self-scoring, risk assessment software that relies on neurocognitive testing to predict reoffense. This assessment, run entirely on a tablet, measures decision-making via a suite of neurocognitive tests in less than 30 minutes. The software measures several cognitive and decision-making traits of the user, including impulsivity, empathy, aggression, and several other traits linked to reoffending. Our analysis measured whether this assessment successfully predicted recidivism by testing probationers in a large urban city (Houston, TX, United States) from 2017 to 2019. To determine predictive validity, we used machine learning to yield cross-validated receiver–operator characteristics. Results gave a recidivism prediction value of 0.70, making it comparable to commonly used risk assessments. This novel approach diverges from traditional self-reporting, interview-based, and criminal-records-based approaches, and can also add a protective layer against bias, while strengthening model accuracy in predicting reoffense. In addition, subjectivity is eliminated and time-consuming administrative efforts are reduced. With continued data collection, this approach opens the possibility of identifying different levels of recidivism risk, by crime type, for any age, or gender, and seeks to steer individuals appropriately toward rehabilitative programs. Suggestions for future research directions are provided
Thermal degradation of azobenzene dyes
Get PDFTen azobenzene dyes were tested for their thermal degradation products from ambient temperature to 800 °C using a thermogravimetric technique. Degradation products were analyzed at each 100 °C increment using gas chromatography-mass spectrometry. Products were identified based on their mass spectral data and their retention times. Thermal degradation from all dyes resulted in loss of the azo group as nitrogen gas and aromatic free radicals. Electron withdrawing groups enhance the dissociation of the phenyl nitrogen bond at the benzene moiety carrying the electron withdrawing group. On the other hand, electron donating groups inhibited the dissociation of the phenyl-N bond of the benzene moiety carrying the electron donating groups. The loss of nitrogen molecule from the dyes appeared to be taken place in a two-step rather than a one-step reaction in which the phenyl nitrogen bond of the phenyl group carrying the electron withdrawing group splits to form phenyl and azo phenyl radicals following by the loss of a nitrogen molecule and a new phenyl radical. This was also supported by calculating degradation reaction enthalpies and bond dissociation energies using density functional theory quantum mechanics
An Estimate of the Pitting Strength of Steel Materials
Get PDFA single expression for estimating the nominal pitting strength of steel materials, based on surface hardness, is developed from first principles for a reliability of 99% at 107 load cycles. It requires the hardness values to be measured in Vicker’s hardness scale. The expression may be used for any steel material processed by hot rolling, cold drawing, quenching and tempering or case-hardening. The formulation incorporates a nominal design factor at 99% reliability which is estimated from a probabilistic model based on the lognormal probability density function. Pitting strength estimates from the expression are compared with those of American Gear Manufacturers Association (AGMA) estimates and data from other sources as indicated in Tables 3 and 4. The expression predicts lower values at low hardness but higher values at high hardness. The variance is between -15.21% and 10.13% for through-hardened steels. For case-hardened steels, the variances range from 14.23% to 20.26% between the estimates and available data. These variances appear to be reasonable considering the many factors involved in pitting resistance. The main advantage of this study is that pitting strength of new steel materials may be estimated for initial design sizing without long and costly contact fatigue testing which of course is necessary for design validation. Also, the estimation method developed may be applied to other materials, metallic and non-metallic. Suggestions are made for estimating some pertinent pitting strength adjustment factors when considering field or service pitting strength