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Main biliary cirrhosis related to myasthenia gravis after postpartum: a case statement.
A simple sample preparation approach employing the dispersive pipette extraction (DPX) technique is proposed to determine twelve polyphenols, including phenolic acids and flavonoids in wines, followed by identification and quantification by LC-MS/MS. The extraction parameters, including sample volume and pH, salting out effect, time and cycles of extraction and desorption, and desorption solvent were optimized using univariate and multivariate designs. The analytical performance was satisfactory, with determination coefficients greater than or equal to 0.9877, precisions with values lower than 20 %, and recoveries ranging from 87 to 114 %. The applicability of the method was evaluated in red wine. The major compounds determined in the sample were (-)-epicatechin (23.5 mg L-1), (+)-catechin (19.2 mg L-1), and myricetin (14.6 mg L-1). The green character of the analytical procedure and the sample preparation step were evaluated by three analytical metrics.The effects of heating temperature on epitopes, IgE-binding capacity, and conformation of soybean protein isolate (SPI) were investigated in this study. Indirect ELISA demonstrated that the IgE binding capacity of SPI was increased by 13.1 %-31.6 % after being heated at 60-100 °C for 20 min. SDS-PAGE demonstrated no changes in protein profiles, and native PAGE revealed the formation of aggregates. Structural analyses demonstrated the protein unfolding, appearing temperature-dependent, thus exposing conformational epitopes. Peptide mapping analysis revealed the changes in peptide profiles of major allergens (Gly m 4, Gly m 5, Gly m 6, P28, and Kunitz trypsin inhibitor). LC/MS-MS demonstrated that heating caused the masking or exposure of linear epitopes in Gly m 4 - Gly m 6 and P28. Therefore, heating caused structural changes to expose epitopes to increase IgE binding capacity in SPI. Patients with soybean allergy should avoid the heated SPI until the results of clinical trials are confirmed.The microbiota plays important roles for polyphenols exerting bioactivity, which needs support to calculate the accumulated polyphenols in the gastrointestinal tract. Taking phlorizin as an example, fecal excretion kinetics was suggested to be ingenious for achieving it. No phlorizin was excreted with feces, implying almost 100 % total availability. Combined with its 0-5 % bioavailability, more than 95 % of phlorizin quantitatively accumulated in the gastrointestinal tract. Instead, trace phloretin was excreted, and the acquired kinetic parameters were influenced by physical conditions and dietary patterns. Dosage-total-availability curves indicated different relationships among normal-diet and obese mice, resulting in critical dosages of ∼ 159 and ∼ 196 mg/kg when taking 95 % total availability by phloretin. The dietary matrix affects the intake, digestion, metabolism and absorption of polyphenols, and may alter its total availability, and fecal excretion kinetics can provide further support for polyphenol dietary supplements targeting microbiota.Molecular dynamics (MD) simulation is used increasingly to explore mechanisms of interactions and conformational relationships between food proteins and other food compounds. MD simulation can better understand the structural changes between food proteins and small molecules at the molecular level. Based on the current extensive literature, visualization models established by MD simulation in the future may provide greater insight into finer molecular changes in food proteins and small molecules interactions. Development and software as well as force fields used in MD simulation for food protein and interaction systems were reviewed. The review focuses on the status of MD simulation technology in exploring food protein functional mechanisms, and bioactive substance delivery, food processing and storage, and food additives. Finally, current trends and applications were considered. This review provides an overview for the wider application of MD simulation technology in the food protein research field.Despite novel biological targets emerging at an impressive rate for anticancer therapy, antitubulin drugs remain the backbone of numerous oncological protocols and their efficacy has been demonstrated in a wide variety of adult and pediatric cancers. In the present contribution, we set to develop analogs of a potent but neglected antitubulin agent, TN-16, originally discovered via modification of tenuazonic acid (3-acetyl-5-sec-butyltetramic acid). To this extent, we developed a novel multicomponent reaction to prepare TN-16, and then we applied the same reaction for the synthesis of aza-analogs. In brief, we prepared a library of 62 novel compounds, and three of these retained nanomolar potencies. TN-16 and the active analogs are cytotoxic on cancer cell lines and, as expected from antitubulin agents, induce G2/M cell cycle arrest. These agents lead to a disruption of the microtubules and an increase in α-tubulin acetylation and affect in vitro polymerization, although they have a lesser effect in cellular tubulin polymerization assays.50 New drugs including 36 chemical entities and 14 biologics were approved by the U.S. Food and Drug Administration during 2021. Among the marketed drugs, 31 new small molecule agents (29 small molecule drugs and 2 diagnostic agents) with privileged structures and novel clinical applications represent as promising leads for the development of new drugs with the similar indications and improved therapeutic efficacy. This review is mainly focused on the clinical applications and synthetic methods of 29 small molecule drugs newly approved by the FDA in 2021. We believed that insight into the synthetic approaches of drug molecules would provide creative and practical inspirations for the development of more efficient and practical synthetic technologies to meet with new drug discovery.The cytochrome bcc-aa3 oxidase (Cyt-bcc) of Mycobacterium tuberculosis (Mtb) is a promising anti-tuberculosis target. However, when Cyt-bcc is inhibited, cytochrome bd terminal oxidase (Cyt-bd) can still maintain the activity of the respiratory chain and drive ATP synthesis. Through virtual screening and biological validation, we discovered two FDA-approved drugs, ivacaftor and roquinimex, exhibited moderate binding affinity to Cyt-bd. Structural modifications of them led to 1-hydroxy-2-methylquinolin-4(1H)-one derivatives as potent new Cyt-bd inhibitors. Compound 8d binds to Cyt-bd with a Kd value of 4.17 μM and inhibits the growth of the Cyt-bcc knock-out strain (ΔqcrCAB, Cyt-bd+) with a MIC value of 6.25 μM. The combination of 8d with the Cyt-bcc inhibitor Q203 completely inhibited oxygen consumption of the wild-type strain and the inverted-membrane vesicles expressing M. tuberculosis Cyt-bd (ΔcydABMtbCydAB+). Our study provides a promising starting point for the development of novel dual chemotherapies for tuberculosis.In order to take advantage of both immunotherapeutic and metabolic antitumor agents, novel dual indoleamine 2,3- dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) inhibitors were designed. Thioredoxin reductase 1 (TrxR1) is a main ROS modulator within CRC cells. Indoleamine 2,3-dioxygenase (IDO1) is crucial controller for tryptophan (Trp) metabolism that is also important for CRC immunotherapy. Herein, ten compounds 12a-j containing hydroxyamidine scaffold were designed, synthesized and evaluated for inhibitory activities against IDO1/TrxR1 enzyme and CRC cells. Among these compounds, the most active compound 12d (ZC0109) showed excellent and balanced activity against both IDO1 (IC50 = 0.05 μM) and TrxR1 (IC50 = 3.00 ± 0.25 μM) were selected for further evaluation. selleck products Compound ZC0109 exhibited good dual inhibition against IDO1 and TrxR1 both in vitro and in vivo. Further mechanistic studies reveal that, through IDO1 and TrxR1 inhibition by ZC0109 treatment, accumulated ROS effectively induced apoptosis and G1/S cell cycle arrest in cancer cells. In vivo evaluation demonstrated excellent anti-tumor effect of ZC0109 with the notable ability of promoting ROS-induced apoptosis, reducing kynurenine level in plasma and restoring anti-tumor immune response. Thus, ZC0109 represents a potential CRC therapy agent for further development.Monopolar spindle kinase 1 (Mps1), a core component of the spindle assembly checkpoint (SAC), plays a crucial role in the transition of cells from mid-to late mitosis. As an attractive therapeutic target, inhibition of Mps1 induces cell cycle arrest and apoptosis in a variety of tumors, including breast cancer. However, early clinical development of Mps1 inhibitors remains unsatisfactory. Here, we designed and synthesized a new class of Mps1 inhibitors with 7H-pyrrolo[2,3-d]pyrimidine structure using a scaffold hopping approach. Structure-activity relationship (SAR) revealed that 12 is a potent Mps1 inhibitor (IC50 = 29 nM), which inhibited phosphorylation of Mps1 in vitro and in vivo. Treatment with 12 not only impeded proliferation of breast cancer cell lines, but also induced cell cycle arrest and apoptosis of MCF-7 and 4T1 cells. 12 suppressed tumor growth in vivo, and no obvious toxicities were observed. These results demonstrated the potential of Mps1 inhibitor 12 for the treatment of breast cancer.Despite its ease in experimental set up, the low sensitivity of MQMAS experiments is often a limiting factor in many practical applications. This is mainly due to the large radiofrequency (RF) field requirement of the two short hard-pulses often used for the optimum MQ excitation and conversion steps. Very recently, two novel MQMAS experiments have been proposed for I = 3/2 nuclei, namely lp-MQMAS and coslp-MQMAS, enabling an efficient MQ excitation/conversion with a reduced RF requirement, by utilizing two long pulses lasting one rotor period each, with or without cosine modulation. In this study, we focus on the practical considerations of these new methods and discuss their pros and cons to elucidate their appropriate use under both moderate and fast spinning conditions. Using four I = 3/2 (87Rb, 71Ga, 35Cl and 23Na) nuclei at a moderate magnetic field (B0 = 14.1 T), we show the superior use of these experiments, especially for samples with large CQ values and/or low-gamma nuclei. Compared to all other existing sequences, the coslp-MQMAS method with initial WURST signal enhancement is the most robust, efficient and resolved high-resolution 2D method for spin 3/2 nuclei. Furthermore, using 23Na-1H spin systems, we demonstrate the sensitivity advantage of the WURST coslp-MQ-HETCOR acquisition upon 1H detection and fast MAS conditions.In this work, we expand on past portable magnetic resonance flow methods and propose a novel method for characterizing circular (laminar) Couette flow of non-Newtonian fluids. Symmetry of the flow system combined with a constant magnetic field gradient leads to phase interference, affecting the signal magnitude, and net phase cancellation when averaging across the excited slice, preventing the use of phase-sensitive methods. Therefore, we utilize the dependence of signal magnitude at variable echo times and shear rates to characterize rheological properties. Theoretical equations governing the velocity distributions of fluids that obey a simple power-law model are used to obtain integral expressions for signal magnitude. Integral expressions can be simplified by approximating a thin excited slice or complete excitation of the Couette cell depending on experimental parameters. With simple data acquisition and analysis procedures employed, our measurements of the flow behavior indices of non-Newtonian xanthan gum dispersions are in close agreement with conventional rheological magnetic resonance measurements.
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