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Resumen: Los asfaltenos son mezclas ultracomplejas que impactan negativamente la refinación, producción y transporte del petróleo. El interés en su estudio abarca desde su caracterización para definir su estructura molecular, hasta la comprensión de su comportamiento interfacial. Los asfaltenos presentan una gran diversidad de grupos funcionales y diferentes tipos de asociaciones como las de tipo no covalentes, enlaces de hidrógeno, complejo de coordinación e interacciones entre núcleos aromáticos paralelos. El objetivo de este trabajo fue analizar la composición presente en asfaltenos extraídos de crudos pesados y extrapesados mediante espectroscopía derivada. Se prepararon soluciones de asfaltenos en el rango de concentración de 20 mg/L a 100 mg/L y se analizaron con espectroscopía UV-Vis. La selección de los espectros de orden cero para el procesamiento se realizó con base en la nitidez presente. Los espectros fueron procesados con OriginPro 8.5, para la obtención de espectros derivados de primer y segundo orden. El procesamiento de los espectros de orden cero fue realizado con los filtros Savitsky-Golay y transformada rápida de Fourier (FFT). Los espectros derivados obtenidos presentaron señales nítidas con presencia de poco ruido, lo que hizo posible la identificación de grupos funcionales aromáticos, de 1 a 4 anillos en el rango de longitudes onda de 200 nm a 450 nm. El uso de filtros mejoró la calidad de las señales y permitió la identificación de componentes y estructuras presentes en asfaltenos. El filtro de Savitsky-Golay incrementó la resolución de los espectros derivados de asfaltenos extraídos de crudos pesados y el filtro FFT de asfaltenos de crudos extrapesados. Se observaron diferencias morfológicas entre los asfaltenos extraídos de crudos pesados y extrapesados mediante SEM, que pueden ser relacionadas con la composición y estructuras aromáticas presentes en asfaltenos.
Abstract: Asphaltenes are ultra-complex mixtures that negatively impact oil refining, production and transportation. The interest in its study ranges from its characterization to define its molecular structure, to the understanding of its interfacial behavior. Asphaltenes present a great diversity of functional groups and different types of associations such as non-covalent ones, hydrogen bonds, coordination complexes and interactions between parallel aromatic nuclei. The objective of this work was to analyze the composition present in asphaltenes extracted from heavy and extra-heavy crude oils using derivative spectroscopy. Asphaltene solutions were prepared in the concentration range of 20 mg/L to 100 mg/L and analyzed with UV-Vis spectroscopy. The selection of zero-order spectra for processing was made based on the sharpness present. The spectra were subsequently processed with OriginPro 8.5, to obtain first and second-order derived spectra. The processing of the zero order spectra was performed with the Savitsky-Golay and Fast Fourier transform (FFT) filters. The derived spectra obtained presented clear signals with the presence of little noise, which made possible the identification of aromatic functional groups, from 1 to 4 rings in the wavelength range of 200 nm to 450 nm. The use of filters improved the quality of the signals and allowed the identification of components and structures present in asphaltenes. The Savitsky-Golay filter increased the resolution of the spectra derived from asphaltenes extracted from heavy crude oils and the FFT filter increased the asphaltenes extracted from heavy crude oils. Morphological differences between asphaltenes extracted from heavy and extra-heavy crude oils were observed by SEM, which maybe related to the composition and aromatic structures present in asphaltenes.
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Objective To evaluate the pharmacodynamics of astragaloside Ⅳ derivatives for chronic heart failure, screen the candidate compounds and preliminarily explore the mechanism of the candidate compound HHQ16 against heart failure. Methods Chronic heart failure was induced by left anterior descending artery ligation in C57BL/6 mice for 4 weeks, and the mice were divided into 4 groups, including sham group, model group, positive control captopril group, and astragaloside Ⅳ derivatives group. After continuous intragastric administration for four weeks, the cardiac function was detected by echocardiography, and the optimal astragaloside Ⅳ derivative HHQ16 was selected for the treatment of heart failure. The preliminary mechanism for HHQ16 was further explored. The size of heart was observed by gross morphology; pathological changes were observed by HE staining; collagen deposition in the myocardium was observed by Masson staining; protein levels of myocardial fibrosis indexes COL1, COL3, and αSMA were detected by immunohistochemical staining, and mRNA levels of myocardial fibrosis indexes COL1, COL3, αSMA, and TGF-β1 were determined by qPCR technique. Results All astragaloside Ⅳ derivatives significantly improved cardiac function with increasing LVEF and LVFS, of which HHQ16 was the optimal compound. Compared with the model group, the heart volume of HHQ16 group was significantly reduced; myocardial hypertrophy was reduced; collagen deposition in myocardial tissues was reduced; and myocardial fibrosis indexes, COL1, COL3, αSMA and TGF-β1 mRNA levels, as well as the protein levels of COL1, COL3 and αSMA were significantly reduced. Conclusion HHQ16 is an optimal astragaloside Ⅳ derivatives for the treatment of chronic heart failure in mice, which could improve cardiac function by improving myocardial remodeling, and inhibit myocardial hypertrophy and myocardial fibrosis.
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We designed and synthesized eighteen lycorine derivatives with five different structural types, and evaluated their antiviral activities on a HCoV-OC43-infected H460 cell model. Structure-activity relationships suggested that the introduction of appropriate substituents on the 6N atom of lycorine was beneficial to activity. Compound 6a gave a good activity with the half effective concentration (EC50) and selectivity index (SI) values of 2.36 μmol·L-1 and 16.52, respectively. Surface plasmon resonance (SPR) result indicated that 6a might target the non-structural protein 12 (NSP12) subunit in RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with the dissociation constant (KD) value of 1.36 μmol·L-1. Molecular docking indicated that 6a might act on nidovirus RdRp-associated nucleotidyltransferase (NiRAN) catalytic center of NSP12, distinct from the mechanism of nucleoside-like drugs such as remdesivir. This study provides scientific data for the development of lycorine derivatives into a new class of anti-SARS-CoV-2 small molecule inhibitors.
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Objective @#To evaluate the clinical effect of enamel matrix derivative(EMD) assisted with connective tissue graft(CTG) in the treatment of gingival recession.@*Methods @#Search The Cochrane Library, PubMed, EMbase, Web of Science, Wanfang Public Database,VIP database and CNKI to search for randomized controlled trials of EMD in the treatment of gingival recession. The search period is from the establishment of the databases to October 3, 2022. The test group was treated with EMD+CTG, while the control group was treated with CTG alone. Meta-analyses were performed using Review Manager 5.4.1 and Stat12.0.@*Results@# Meta analysis results showed that only 12 months after treatment, there was a statistically significant difference in the PD and CAL outcome indicators between the EMD assisted treatment group and the control group [MDPD=-0.10, 95% CI (-0.19, -0.01), P = 0.03], [MDCAL=-0.38, 95% CI(-0.71, -0.04), P = 0.03]. There was no significant difference between the test group and the control group in other indicators.@*Conclusion @#EMD assisted CTG in the treatment of gingival recession may be beneficial to the reduction of PD and CAL.
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OBJECTIVE To evaluate the effectiveness, safety, economy, innovation, suitability and accessibility of recombinant Mycobacterium tuberculosis fusion protein (EC), and to provide evidence for selecting skin detection methods for tuberculosis infection diagnosis and auxiliary diagnosis of tuberculosis. METHODS The effectiveness and safety of EC compared with purified protein derivative of tuberculin (TB-PPD) were analyzed by the method of systematic review. Cost minimization analysis, cost-effectiveness analysis and cost-utility analysis were used to evaluate the short-term economy of EC compared with TB-PPD, and cost-utility analysis was used to evaluate the long-term economy. The evaluation dimensions of innovation, suitability and accessibility were determined by systematic review and improved Delphi expert consultation, and the comprehensive score of EC and TB-PPD in each dimension were calculated by the weight of each indicator. RESULTS The scores of effectiveness, safety, economy, innovation and suitability of EC were all higher than those of TB-PPD. The affordability scores of the two drugs were consistent, while the availability score of EC was lower than those of TB-PPD. After considering dimensions and index weight, the scores of effectiveness, safety, economy, innovation, suitability, accessibility and the comprehensive score of EC were all higher than those of TB-PPD. CONCLUSIONS Compared with TB-PPD, EC performs better in all dimensions of effectiveness, safety, economy, innovation, suitability and accessibility. However, it is worth noting that EC should further improve its availability in the dimension of accessibility.
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To improve the stability of amino acid ester derivatives of DB02, a series of 24 amide derivatives of DB02 amino acids as non-nucleoside HIV-1 reverse transcriptase inhibitor were designed and synthesized based on bioisosterism by replacing amino acid ester scaffold with more stable amide bond. The anti-HIV-1 activity of these compounds was evaluated by MTT assay and counting the number of syncytia. Most of the target compounds showed a potential anti-HIV-1 activity, among which compounds 2d, 2i, 2l, 2s, and 2w had better antiviral effect than lead compound DB02, with a therapeutic index > 1 000.00. Finally, the structure-activity relationship of these compounds was discussed, which provided new ideas for the further development of DB02 derivatives.
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The chemical constituents from the fruits of Morinda citrifolia were systematically explored by chromatographic fractionation methods including silica gel, octadecylsilyl(ODS) gel, Sephadex LH-20 gel, and preparative high performance liquid chromatography(pre-HPLC). The chemical structures of all isolated compounds were identified on the basis of their physicochemical properties, spectroscopic analyses, as well as the comparisons of their physicochemical and spectroscopic data with the reported data in literature. As a result, 22 isolated compounds from the 90% ethanol extract of the fruits of M. citrifolia were identified, which were moricitritone(1), 2'-deoxythymidine(2), cyclo-(L-Pro-L-Tyr)(3), methyl-5-hydroxy-2-pyridinecarboxylate(4), methyl pyroglutamate(5), bisbenzopyran(6), epipinoresinol(7), 3, 3'-bisdemethyl pinoresinol(8), 3, 3'-bisdemethyltanegool(9), trimesic acid(10), crypticin B(11), kojic acid(12), vanillic acid(13), protocatechoic acid(14), 5-hydroxymethyl furfural(15), blumenol A(16), 1-O-(9Z, 12Z-octadecadienoyl) glycerol(17), mucic acid dimethylester(18), methyl 2-O-β-D-glucopyranosylbenzoate(19), 2-phenylethyl-O-β-D-glucoside(20), scopoletin(21), and quercetin(22). Among them, compound 1 was a new pyrone derivative, compounds 2, 4-7, 10-12, and 17 were isolated from the plants belonging to Morinda genus for the first time, and compound 18 was obtained from M. citrifolia for the first time. Moreover, on the basis of testing the activities of all isolated compounds on inhibiting the proliferation of synovial fibroblasts in vitro by MTS assay, the anti-rheumatoid arthritis activities of all isolated compounds were initially evaluated. The results showed that compounds 1-6, 9, 19, and 20 exhibited remarkable anti-rheumatoid arthritis activities, which displayed the inhibitory effects on the proliferation of MH7A synovial fibroblast cells with the IC_(50) values in the range of(3.69±0.08) to(168.96±0.98) μmol·L~(-1).
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Fruit/chemistry , Morinda/chemistry , Synoviocytes , Cell Proliferation , ArthritisABSTRACT
Four new triterpenoids, together with six known analogues, were isolated from an aqueous extract of the Ziziphus jujuba var. spinosa seeds, by multiple column chromatographic separation methods using stationary phases of macroporous adsorption resin, MCI resin, normal phase silica gel, Sephadex LH-20, and Toyopearl HW-40C as well as preparative thin-layer chromatography and reversed-phase HPLC. Their structures were determined by spectroscopic data analysis, the new structures were trivially named jujubaceanothoside A (1), 23-epijujuboside A (2), and jujubosides J and K (3 and 4), while the known analogues were identified as jujubosides A-C (5-7) and II (8), alphitolic acid (9), and betulinic acid (10). The structure of 1 was confirmed by single crystal X-ray diffraction.
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Magnolol, a hydroquinone containing an allyl side chain, is one of the major active components of magnolia for antioxidation and anti-aging. To enhance the anti-aging activity and improve the intramolecular hydrogen bonding of magnolol, magnolol was reacted with cinnamic acid to obtain 2-O-cinnamic acid magnolol by esterification. The anti-aging activity of magnolol 2-O-cinnamate was investigated based on Caenorhabditis elegans model. The results showed that 2-O-cinnamic acid magnolol can reduce lipofuscin accumulation in the nematode body, and the effect is better than that of magnolol. 2-O-Cinnamic acid magnolol can extend nematode lifespan, reduce ROS levels in nematodes during normal aging and oxidative stress and improve nematode stress resistance under heat stress and oxidative stress. 2-O-Cinnamic acid magnolol could induce DAF-16 translocation from the cytoplasm to the nucleus and upregulate the expression of the sod-3 gene encoding superoxide dismutase in the nematode TJ356 expressing DAF-16 fused with GFP. 2-O-Cinnamic acid magnolol did not improve the survival rate of hsp-16.2 gene deficient nematodes under oxidative stress, indicating that 2-O-cinnamic acid magnolol improves stress resistance of nematodes under oxidative stress may be associated with sod-3 and hsp-16.2. Moreover, 2-O-cinnamic acid magnolol did not extend the lifespan of daf-16 and age-1 mutants, indicating that age-1 and daf-16 are required for 2-O-cinnamic acid magnolol to delay aging. It showed that magnolol 2-O-cinnamic acid has the potential to improve antioxidant capacity and delay aging, and the mechanism may be related to the insulin/insulin-like growth factor signaling pathway.
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Pinostrobin, marker compounds from Boesenbergia rotunda with various pharmacological activities, have been studied extensively, including synthesizing its derivatives, which have potent pharmacological activities. This study aims to describe research related to B. rotunda, pinostrobin, and their derivatives. Metadata information was collected from Scopus in August 2022, with three keywords searched for article titles, abstracts, and keywords. Analysis and research mapping were carried out with VOSviewer. The most widely used synonym for the plant name was "Boesenbergia rotunda", in which Norzulaani Khalid from the University of Malaya, Malaysia, mostly reported research with the keywords "Boesenbergia rotunda", "pinostrobin", and "derivative". The majority of researchers come from institutions in Southeast Asia, such as Malaysia, Thailand, and Indonesia. Interestingly, no Chinese researchers have reported studies on this topic. The journals and publishers that publish the most articles with these three keywords are Bioorganic and Medicinal Chemistry Letters and Elsevier, respectively. This information will make it easier for researchers on this topic to find partners for collaboration and determine journals to publish their research results.
La pinostrobina, compuesto de marcadores de Boesenbergia rotunda con diversas actividades farmacológicas, se ha estudiado ampliamente, incluida la síntesis de sus derivados que tienen potentes actividades farmacológicas. Este estudio tuvo como objetivo describir investigaciones relacionadas con B. rotunda, pinostrobina y sus derivados. La información de metadatos se recopiló de Scopus en agosto de 2022, con tres palabras clave buscadas para títulos de artículos, resúmenes y palabras clave. El análisis y el mapeo de la investigación se realizaron con VOSviewer. El sinónimo más utilizado para el nombre de la planta fue "Boesenbergia rotunda", en el que Norzulaani Khalid de la Universidad de Malaya, Malasia, informó principalmente sobre investigaciones con las palabras clave "Boesenbergia rotunda", "pinostrobina" y "derivado". La mayoría de los investigadores provienen de instituciones del sudeste asiático como Malasia, Tailandia e Indonesia. Curiosamente, ningún investigador chino ha informado de estudios sobre este tema. Las revistas y editoriales que más artículos publican con estas tres palabras clave son Bioorganic and Medicinal Chemistry Letters y Elsevier. Esta información facilitará a los investigadores sobre este tema encontrar colaboraciones y determinar las revistas para publicar los resultados de sus investigaciones.
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Objective:To investigate the effects of different small monitor unit (MU) beam deletion optimization method in the CyberKnife treatment planning system on the calculated planned dose to brain tumors.Methods:A total of 17 patients with brain metastases treated in our hospital from June, 2021 to February, 2022 were selected for this study. A treatment plan was designed for each patient using the multiPlan system in the CyberKnife VSI system as the group without optimization. To improve the efficiency, the generated original plans should be optimized first by deleting some small MUs, forming an experience group and an optimization group for each patient. For the experience group, beams below 30 MU were deleted according to experience. For the optimization group, beams below the MU value calculated based on the second derivative method were deleted. Finally, the parameters of the two groups were statistically compared. The main evaluation parameters included the node number, the beam number, the total number of MUs, the estimated treatment duration, doses to 2% and 95% planning target volumes (PTV D2 and PTV D95), average dose to PTV ( Dmean), average dose to brain tissue ( Dmean-Brain), conformity index (CI), new conformity index (nCI), gradient index (GI), coverage, and the maximum doses to the brainstem and left and right lens ( Dmax-BS, Dmax-LL, and Dmax-RL), and the average doses to the dose shells 20 mm and 40 mm away from PTV (Shell20 and Shell40). Results:The two optimization method met the requirements for the prescription dose delivery to more than 98% PTV. There were statistical differences in the node number ( H = 7.97, P< 0.05) and estimated treatment duration ( H = 6.60, P < 0.05) among the group without MP optimization, the experience group, and the optimization group, with the estimated treatment duration and node number of the optimization group less than those of the group without MP optimization ( P < 0.05). There were no statistically significant differences in other parameters among the three groups ( P > 0.05). The PTV was moderately positively correlated with the treatment duration ( r=0.79, P < 0.01) and beam number ( r=0.78, P < 0.01) of the experience group, and was also moderately positively correlated with the treatment duration ( r=0.69, P < 0.01) and beam number ( r=0.71, P < 0.01) of the optimization group. Conclusions:For the CyberKnife planning of heads, the small MU beam deletion optimization method based on the second derivative can further shorten the treatment duration while ensuring no significant differences in the distribution of doses to organs at risk and targets. Moreover, this method is more effective in optimizing the plans for a large PTV volume.
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@#Objective To the effects of VALD-3,a derivative of o-vanilla Schiff base ligand,on proliferation,migration and apoptosis of colorectal cancer cells and evaluate its mechanism.Methods HT-29 and HCT116 cells were cultured in vitro,and the inhibitory effects of VALD-3(5,10,20 and 40 mg/L) on proliferation of the two kinds of cells were detected by MTT assay;The effects of VALD-3(10,20 and 40 mg/L) on the morphological changes of the cells were observed by inverted microscope,while the effects on the migration ability of HT-29 cells were detected by cell scratch test,and the effects on the apoptosis of HT-29 cells were detected by flow cytometry and Hoechst 33258 fluorescence staining;The effects of VALD-3(5,10,20 and 40 mg/L) on the expression of apoptosis-related proteins in HT-29 cells were detected by Western blot.Negative control groups were set up(with no VALD-3).Results Compared with the negative control group,the survival rates of HT-29 and HCT116 cells in 10,20 and 40 mg/L VALD-3 treated groups significantly decreased(t=7.717~2 006.148,each P <0.05);the number of HT-29 and HCT116 cells in 10,20 and 40 mg/L VALD-3groups decreased significantly with the increase of VALD-3 concentration,the cells appeared irregular morphology and gradually became round and smaller,and cell fragments increased;In 10,20 and 40 mg/L VALD-3 treated groups,the migration rate of HT-29 cell scratches decreased significantly(t=7.596~73.780,each P <0.01),the apoptosis rate increased significantly(t=7.092~8.057,each P <0.01),and the number of apoptotic cells increased significantly with strong bright blue fluorescence,chromatin concentration and nuclear fragmentation;The levels of cleaved caspase-3 and Bax protein in HT-29 cells treated with 5,10,20 and 40 mg/L VALD-3 significantly increased(t=2.998~24.901,each P <0.05),the level of Bcl-2 protein in 40 mg/L VALD-3 group decreased significantly(t=10.035,P <0.05),and the levels of cleaved caspase-8 in 20 and 40 mg/L VALD-3 group significantly increased(t=12.630 and 8.064 respectively,each P <0.01).Conclusion VALD-3 inhibited the proliferation and migration of colorectal cancer cells and induced apoptosis by regulating the expression of cleaved caspase-3,cleaved caspase-8,Bax and Bcl-2 proteins.
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Rutin is extracted from Ruta graveolens L. with many pharmacological activities such as anti-inflammation, anti-oxidation , protecting cardiovascular system and analgesia. As a natural product, rutin has the advantages of low side effects and difficult tolerance, but its instability and low bioavailability still limit its clinical application. This paper summarizes the analgesic mechnism of rutin, and looks forward to the clinical applica¬tion of rutin based on its derivative and dosage forms. It is expected to provide ideas for further analgesic research and drug development and application of rutin in the future.
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Aim To develop a ultra-high performance liquid chromatography electrospray-ionization tandem mass spectrometry ( UPLC-MS/MS ) method for the simultaneous determination of salidroside derivative pOBz in rat plasma and brain tissue, and to study the pharmacokinetic profile and penetration of the blood-brain barrier in rats after a single dose intravenous administration of pOBz. Methods SD rats were administered pOBz at a dose of 50 mg • kg
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Aim To explore the signaling pathway of matrine derivative ZS10 in inhibiting proliferation and inducing apoptosis of BEL-7402 cells. Methods ZS10 was synthesized by organic synthesis. The inhibitory effect of ZS10 on the proliferation of BEL-7402 cells was analyzed by MTT method at the time of 24 h, 48 h and 72 h, respectively, and IC50 was calculated. DAPI staining was used to observe the state of BEL-7402 cells. Clone formation method was used to observe the colony formation of BEL-7402 cells, flow cytometry was used to observe the cell cycle arrest and apoptosis of BEL7402 cells, and Western blot was used to detect the expression level of PI3K/AKT pathway and related proteins. Results MTT results showed that the IC50 was(6.62±1.11)μmol·L-1; DAPI staining showed that the cell state changed significantly with the increase of drug concentration, and the results of colony formation showed that ZS10 significantly inhibited the colony formation of BEL-7402 cells. The results of flow cytometry showed that ZS10 induced S phase arrest and cycle apoptosis of BEL-7402 cells. Western blot showed that ZS10 at the concentration of 08 μ mol·L-1 could regulate the PI3K/AKT pathway and its related proteins in a dose-dependent manner. Compared with the control group, the expression of PI3K, AKT, P-AKT and anti-apoptotic protein Bcl-2 significantly decreased, the expression of pro-apoptotic protein Bax significantly increased, the expression of Cyclin D1 and CDK2 significantly decreased, and the expression of EGFR and N-cadherin, Vimentin significantly decreased in the treatment group. The expression of E-cadherin increased. Conclusions Matrine derivative ZS10 can inhibit the growth and proliferation of hepatocellular carcinoma cell line BEL-7402.
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Aim To investigate the effects of HXL130 on the proliferation, invasion and migration of prostate cancer PC3 cells and its molecular mechanism. Methods MTT assay was used to detect the effect of HXL130 on the proliferation of prostate cancer PC3 cells. Hoechst 33258 staining and flow cytometry were used to detect the effects on apoptosis and cell cycle of cancer cells. Transwell was used to detect the effects of compounds on the invasion and migration of cancer cells. Proteomic sequencing was employed to detect differentially expressed proteins (DEPs) induced by compound treatment of cancer cells. Bioinformatics was used to analyze the functions of DEPs and the related signaling pathways regulated by DEPs, and Western blot was used to verify the result. Results The survival rate of PC3 cells decreased with the increase of HXL130 concentration and treatment time. HXL130 could significantly induce cell apoptosis and block G
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@#Thioredoxin-interacting protein (TXNIP), which mainly regulates glucose homeostasis in pancreatic β cells, is a novel target in the treatment of diabetes.In this study, 4-hydroxybenzopyrimidine was used as the raw material, four nitrogen-containing rings (imidazole, methylpiperazine, pyrazole, morpholine) were introduced, benzopyrimidine skeleton with nitrogen-containing rings derivatives targeting TXNIP was designed and synthesized, and the protective effect of compounds on palmitic acid-stimulated islet β cells was investigated.A total of 20 benzopyrimidine derivatives were designed and synthesized, and the structures were confirmed by 1H NMR and ESI-MS.Pharmacological studies showed that most of the compounds exhibited protective effects on islet β cells, with better axtivity for compounds C-1, C-2, C-4 and D-2 (cell survival rate > 70%) compared with PA model group (38.3%), Among the four compounds, D-2 had the highest activity of 87.2%, so it could become a potential new anti-diabetic chemical entity.
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@#The in vitro release is an important index to evaluate the quality of liposome formulation.Currently, there is no evaluation method for the in vitro release of liposome in pharmacopoeia of various countries, which leads to the lack of unified standard and safety guarantee for the quality evaluation of liposome formulation.Taking the self-made paclitaxel derivative liposomes as an example, the paddle membrane binding method established by optimizing external release conditions was used to simulate the complete release of paclitaxel derivative drugs in 12 hours under physiological conditions.The results showed that using 0.5% SDS-HEPES as the release medium and a dialysis bag with a molecular weight cutoff of 1 000 kD to release the liposome solution met the requirements and had discrimination ability, providing a reference for the development of drug-loaded liposomes release methods in vitro.
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Toll-like receptor 2 (TLR2) mediated macrophages regulate the protective immune response to infectious microorganisms, but the aberrant activation of macrophages often leads to pathological inflammation, including tissue damage. In this study, we identified antagonists of TLR2 by screening 2100 natural products and subsequently identified Taspine, an aporphine alkaloid, as an excellent candidate. Furthermore, analysis of the 10 steps chemical synthesis route and structural optimization yielded the Taspine derivative SMU-Y6, which has higher activity, better solubility, and improved drug-feasible property. Mechanistic studies and seq-RNA analysis revealed that SMU-Y6 inhibited TLR2 over other TLRs, hindered the formation of TLR2/MyD88 complex, and blocked the downstream NF-κB and MAPK signaling pathway, thus suppressing the release of inflammatory cytokines. SMU-Y6 could stabilize TLR2 and bind to TLR2 protein with a Kd of 0.18 μmol/L. Additionally, SMU-Y6 could efficiently reverse the M1 phenotype macrophage polarization, reduce the production of cytokines as well as infiltration of neutrophiles and alleviate the local inflammation in mice with acute paw edema and colitis. Collectively, we reported the first aporphine alkaloid derivative that selectively inhibits TLR2 with high binding affinity and superior drug-feasible property, thus providing an urgently-needed molecular probe and potential drug candidate for inflammatory and autoimmune disease therapy.
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Resumen A partir de 1991 se creó una nueva constitución que incluyera a todos los actores políticos además de los que tradicionalmente estaban excluidos en la constitu ción de 1886, con la esperanza de dar final a los conflictos armados, los paros e inconformidades ciudadanas. Las cuales fueron capitalizadas por los estudian tes en la séptima papeleta. Pero pocos años después se inició una cascada de reformas que evidencian una constante disputa por el poder de las elites, grupos emergentes legales e ilegales, y la población que comenzó a sentirse partícipe del poder. Pero ¿cuál es la finalidad de dichos cambios constitucionales? Dicha respuesta se intentará responder primero describiendo los cambios, segundo comparando dichos cambios a la luz de los principios y valores de la Carta y fi nalmente desde una visión crítica comprender a quien benefician, lo anterior se hará bajo una metodología descriptiva-histórica-critica-decolonial.
Abstract In 1991, a new constitution was created to include all political stakeholders in addition to those traditionally excluded in the 1886 constitution, in the hope of putting an end to armed conflicts, strikes and citizen discontent. These citizen demonstrations were capitalized by the students in the seventh ballot, which prompted the convocation of the constituent assembly. After the promulgation of the new constitution of 1991, a cascade of reforms began, which evidenced a constant dispute for power between the elites, emerging legal and illegal groups, and the population that began to feel part of the power. But, what was the purpose of these constitutional changes?