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1.
Phytomedicine ; 93: 153770, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34678528

RESUMO

BACKGROUND: Syringa microphylla Diels is a plant in the family Syringa Linn. For hundreds of years, its flowers and leaves have been used as a folk medicine for the treatment of cough, inflammation, colds, sore throat, acute hepatitis, chronic hepatitis, early liver cirrhosis, fatty liver, and oesophageal cancer. PURPOSE: For the first time, we have comprehensively reviewed information on Syringa microphylla Diels that is not included in the Pharmacopoeia, clarified the pharmacological mechanisms of Syringa microphylla Diels and its active ingredients from a molecular biology perspective, compiled in vivo and in vitro animal experimental data and clinical data, and summarized the toxicology and pharmacokinetics of Syringa microphylla Diels. The progress in toxicology research is expected to provide a theoretical basis for the development of new drugs from Syringa microphylla Diels, a natural source of compounds that are potentially beneficial to human health. METHODS: The PubMed, Google Scholar, China National Knowledge Infrastructure, Web of Science, SciFinder Scholar and Thomson Reuters databases were utilized to conduct a comprehensive search of published literature as of July 2021 to find original literature related to Syringa microphylla Diels and its active ingredients. RESULTS: To date, 72 compounds have been isolated and identified from Syringa microphylla Diels, and oleuropein, verbascoside, isoacteoside, echinacoside, forsythoside B, and eleutheroside B are the main active components. These compounds have antioxidant, antibacterial, anti-inflammatory, and neuroprotective effects, and their safety and effectiveness have been demonstrated in long-term traditional applications. Molecular pharmacology experiments have indicated that the active ingredients of Syringa microphylla Diels exert their pharmacological effects in various ways, primarily by reducing oxidative stress damage via Nrf2/ARE pathway regulation, regulating inflammatory factors and inducing apoptosis through the MAPK and NF-κB pathways. CONCLUSION: This comprehensive review of Syringa microphylla Diels provides new insights into the correlations among molecular mechanisms, the importance of toxicology and pharmacokinetics, and potential ways to address the limitations of current research. As Syringa microphylla Diels is a natural low-toxicity botanical medicine, it is worthy of development and utilization and is an excellent choice for treating various diseases.


Assuntos
Syringa , Animais , Antioxidantes , Etnofarmacologia , Humanos , Medicina Tradicional , Compostos Fitoquímicos/toxicidade , Extratos Vegetais/toxicidade
2.
PLoS One ; 16(7): e0254615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34297742

RESUMO

Leukocytes have an essential role in patient clinical trajectories and progression. Traditional methods of leukocyte enrichment have many significant limitations for current applications. It is demonstrated a novel 3D printing leukocyte sorting accumulator that combines with centrifugation to ensure label-free initial leukocyte enrichment based on cell density and size. The internal structure of leukocyte sorting accumulator (revealed here in a new design, leukocyte sorting accumulator-3, upgraded from earlier models), optimizes localization of the buffy coat fraction and the length of the period allocated for a second centrifugation step to deliver a higher recovery of buffy coats than earlier models. Established methodological parameters were evaluated for reliability by calculating leukocyte recovery rates and erythrocyte depletion rates by both pushing and pulling methods of cell displacement. Results indicate that leukocyte sorting accumulator-3 achieves a mean leukocytes recovery fraction of 96.2 ± 2.38% by the pushing method of layer displacement. By the pulling method, the leukocyte sorting accumulator-3 yield a mean leukocytes recovery fraction of 94.4 ± 0.8%. New procedures for preliminary enrichment of leukocytes from peripheral blood that avoid cellular damage, as well as avert metabolic and phase cycle intervention, are required as the first step in many modern clinical and basic research assays.


Assuntos
Procedimentos de Redução de Leucócitos/métodos , Leucócitos/citologia , Impressão Tridimensional/instrumentação , Buffy Coat/classificação , Buffy Coat/citologia , Centrifugação/instrumentação , Centrifugação/métodos , Humanos , Procedimentos de Redução de Leucócitos/instrumentação , Leucócitos/classificação
3.
3 Biotech ; 11(7): 320, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34194904

RESUMO

Nisin is an antimicrobial peptide which is widely used as preservative, while lactic acid is a natural organic acid applied in the food industry. The aim of this work was to study the process for nisin and lactic acid production from starch of sweet potato with simultaneous saccharification and fermentation (SSF) by Lactococcus lactis subsp. Lactis with two stage pH adjustment. The factors impacting the nisin and lactic acid production including starch concentration, glucosidase concentration, CaCO3 and Tween-80 were studied. The nisin titre reached a high of 2516.41 IU/mL, while the lactic acid reached a high of 37.06 g/L when the optimal conditions were 40 g/L starch, 100 U glucosidase/g starch, 2.5% CaCO3 and 1 mL/L Tween-80. The lactic acid and nisin were separated by a two stage pH adjustment at last. The SSF of starch from sweet potato coupled with a two stage pH adjustment is a promising method to produce nisin and lactic acid.

4.
Sci Prog ; 104(3): 368504211029431, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34236899

RESUMO

With the higher rotational speeds and loads in bearings, the gaseous cavitation becomes more and cannot be ignorable in the bearing designs. However, there is no enough research in non-equilibrium gaseous cavitation model. This paper builds a new gaseous cavitation model based on the Bunsen solubility and bubble dynamics. The equilibrium pressure is calculated by the Bunsen solubility based on the local pressure and its pressure difference with the local pressure decides the cavitation mass transfer rate in this new model for gaseous cavitation. A titling-pad journal bearing at 3000 rpm and under 299 kN load is chosen as the research object with this new model and an original equilibrium model applied. As for the minimum film thickness and bearing force balance, this new model performs in better accordance with the experiment than the equilibrium model. According to the multiphase distributions in the bearing film, the gaseous cavitation rate in this new model can simulate the non-equilibrium processes of dissolution and cavitation under the high rotational speed, which is close to the physical gaseous cavitation process. This new model is developed and applied successfully in tilting-pad journal bearings for simulating the non-equilibrium gaseous cavitation.

5.
Adv Sci (Weinh) ; 8(13): 2002860, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34258150

RESUMO

Even though ZnO is commonly used as the ETL in the perovskite solar cell (PSC), the reactivity of perovskite deposited thereupon limits its performance. Herein, an ethylene diamine tetraacetic acid-complexed ZnO (E-ZnO) is successfully developed as a significantly improved electron selective layer (ESLs) in perovskite device. It is found that E-ZnO exhibits higher electron mobility and better matched energy level with perovskite compared to ZnO. In addition, in order to eliminate the proton transfer reaction at the ZnO/perovskite interface, a high quality perovskite film fabrication process that requires neither annealing nor antisolvent is developed. By taking advantages of both E-ZnO and the new process, the highest efficiency of 20.39% is obtained for PSCs based on E-ZnO. Moreover, the efficiency of unencapsulated PSCs with E-ZnO retains 95% of its initial value exposed in an ambient atmosphere after 3604 h. This work provides a feasible path toward high performance of PSCs, and it is believed that the present work will facilitate transition of perovskite photovoltaics in flexible and tandem devices since the annealing- and antisolvent-free technology.

6.
ChemSusChem ; 14(15): 3182-3189, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34124848

RESUMO

Most studies choose passivators essentially in a trial-and-error fashion in an attempt to attain high efficiency in perovskite solar cells (PSCs). Using deep-level transient spectroscopy (DLTS) measurements, the type of defects in perovskite films was determined to guide the passivator selection for PSCs. Three kinds of positively charged defects were found in the target PSC system. Fluorinated phenylethylamine hydroiodide (FPEAI) was chosen to passivate the surface defects due to the electronegativity and hydrophobicity of fluorine. Due to the decreased surface roughness, increased hydrophobicity, lowered defect density, and improved carrier dynamics as observed by ultrafast transient absorption spectroscopy (TAS), a PSC with meta-F-PEAI had the best efficiency over 23 % with open-circuit voltage of 1.155 V and fill factor of 80.15 %. In addition, the long-term stability of the PSC was significantly improved. The present work provides a new means to select the best passivator for different types of defects.

7.
Adv Mater ; 33(27): e2100770, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34057256

RESUMO

Perovskite solar cells exhibit not only high efficiency under full AM1.5 sunlight, but also have great potential for applications in low-light environments, such as indoors, cloudy conditions, early morning, late evening, etc. Unfortunately, their performance still suffers from severe trap-induced nonradiative recombination, particularly under low-light conditions. Here, a holistic passivation strategy is developed to reduce traps both on the surface and in the bulk of micrometer-thick perovskite film, leading to a record efficiency of 40.1% under 301.6 µW cm-2 warm light-emitting diode (LED) light for low-light solar-cell applications. The involvement of guanidinium into the perovskite bulk film and 2-(4-methoxyphenyl)ethylamine hydrobromide (CH3 O-PEABr) passivation on the perovskite surface synergistically suppresses the trap states. The charge carrier lifetimes of the perovskite film increase by tenfold and fivefold to 981 ns and 8.02 µs at the crystal surface and in its bulk, respectively. The decreased nonradiative recombination loss translates to a high open-circuit voltage (Voc ) of 1.00 V, a high short-circuit current (Jsc ) of 152.10 µA cm-2 , and a fill factor (FF) of 79.52%. Note that this performance also stands as the highest among all photovoltaics measured under indoor light illumination. This work of trap passivation for micrometer-thick perovskite film paves a way for high-performance, self-powered IoT devices.

8.
Eur J Med Chem ; 220: 113451, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33895500

RESUMO

All-trans-retinoic acid (ATRA) is effective for preventing cancer and treating skin diseases and acute promyelocytic leukaemia (APL). These pharmacological effects of ATRA are mainly mediated by retinoid X receptors (RXRs) and retinoic acid receptors (RARs). This article provides a comprehensive overview of the clinical progress on and the molecular mechanisms of ATRA in the treatment of APL. ATRA can promote the transcriptional activation of differentiation-related genes and regulate autophagy by inhibiting mTOR, which results in anti-APL effects. In detail, the structures, pharmacological effects, and clinical studies of 68 types of ATRA analogues are described. These compounds have excellent antitumour therapeutic potential and could be used as lead compounds for further development and research.


Assuntos
Antineoplásicos/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tretinoína/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Serina-Treonina Quinases TOR/metabolismo , Tretinoína/análogos & derivados , Tretinoína/química
9.
Per Med ; 18(2): 129-139, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33565322

RESUMO

Aim: To explore the role of urine cell-free DNA (ucfDNA) concentration and integrity indexes as potential biomarkers for lung cancer diagnosis. Materials & methods: Quantitative real-time PCR targeting Arthrobacter luteus (ALU) repeats at three size fragments (ALU-60, 115 and 247 bp) was performed in 55 lung cancer patients and 35 healthy individuals. Results: ucfDNA concentration and integrity indexes were significantly higher in lung cancer patients than in healthy controls. The area under the receiver operating characteristic curve for differentiating patients with stage I/II from healthy controls by ALU fragments concentration were 0.856, 0.909 and 0.932, respectively. In addition, the ucfDNA integrity indexes in patients with lymph node metastasis were significantly higher than in patients with non-metastatic. Conclusion: ucfDNA concentration and integrity indexes could serve as promising biomarkers for lung cancer diagnosis.

10.
Eur J Med Chem ; 213: 113201, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33524687

RESUMO

The widespread nature of several viruses is greatly credited to their rapidly altering RNA genomes that enable the infection to persist despite challenges presented by host cells. Within the RNA genome of infections is RNA-dependent RNA polymerase (RdRp), which is an essential enzyme that helps in RNA synthesis by catalysing the RNA template-dependent development of phosphodiester bonds. Therefore, RdRp is an important therapeutic target in RNA virus-caused diseases, including SARS-CoV-2. In this review, we describe the promising RdRp inhibitors that have been launched or are currently in clinical studies for the treatment of RNA virus infections. Structurally, nucleoside inhibitors (NIs) bind to the RdRp protein at the enzyme active site, and nonnucleoside inhibitors (NNIs) bind to the RdRp protein at allosteric sites. By reviewing these inhibitors, more precise guidelines for the development of more promising anti-RNA virus drugs should be set, and due to the current health emergency, they will eventually be used for COVID-19 treatment.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , Reposicionamento de Medicamentos , Inibidores Enzimáticos/uso terapêutico , Animais , Antivirais/química , COVID-19/epidemiologia , Inibidores Enzimáticos/química , Humanos , Nucleosídeos/química , Nucleosídeos/uso terapêutico , Pandemias , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia
11.
Sci Adv ; 7(7)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33568474

RESUMO

The triple-cation mixed-halide perovskite (FA x MA y Cs1-x-y )Pb(IzBr1-z )3 (FAMACs) is the best composition for thin-film solar cells. Unfortunately, there is no effective method to prepare large single crystals (SCs) for more advanced applications. Here, we report an effective additive strategy to grow 2-inch-sized high-quality FAMACs SCs. It is found that the judiciously selected reductant [formic acid (FAH)] effectively minimizes iodide oxidation and cation deprotonation responsible for phase segregation. Consequently, the FAMACs SC shows more than fivefold enhancement in carrier lifetimes, high charge mobility, long carrier diffusion distance, as well as superior uniformity and long-term stability, making it possible for us to design high-performance self-powered integrated circuit photodetector. The device exhibits large responsivity, high photoconductive gain, excellent detectivity, and fast response speed; all values are among the highest reported to date for planar-type single-crystalline perovskite photodetectors. Furthermore, an integrated imaging system is fabricated on the basis of 12 × 12 pixelated matrixes of the single-crystal photodetectors.

12.
Mol Med ; 27(1): 4, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413076

RESUMO

BACKGROUND: Vascular cognitive impairment (VCI) is a common cognitive disorder caused by cerebrovascular disease, ranging from mild cognitive impairment to dementia. Studies have shown that aerobic exercise might alleviate the pathological development of VCI, and our previous study observed that aerobic exercise could alleviate VCI through NF-κB/miR-503/BDNF pathway. However, there are few studies on the mechanism. Therefore, it is of great significance to fill the gaps in the mechanism for the early diagnosis of VCI and the clinical prevention and treatment of vascular dementia. METHODS: CircRNA microarray analysis and quantitative real-time PCR were used to detect the expression of circRNA regulating synaptic be exocytosis 2 (RIMS2) (circRIMS2). Cell apoptosis was determined by TdT-mediated dUTP nick-end labeling (TUNEL) assay. The dual-luciferase reporter assay was performed to verify the interaction between circRIMS2 and miR-186, as well as miR-186 and BDNF. RNA pull-down assay detected the binding between circRIMS2 and miR-186. A VCI mouse model was established by repeated ligation of bilateral common carotid arteries (2VO). The lentiviral interfering vector was injected into the VCI mice through the lateral ventricle. The mice in the aerobic exercise group performed 30 min (12 m/min) running for 5 days a week. A Morris water maze test was performed after 4 weeks. RESULTS: The expression of circRIMS2 and BDNF in the serum of VCI patients was significantly reduced, miR-186 expression was increased, and the expression of circRIMS2 was increased in the 2VO group of mice undergoing aerobic exercise. The expression levels of circRIMS2 and BDNF in the oxygen and glucose deprivation-treated (OGD-treated) cells were decreased, the miR-186 expression and cell apoptosis were increased, while the effect was weakened after transfection with the lentiviral vector pLO-ciR-RIMS2. CircRIMS2 could bind to miR-186, and after interference with circRIMS2 in HT22 cells, the expression of miR-186 was increased. Besides, miR-186 could bind to BDNF, and BDNF expression was decreased because of the overexpression of miR-186 in HT22 cells. The expression level of BDNF in the pLO-ciR-RIMS2 group was increased, and apoptosis was decreased, but the miR-186 mimic weakened the effect of pLO-ciR-RIMS2. Aerobic exercise could shorten the average time that mice reached the platform in the Morris water maze, increase the expression level of circRIMS2 and BDNF, reduce miR-186 expression, and inhibit neuronal apoptosis. However, the interference with circRIMS2 weakened this effect. CONCLUSION: The expression of circRIMS2 was down-regulated in VCI and aerobic exercise reduced neuronal apoptosis, and circRIMS2 improved VCI through the circRIMS2/miR-186/BDNF axis.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Disfunção Cognitiva/reabilitação , Terapia por Exercício/métodos , MicroRNAs/genética , Neurônios/citologia , RNA Circular/genética , Animais , Apoptose , Estudos de Casos e Controles , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Regulação para Baixo , Exercício Físico , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Análise em Microsséries , Teste do Labirinto Aquático de Morris , Neurônios/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
13.
Adv Mater ; 33(8): e2006010, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33475209

RESUMO

Low ionic migration is required for a semiconductor material to realize stable high-performance X-ray detection. In this work, successful controlled incorporation of not only methylammonium (MA+ ) and cesium (Cs+ ) cations, but also bromine (Br- ) anions into the FAPbI3 lattice to grow inch-sized stable perovskite single crystal (FAMACs SC) is reported. The smaller cations and anions, comparing to the original FA+ and I- help release lattice stress so that the FAMACs SC shows lower ion migration, enhanced hardness, lower trap density, longer carrier lifetime and diffusion length, higher charge mobility and thermal stability, and better uniformity. Therefore, X-ray detectors made of the superior FAMACs SCs show the highest sensitivity of (3.5 ± 0.2) × 106 µC Gyair -1 cm-2 , about 29 times higher than the latest record of 1.22 × 105 µC Gyair -1 cm-2 for polycrystalline MAPbI3 wafer under the same 40 keV X-ray radiation. Furthermore, the FAMACs SC X-ray detector shows a low detection limit of 42 nGy s-1 , stable dark current, and photocurrent response. Finally, it is demonstrated that high contrast X-ray imaging is realized using the FAMACs SC detector. The effective triple-cation mixed halide strategy and the high crystalline quality make the present FAMACs SCs promising for next-generation X-ray imaging systems.

14.
Angew Chem Int Ed Engl ; 60(8): 4238-4244, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33156572

RESUMO

Surface defects have been a key constraint for perovskite photovoltaics. Herein, 1,3-dimethyl-3-imidazolium hexafluorophosphate (DMIMPF6 ) ionic liquid (IL) is adopted to passivate the surface of a formamidinium-cesium lead iodide perovskite (Cs0.08 FA0.92 PbI3 ) and also reduce the energy barrier between the perovskite and hole transport layer. Theoretical simulations and experimental results demonstrate that Pb-cluster and Pb-I antisite defects can be effectively passivated by [DMIM]+ bonding with the Pb2+ ion on the perovskite surface, leading to significantly suppressed non-radiative recombination. As a result, the solar cell efficiency was increased to 23.25 % from 21.09 %. Meanwhile, the DMIMPF6 -treated perovskite device demonstrated long-term stability because the hydrophobic DMIMPF6 layer blocked moisture permeation.

15.
World J Clin Cases ; 8(21): 5070-5085, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33269244

RESUMO

Evaluating patients with chronic venous leg ulcers (CVLUs) is essential to find the underlying etiology. The basic tenets in managing CVLUs are to remove the etiological causes, to address systemic and metabolic conditions, to examine the ulcers and artery pulses, and to control wound infection with debridement and eliminating excessive pressure on the wound. The first-line treatments of CVLUs remain wound care, debridement, bed rest with leg elevation, and compression. Evidence to support the efficacy of silver-based dressings in healing CVLUs is unavailable. Hydrogen peroxide is harmful to the growth of granulation tissue in the wound. Surgery options include a high ligation with or without stripping or ablation of the GSVs depending on venous reflux or insufficiency. Yet, not all CVLUs are candidates for surgical treatment because of comorbidities. When standard care of wound for 4 wk failed to heal CVLUs effectively, use of advanced wound care should be considered based on the available evidence. Negative pressure wound therapy facilitates granulation tissue development, thereby helping closure of CVLUs. Autologous split-thickness skin grafting is still the gold standard approach to close huge CVLUs. Hair punch graft appears to have a better result than traditional hairless punch graft for CVLUs. Application of adipose tissue or placenta-derived mesenchymal stem cells is a promising therapy for wound healing. Autologous platelet-rich plasma provides an alternative strategy for surgery for safe and natural healing of the ulcer. The confirmative efficacy of current advanced ulcer therapies needs more robust evidence.

16.
Org Biomol Chem ; 18(44): 9081-9087, 2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33141138

RESUMO

Burchellin and its analogues are a class of neolignan natural products containing a rare core with three contiguous stereogenic centers. In previous reports, racemic burchellin was synthesized without accessing each of the enantiomers. In this paper, a concise and efficient total synthetic route to divergently access the enantiomers of burchellin and those of its 1'-epi-diastereoisomer over six steps for each is disclosed, where each of the enantiomers was obtained by preparative chiral phase HPLC purification. The key steps include the construction of a 2,3-dihydrobenzofuran moiety by two Claisen rearrangements and a one-step rearrangement/cyclization and subsequent tandem ester hydrolysis/oxy-Cope rearrangement/methylation to furnish the basic skeleton of burchellin. The structures and absolute configurations of the four stereoisomers were determined using spectroscopic data analyses and comparison of experimental and calculated electronic circular dichroism data. These stereoisomers were found to have potent antiviral effects against coxsackie virus B3, and is the first time that bioactivity has been reported for these compounds.

17.
Adv Mater ; 32(47): e2004979, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33079444

RESUMO

Slot-die coating holds advantages over other large-scale technologies thanks to its potential for well-controlled, high-throughput, continuous roll-to-roll fabrication. Unfortunately, it is challenging to control thin.film uniformity over a large area while maintaining crystallization quality. Herein, by using a high-pressure nitrogen-extraction (HPNE) strategy to assist crystallization, a wide processing window in the well-controlled printing process for preparing high-quality perovskites is achieved. The yellow-phase perovskite generated by the HPNE acts as a crucial intermediate phase to produce large-area high-quality perovskite film. Furthermore, an ionic liquid is developed to passivate the perovskite surface to reduce surface defect density and to suppress carrier recombination, resulting in significantly increased efficiency to 22.7%, the highest for large-area fabrication. The strategies are successfully extended to large-area device fabrication, making it possible to produce a 40 × 40 mm2 module with stabilized PCE as high as 19.4%, the highest-efficiency for a large-area module to date.

18.
Eur J Med Chem ; 206: 112711, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32810751

RESUMO

This review fully describes the coronavirus 3CLpro peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CLpro inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CLpro Cys145 residue and thereby achieve irreversible inhibition effects, whereas nonpeptidic small molecule inhibitors mainly interact with residues in the S1', S1, S2 and S4 pockets via hydrogen bonds, hydrophobic bonds and van der Waals forces. Based on the emerging PROTAC technology and the existing 3CLpro inhibitors, 3CLpro PROTAC degraders are hypothesised to be next-generation anti-coronavirus drugs.


Assuntos
Antivirais/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/uso terapêutico , Proteases 3C de Coronavírus , Cisteína Endopeptidases , Humanos , Peptidomiméticos , Inibidores de Proteases/uso terapêutico
19.
Mol Med Rep ; 22(3): 1994-2002, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32705177

RESUMO

Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. Mutations in the TPMT gene can affect drug activity, which may have adverse effects in humans. Thus, genotyping can help elucidate genetic determinants of drug response to thiopurines and optimize the selection of drug therapies for individual patients, effectively avoiding palindromia during maintenance treatment caused by insufficient dosing and the serious side effects caused by excessive doses. The current available detection methods used for TPMT*3B and TPMT*3C are complex, costly and time­consuming. Therefore, innovative detection methods for TPMT genotyping are urgently required. The aim of the present study was to establish and optimize a simple, specific and timesaving TPMT genotyping method. Using the principles of Web­based Allele­Specific PCR and competitive real­time fluorescent allele­specific PCR (CRAS­PCR), two pairs of Scorpion primers were designed for the detection of TPMT*3B and *3C, respectively, and a mutation in TPMT*3A was inferred based on data from TPMT*3B and *3C. In total, 226 samples from volunteers living in Chongqing were used for CRAS­PCR to detect TPMT*3 mutations. Results showed that nine (3.98%) were mutant (MT) heterozygotes and none were MT homozygotes for TPMT*3C, and no TPMT*3A and TPMT*3B mutations were found. Three TPMT*3C MT heterozygotes were randomly selected for DNA sequencing, and CRAS­PCR results were consistent with the sequencing results. In conclusion, in order to improve simplicity, specificity and efficiency, the present study established and optimized CRAS­PCR assays for commonly found mutant alleles of TPMT*3A (G460A and A719G), TPMT*3B (G460A), and TPMT*3C (A719G).


Assuntos
Primers do DNA/genética , Técnicas de Genotipagem/métodos , Metiltransferases/genética , Mutação , Adulto , Animais , Feminino , Voluntários Saudáveis , Humanos , Masculino , Reação em Cadeia da Polimerase , Adulto Jovem
20.
J Med Chem ; 63(13): 6979-6990, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32491863

RESUMO

We report on a cyclic peptide that inhibits matrix metalloproteinase-2 (MMP2) activation with a low-nM-level potency. This inhibitor specifically binds to the D570-A583 epitope on proMMP2 and interferes with the protein-protein interaction (PPI) between proMMP2 and tissue inhibitor of metalloproteinases-2 (TIMP2), thereby preventing the TIMP2-assisted proMMP2 activation process. We developed this cyclic peptide inhibitor through an epitope-targeted library screening process and validated its binding to proMMP2. Using a human melanoma cell line, we demonstrated the cyclic peptide's ability to modulate cellular MMP2 activities and inhibit cell migration. These results provide the first successful example of targeting the PPI between proMMP2 and TIMP2, confirming the feasibility of an MMP2 inhibition strategy that has been sought after for 2 decades.


Assuntos
Metaloproteinase 2 da Matriz/metabolismo , Peptídeos Cíclicos/farmacologia , Sequência de Aminoácidos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Biblioteca de Peptídeos , Peptídeos Cíclicos/química , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidor Tecidual de Metaloproteinase-2/metabolismo
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