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1.
Food Funct ; 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34985089

RESUMO

Polygonum multiflorum (PM), a popular functional food, and a herbal and dietary supplement, is widely used as a tonic in China and East Asia. In recent years, it has attracted great concern for its ability to cause idiosyncratic drug-induced liver injury (IDILI). However, identifying individuals susceptible to IDILI remains challenging. This is a prospective study. For 6 patients whose serum alanine aminotransferase (ALT) levels after consuming PM were abnormally elevated (susceptible group), 15 patients with normal levels of liver injury markers were matched (tolerant group) based on similar baseline characteristics. ProcartaPlex immunoassays were adopted to quantitatively detect 33 serum cytokines in the two groups of patients before consuming PM, to characterize the cytokine profile and screen differential cytokines. Subsequently, the susceptibility of a potential biomarker to regulate PM-induced liver injury was validated in animal models. There were significant differences in the cytokine profiles between the susceptible and tolerant groups, wherein the susceptible patients showed immune perturbation characterized by high expression of multiple inflammatory cytokines, especially the proinflammatory cytokine TNF-α (P = 0.006). Among them, the cytokine TNF-α had the strongest correlation with ALT, where the correlation coefficient was greater than 0.6, and the area under the receiver operating characteristic curve was more than 0.8. Animal experiments revealed that both PM water extract and its susceptibility component of liver injury, cis-stilbene glucoside, could cause liver injury in the mice pre-stimulated using TNF-α. Conversely, administration of the same dose of drugs on control mice did not show any hepatotoxicity. In conclusion, immune perturbation mainly mediated by TNF-α may regulate the susceptibility to PM-induced liver injury. This provides a new perspective for the study of susceptibility to IDILI.

2.
Bioorg Chem ; 119: 105583, 2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34971943

RESUMO

In recent years, bacterial resistance has risen sharply, which seriously endangers public health due to the abuse of antibiotics and the lack of new antibiotics. Therefore, there is an urgent need for new antimicrobial agents to combat multidrug-resistant (MDR) bacterial infections. In this paper, six Oreoch-2 analogues were rationally designed and efficiently synthesized by using the truncation strategy with Oreoch-2 as the lead compound. Evaluation of these analogues against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed. Among them, ZN-5 and ZN-6 were identified to be broad-spectrum effective analogues, which were superior to their parent peptide Oreoch-2. In addition, ZN-5 and ZN-6 had good stability to the physiological environment, and much higher selectivity to bacterial cells than to mammalian cells. Time-kill kinetics and transmission electron microscope (TEM) studies suggested that these analogues were typical bactericidal agents and quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. Moreover, ZN-5 and ZN-6 could inhibit biofilm formation of Staphylococcus aureus ATCC25923. Compared with their parent peptide Oreoch-2, ZN-5 and ZN-6 not only possessed shortened peptide chains, but also showed slightly improved antibacterial activity and greatly reduced hemolysis. This indicates that they are ideal lead compounds of antimicrobial peptides, which can be developed as substitutes for traditional antibiotics.

3.
Neurol Ther ; 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34729706

RESUMO

INTRODUCTION: Many patients with ocular myasthenia gravis (OMG) progress to generalized disease within the first 2 years of the onset of ocular symptoms. Several retrospective studies have identified risk factors associated with generalization, however these studies included patients on immunosuppression therapy or those undergoing thymectomy, which may reduce the generalization risk. In this study we explored the risk factors for generalization in non-immunosuppressed and non-thymectomized patients with OMG. METHODS: Data from patients with OMG treated at seven tertiary hospitals in China were retrospectively reviewed. Clinical characteristics, including sex, age at onset, symptoms at onset, comorbid autoimmune diseases, neostigmine test response, repetitive nerve stimulation (RNS) findings, presence of serum anti-acetylcholine receptor antibody (AChR-Ab), and thymic status based on radiological and pathological studies, were collected. The main outcome measure was disease generalization. The follow-up period was defined as the date of ocular symptom onset to the date of confirmation of generalization or immunotherapy initiation, or last follow-up (defined as 60 months). The Cox proportional hazards model was used to assess the risk factors for generalization. RESULTS: Overall, 572 patients (269 women) were eligible for inclusion in the analysis, of whom 144 developed generalization. The mean (standard deviation) onset age was 45.5 (19.8) years, and the median (interquartile range) follow-up period was 14.5 (7.0-47.3) months. Multivariable Cox regression analysis demonstrated that both early-onset (adjusted hazard ratio [aHR] 5.34; 95% confidence interval [CI] 1.64-17.36; p = 0.005) and late-onset (aHR 7.18; 95% CI 2.22-23.27; p = 0.001) in adulthood, abnormal RNS findings (aHR 3.01; 95% CI 1.97-4.61; p < 0.001), seropositivity for AChR-Ab (aHR 2.58; 95% CI 1.26-5.26; p = 0.01), and thymoma (aHR 1.62; 95% CI 1.05-2.49; p = 0.03) were independently associated with increased risk of generalization. CONCLUSION: The risk of generalization increased significantly in patients with adult-onset OMG, abnormal RNS findings, seropositivity for AChR-Ab, and thymoma, suggesting that these risk factors may predict OMG generalization.

4.
Nanomaterials (Basel) ; 11(11)2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34835913

RESUMO

Steam reforming of glycerol to produce hydrogen is considered to be the very promising strategy to generate clean and renewable energy. The incipient-wetness impregnation method was used to load Ni on the reducible carrier TiO2 (P25). In the process of catalyst preparation, the interaction and electronic effect between metal Ni and support TiO2 were adjusted by changing the calcination temperature, and then the activity and hydrogen production of glycerol steam reforming reaction (GSR) was explored. A series of modern characterizations including XRD, UV-vis DRS, BET, XPS, NH3-TPD, H2-TPR, TG, and Raman have been applied to systematically characterize the catalysts. The characterization results showed that the calcination temperature can contribute to varying degrees of influences on the acidity and basicity of the Ni/TiO2 catalyst, the specific surface area, together with the interaction force between Ni and the support. When the Ni/TiO2 catalyst was calcined at 600 °C, the Ni species can be produced in the form of granular NiTiO3 spinel. Consequently, due to the moderate metal-support interaction and electronic activity formed between the Ni species and the reducible support TiO2 in the NiO/Ti-600C catalyst, the granular NiTiO3 spinel can be reduced to a smaller Ni0 at a lower temperature, and thus to exhibit the best catalytic performance.

5.
J Phys Chem B ; 125(48): 13279-13290, 2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34814686

RESUMO

The photoinduced intramolecular charge separation (CS) and charge recombination (CR) phenomena in a series of donor-bridge-acceptor (D-B-A) molecules are intensively investigated as a means of understanding electron transport through the π-B. Pyrene (Pyr) and triarylamine (TAA) moieties connected via phenylene Bs of various lengths are studied because their CS and CR behaviors can be readily monitored in real time by femtosecond transient absorption (fs-TA) spectroscopy. By combining the steady-state and fs-TA spectroscopic measurements in a variety of solvents together with chemical calculations, the parameters that govern the CS behaviors of these dyads were obtained, such as the solvent effects on free energy and the B-length-dependent electronic coupling (VDA) between D and A. We observed the sharp switch of the CS behavior with the increase of the solvent polarity and B-linker lengths. Furthermore, in the case of the shortest distance between D and A when the electron coupling is sufficiently large, we observed that the CS phenomenon occurs even in low-polar solvents. Upon increasing the length of B, CS occurs only in strong polar solvents. The distance-dependent decay constant of the CS rate is determined as ∼0.53 Å-1, indicating that CS is governed by superexchange tunneling interactions. The CS rate constants are also approximately estimated using Marcus electron transfer theory, and the results imply that the VDA value is the key factor dominating the CS rate, while the facile rotation of the phenylene B is important for modulating the lifetime of the charge-separated state in these D-B-A dyads. These results shed light on the practical strategy for obtaining a high CS efficiency with a long-lived CS state in TAA-B-Pyr derivatives.

6.
Orthop Surg ; 13(8): 2396-2404, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34816604

RESUMO

OBJECTIVE: To describe spinal osteotomy in lateral position, which might be a new strategy for correcting thoracolumbar kyphotic deformity combined with severe hip flexion contracture, and to present two cases in which this method was successfully performed. METHODS: Spinal osteotomies in lateral position were performed in two patients with severe thoracolumbar kyphosis combined with hip flexion contracture, which was not suitable for operation in the prone position. Case 1: a 33-year-old female AS patient still had severe hip flexion contracture due to poor rehabilitation after total hip replacement (THR). The range of movement of the hip was only about 15° in right and 10° in left. Pre-operativethoracic kyphosis (TK), thoracolumbar kyphosis (TLK), lumbar lordosis (LL), and sagittal vertical axis (SVA) were 52.4°, 49.1°, 42.7°, and 315 mm, respectively. Pedicle subtraction osteotomy (PSO) at L3 was performed in the lateral position. The eggshell procedure was used during osteotomy. Case 2: a 45-year-old male AS patient presented coexisting rigid thoracolumbar kyphosis and hip flexion contracture. The range of movement of the hip was only about 20° in right and 25° in left. Pre-operativeTK, TLK, LL and SVA were 34.9°, 66.8°, 58.8° and 290.8 mm, respectively. PSO at L2 was performed in lateral position. The eggshell procedure was also used. RESULTS: Sagittal malalignments of both patients were greatly improved. For case 1, the total operation time was 5.5 h. The blood loss was 1500 mL and the amount of allogeneic blood transfusion was 1580 mL during the operation. SVA was reduced to 127 mm and LL decreased from preoperative 42.7° to -28.4°. The correction angle through L3 was 34.7° and the correction angle through the osteotomy segment was 62.9°. For case 2, the duration of surgery was 6.5 h. The operative blood loss was 2000 mL and the total amount of blood transfusion was 2020 mL. SVA was reduced to 209.8 mm and LL decreased from preoperative 58.8° to 9.2°.The correction angle through L2 was 37.1° and the correction angle through the osteotomy segment was 55°. No intra-operative or post-operative complications were observed. Six months after PSO, case 1 had good posture for standing and sitting. The case 2 underwent bilateral THRs nine months after PSO. CONCLUSION: PSO could be performed in the lateral position successfully. For AS patients who cannot be placed in the prone position due to coexisting severe thoracolumbar kyphosis and hip flexion contracture, performing spinal osteotomy in the lateral position as the first step is an alternative.

7.
Eur J Radiol ; 144: 109991, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34638081

RESUMO

PURPOSE: This systematic review and meta-analysis aimed to evaluate the diagnostic performance of ultrasound elastography in the differentiation of benign and malignant breast non-mass lesions (NMLs). METHODS: PubMed, Cochrane Library, and Embase databases were searched for eligible studies up to end of June 2021. The diagnostic performance of elastography for NMLs was investigated using pooled sensitivity and specificity, likelihood ratio, diagnostic odds ratio (DOR), post-test probability, and the area under hierarchical summary receiver operating characteristic curve (HSROC). RESULTS: Eleven studies involving 812 NMLs (malignant 414) were included. The pooled sensitivity, specificity, DOR, positive likelihood ratio, and negative likelihood of elastography for the differentiation of benign and malignant breast NMLs were 79% (95 %CI: 71-85), 86% (95 %CI: 79-91), 23.32 (95 %CI: 13.38-40.66), 5.67 (95 %CI: 3.79-8.47), and 0.24 (95 %CI: 0.17-0.34), respectively. No significant publication bias existed. The area under the HSROC curve was 90% (95 %CI: 87-92). Fagan plots demonstrated good clinical utility. However, substantial heterogeneity existed. Country, measurement index, and number of lesions served as potential sources of heterogeneity. CONCLUSIONS: The results of this study suggest that elastography has high diagnostic accuracy in differentiating between malignant and benign NMLs. Elastography can be a feasible and non-invasive tool for breast NMLs.


Assuntos
Técnicas de Imagem por Elasticidade , Diagnóstico Diferencial , Humanos , Curva ROC , Sensibilidade e Especificidade
8.
Front Pharmacol ; 12: 693928, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630079

RESUMO

Early identification of individuals susceptible to idiosyncratic drug-induced liver injury (IDILI) is a challenging unmet demand. Diclofenac, one of the most widely available over-the-counter drugs for pain management worldwide, may induce liver dysfunction, acute liver failure, and death. Herein, we report that diclofenac-related hepatobiliary adverse reactions occurred more frequently in cases with immune activation. Furthermore, experiments with rats demonstrated divergent hepatotoxicity responses in individuals exposed to diclofenac, and modest inflammation potentiated diclofenac-induced liver injury. Susceptible rats had unique plasma metabolomic characteristics, and as such, the metabolomic approach could be used to distinguish susceptible individuals. The 23 identified susceptibility-related metabolites were enriched by several metabolic pathways related to acute-phase reactions of immunocytes and inflammatory responses, including sphingolipid, tyrosine, phenylalanine, tryptophan, and lipid metabolism pathways. This finding implies a mechanistic role of metabolic and immune disturbances affects susceptibility to diclofenac-IDILI. Further nine metabolite biomarkers with potent diagnostic capabilities were identified using receiver operating characteristic curves. These findings elucidated the potential utility of metabolomic biomarkers to identify individuals susceptible to drug hepatotoxicity and the underlying mechanism of metabolic and immune disturbances occurring in IDILI.

9.
Front Immunol ; 12: 730483, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512666

RESUMO

The antiviral innate immunity is the first line of host defense against viral infection. Mitochondrial antiviral signaling protein (MAVS, also named Cardif/IPS-1/VISA) is a critical protein in RNA virus-induced antiviral signaling pathways. Our previous research suggested that E3 ubiquitin-protein ligases RING-finger protein (RNF90) negatively regulate cellular antiviral responses by targeting STING for degradation, though its role in RNA virus infection remains unknown. This study demonstrated that RNF90 negatively regulated RNA virus-triggered antiviral innate immune responses in RNF90-silenced PMA-THP1 cells, RNF90-deficient cells (including HaCaTs, MEFs, and BMDMs), and RNF90-deficient mice. However, RNF90 regulated RNA virus-triggered antiviral innate immune responses independent of STING. RNF90 promoted K48-linked ubiquitination of MAVS and its proteasome-dependent degradation, leading to the inhibition of innate immune responses. Altogether, our findings suggested a novel function and mechanism of RNF90 in antiviral innate immunity.

10.
Am J Reprod Immunol ; 86(6): e13500, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34558137

RESUMO

A common genetic variant in the follicle stimulating hormone receptor gene (FSHR) 5'-untranslated region has been previously reported to influence FSHR gene expression. However, studies on the ovarian response to exogenous gonadotropin stimulation are limited. The aim of this study was to evaluate the association of variants at positions -29 of the FSHR gene with the ovarian response to exogenous FSH stimulation in Chinese women. The genotypes of the FSHR gene were assayed using the Sequenom MassARRAY system. Total RNA and protein was extracted from granulosa cells, and FSHR expression at the mRNA and protein levels was assessed using quantitative PCR and western blotting. Our data revealed that there was no association between the FSHR genotype at the -29 position and the outcome of controlled ovarian stimulation. The expression of FSHR, at both the mRNA and protein levels, was similar amongst the different FSHR genotypes assessed, but was significantly reduced in the low responders. These results indicate that the variants caused by mutations at position -29 are not associated with ovarian response, and the low ovarian response to gonadotropin stimulation may be caused by decreased FSHR expression.

11.
J Phys Chem B ; 125(40): 11275-11284, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34587453

RESUMO

In the past decades, tremendous efforts have been invested into organic molecules involved in the excited-state intramolecular proton transfer (ESIPT) reaction due to their enormously Stokes-shifted fluorescence and distinctive photophysical properties. The alterations of the environmental medium can effectively adjust the luminous performance of ESIPT molecules, which inspires us to unravel the solvent effect on the ESIPT mechanism. Here, we report the solvent-dependent excited-state properties of two new seven-membered ring pyrrole-indole ESIPT molecules, g-PPDBI and e-PPDBI, by steady-state spectra, picosecond transient fluorescence spectra, femtosecond transient absorption spectra, and theoretical calculations. The bathochromic-shifted normal fluorescence and the negligibly shifted tautomer fluorescence suggest the occurrence of an excited-state intramolecular proton-coupled charge transfer reaction. Thus, the solvent effect plays a vital role in stabilizing the intramolecular charge transferred state, resulting in a higher ESIPT reaction barrier in more polar solvents. Additionally, the observation of the slight dynamic difference between PPDBIs with different π-conjugation positions provides a new strategy to adjust the performance of ESIPT molecules.


Assuntos
Prótons , Pirróis , Ligação de Hidrogênio , Indóis , Solventes
12.
Langmuir ; 37(40): 11707-11715, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34570511

RESUMO

The unconjugated bilirubin (BR) may penetrate through the cell membrane and cause a severe cytotoxicity. However, the molecular mechanism underlying the penetration of BR into the cell membrane is still largely unknown. In this work, we systematically investigate the interaction of BR and a lipid bilayer under different conditions by using all-atom molecular dynamics simulations. It is found that BR at the Z,Z conformation can easily enter into the interior of the lipid bilayer due to its hydrophobicity. However, when BR transforms from the Z,Z conformation to the E,E conformation (after the blue-light emission), its penetration ability is greatly reduced (especially at its ionized state). This study may offer useful physical insights into the effect of phototherapy on the penetration behavior and the cytotoxicity of the unconjugated BR.


Assuntos
Bilirrubina , Bicamadas Lipídicas , Membrana Celular , Conformação Molecular , Simulação de Dinâmica Molecular
13.
Am J Med Sci ; 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34332968

RESUMO

OBJECTIVE: The purpose of the current study was to describe the clinico-pathological characteristics and outcomes in patients with lupus nephritis with IgA deposits in the kidneys. MATERIALS AND METHODS: A total of 258 patients with lupus nephritis with complete clinical data and follow-up was enrolled. They were divided into two groups: the IgA deposits group and the non-IgA deposits group. Their clinico-pathological features and outcomes between the two groups were further compared. RESULTS: Patients with IgA deposits had significantly lower prevalence of acute kidney failure, higher eGFR, lower plasma levels of C3a, and lower renal pathological chronicity indices scores than those with non-IgA deposits (19.4% vs. 31.8%, 80.9±35.6 vs. 69.1±39.6 ml/min/1.73m2, 1045.48 [559.41, 1796.34] vs. 1920.77 [1155.08, 2986.96]ng/ml, and 2 [1, 3] vs. 2.5 [2, 4], respectively, all P<0.05). Patients with IgA deposits also had a higher frequency of the CFH rs6677604-AA/GA genotype in comparison with those with non-IgA deposits (12.0% vs. 8.2%, P=0.469). Using the multivariable Cox hazard analysis, the IgA deposits were identified as a protective factor of survival from the composite events (HR 0.423; 95% CI, 0.219 to 0.816; P=0.01). CONCLUSIONS: Patients with IgA deposits presented with milder renal damage and a good prognosis, which suggested its protective role in lupus nephritis.

14.
Eur J Med Chem ; 224: 113723, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34340044

RESUMO

The death caused by pathogenic bacteria has always been a severe threat to mankind. The prevalence of drug resistance among bacteria underscores an urgent goal for new antibacterial agents with novel mode of action. Here we first designed and synthesized a class of benzothiazolyl-5-methylphenanthridium derivatives and evaluated their antibacterial activity. On this basis, we further designed and synthesized another class of novel indolyl-5-methylphenanthridium derivatives by optimizing the benzothiazolyl-5-methylphenanthridium core and evaluated their antibacterial activity targeting the bacterial cell division protein FtsZ. The results showed that the indolyl-5-methylphenanthridium derivatives had greatly improved activity against various drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (VRE). Among them, compound C5 displayed excellent antibacterial activity against susceptible (MIC = 1 µg/mL), methicillin-resistant and clinical isolated S. aureus (MIC = 2 µg/mL). With low hemolytic activity towards mice red blood cells, C5 exhibited good antibacterial effect in vivo in preliminary pharmacodynamic assay. More importantly, C5 was difficult to induce bacterial resistance. Further mechanism studies proved that C5 could inhibit bacterial cell division by promoting FtsZ polymerization, leading to disorderly polymerization and disordered knots. Therefore, our findings suggest that this class of novel indolyl-5-methylphenanthridium derivatives are promising for future antibacterial agents.

15.
Quant Imaging Med Surg ; 11(7): 3252-3262, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34249651

RESUMO

Background: This study sought to develop and validate a nomogram combining the elastographic Q-analysis score (EQS), the Prostate Imaging Reporting and Data System (PI-RADS) score, and clinical parameters for the stratification of patients with prostate cancer (PCa). Methods: A retrospective study was conducted of 375 patients with 375 lesions who underwent volume-navigation transrectal ultrasound (TRUS) and multiparametric magnetic resonance imaging (MP-MRI)-fusion targeted biopsies between April 2017 and January 2020. Based on a multivariate logistic regression model, a nomogram was created to assess any PCa and high-risk PCa [Gleason score (GS) ≥4+3] using data from patients diagnosed between April 2017 and June 2019 (n=271), and was validated in patients diagnosed after July 2019 (n=104). The nomogram's performance was evaluated based on its discrimination, calibration, and clinical usefulness. Results: The areas under the curve (AUCs) of the nomogram for predicting any PCa and high-risk PCa were 0.949 [95% confidence interval (CI), 0.921 to 0.978] and 0.936 (95% CI, 0.906 to 0.965), respectively, in the training cohort, and 0.946 (95% CI, 0.894 to 0.997) and 0.971 (95% CI, 0.9331 to 1), respectively, in the validation cohort. The nomogram was well calibrated, and no significant difference was found between the predicted and observed probabilities. A decision curve analysis (DCA) for the nomogram with and without the EQS showed that the threshold probability of for any PCa was <67%. Conclusions: The nomogram that combined elastography-derived and MP-MRI data was more clinically useful than the model based on PI-RADS and clinical parameters alone. Our nomogram could aid urologists to make decisions and avoid unnecessary biopsies.

16.
Front Neurol ; 12: 652941, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935953

RESUMO

Objective: To determine the association between serum phosphate level and 1-year clinical outcomes in patients with acute ischemic stroke and transient ischemic attack. Methods: We included 7,353 patients with acute ischemic stroke and transient ischemic attack from the China National Stroke Registry III for analysis. Participants were divided into 4 groups according to serum phosphate quartiles. Composite end point included recurrent stroke, myocardial infarction, other ischemic vascular events, and all-cause mortality. Poor functional outcome is defined as modified Rankin Scale score of 3 to 6. Multivariable Cox regression or logistic regression was used to evaluate the independent association of serum phosphate with 1-year all-cause mortality, recurrent stroke, composite end point and poor functional outcome. Results: The mean age of the included 7,353 patients was 62.5 years, and 68.6% of them were men. Plotting hazard ratios over phosphate levels suggested a U-shaped association especially for recurrent stroke and composite end point, and therefore the third quartile group was set as reference group. Compared with the third quartile of phosphate (1.06-1.20 mmol/L), the adjusted hazard ratios/odds ratios (95% CI) of the lowest quartile (<0.94 mmol/L) were 0.98 (0.67-1.42) for all-cause mortality, 1.31 (1.05-1.64) for stroke recurrence, 1.26 (1.02-1.57) for composite end point, and 1.27 (1.01-1.61) for poor functional outcome, and the adjusted odds ratio of the highest quartile (≥1.2 mmol/L) was 1.40 (1.11-1.77) for poor functional outcome. Conclusions: Serum phosphate may be an independent predictor of stroke recurrence, composite end point and poor functional outcome after ischemic stroke.

17.
Bioorg Chem ; 113: 104992, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051415

RESUMO

Bacterial infections are still the main significant problem of public health in the world, and their elimination will greatly rely on the discovery of antibacterial drugs. In the processes of our searching for novel macrolide derivatives with excellent activity against sensitive and resistant bacteria, three series of novel N11-, C12- and C13-substituted 15-membered homo-aza-clarithromycin derivatives were designed and synthesized as Series A, B and C by creatively opening the lactone ring of clarithromycin (CAM), introducing various 4-substituted phenyl-1H-1,2,3-triazole side chains at the N11, C12 or C13 position of CAM and macrolactonization. The results from their in vitro antibacterial activity demonstrated that compounds 20c, 20d and 20f displayed not only the most potent activity against S. aureus ATCC25923 with the MIC values of 0.5, 0.5 and 0.5 µg/mL, but also greatly improved activity against B. subtilis ATCC9372 with the MIC values of less than or equal to 0.25, 0.25 and 0.25 µg/mL, respectively. In particular, compound 11g exhibited the strongest antibacterial effectiveness against all the tested resistant bacterial strains and had well balanced activity with the MIC values of 4-8 µg/mL. Further study on minimum bactericidal concentration and kinetics confirmed that compound 11g possessed a bacteriostatic effect on bacterial proliferation. Moreover, the results of molecular docking revealed an potential additional binding force between compound 11g and U790 in addition to the normal binding force of macrolide skeleton, which may explain why this compound performed the most potent activity against resistant bacteria. The results of cytotoxic assay indicated that compounds 20c, 20d and 20f were non-toxic to human breast cancer MCF-7 cells at its effective antibacterial concentration.


Assuntos
Antibacterianos/farmacologia , Compostos Aza/farmacologia , Bacillus subtilis/efeitos dos fármacos , Claritromicina/farmacologia , Desenho de Fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Compostos Aza/síntese química , Compostos Aza/química , Claritromicina/síntese química , Claritromicina/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
18.
Spectrochim Acta A Mol Biomol Spectrosc ; 259: 119768, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33971438

RESUMO

The tuber development and nutrient transportation of potato crops are closely related to canopy photosynthesis dynamics. Chlorophyll fluorescence parameters of photosystem II, especially the maximum quantum yield of primary photochemistry (Fv/Fm), are intrinsic indicators for plant photosynthesis. Rapid detection of Fv/Fm of leaves by spectroscopy method instead of time-consuming pulse amplitude modulation technique could help to indicate potato development dynamics and guide field management. Accordingly, this study aims to extract fluorescence signals from hyperspectral reflectance to detect Fv/Fm. Hyperspectral imaging system and closed chlorophyll fluorescence imaging system were applied to collect the spectral data and values of Fv/Fm of 176 samples. The spectral data were decomposed by continuous wavelet transform (CWT) to obtain wavelet coefficients (WFs). Three mother wavelet functions including second derivative of Gaussian (gaus2), biorthogonal 3.3 (bior3.3) and reverse biorthogonal 3.3 (rbio3.3) were compared and the bior3.3 showed the best correlation with Fv/Fm. Two variable selection algorithms were used to select sensitive WFs of Fv/Fm including Monte Carlo uninformative variables elimination (MC-UVE) algorithm and random frog (RF) algorithm. Then the partial least squares (PLS) regression was used to establish detection models, which were labeled as bior3.3-MC-UVE-PLS and bior3.3-RF-PLS, respectively. The determination coefficients of prediction set of bior3.3-MC-UVE-PLS and bior3.3-RF-PLS were 0.8071 and 0.8218, respectively, and the root mean square errors of prediction set were 0.0181 and 0.0174, respectively. The bior3.3-RF-PLS had the best detection performance and the corresponding WFs were mainly distributed in the bands affected by fluorescence emission (650-800 nm), chlorophyll absorption and reflection. Overall, this study demonstrated the potential of CWT in fluorescence signals extraction and can serve as a guide in the quick detection of chlorophyll fluorescence parameters.


Assuntos
Solanum tuberosum , Análise de Ondaletas , Clorofila , Fluorescência , Análise dos Mínimos Quadrados , Folhas de Planta
19.
Eur J Med Chem ; 221: 113480, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33964649

RESUMO

With the increasing incidence of antibiotic resistance, new antibacterial agents having novel mechanisms of action hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Four novel series of substituted 9-arylalkyl-10-methylacridinium derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activities against various Gram-positive and Gram-negative bacteria. The results demonstrated that they exhibited broad-spectrum activities with substantial efficacy against MRSA and VRE, which were superior or comparable to the berberine, sanguinarine, linezolid, ciprofloxacin and vancomycin. In particular, the most promising compound 15f showed rapid bactericidal properties, which avoid the emergence of drug resistance. However, 15f showed no inhibitory effect on Gram-negative bacteria but biofilm formation study gave possible answers. Further target identification and mechanistic studies revealed that 15f functioned as an effective FtsZ inhibitor to alter the dynamics of FtsZ self-polymerization, which resulted in termination of the cell division and caused cell death. Further cytotoxicity and animal studies demonstrated that 15f not only displayed efficacy in a murine model of bacteremia in vivo, but also no significant hemolysis to mammalian cells. Overall, this compound with novel skeleton could serve as an antibacterial lead of FtsZ inhibitor for further evaluation of drug-likeness.


Assuntos
Acridinas/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas do Citoesqueleto/antagonistas & inibidores , Desenho de Fármacos , Staphylococcus aureus/efeitos dos fármacos , Acridinas/síntese química , Acridinas/química , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade
20.
Biomed Chromatogr ; 35(9): e5140, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33830528

RESUMO

Owing to the complexity of the composition of herbal and dietary supplements, it is a challenging problem to efficiently screen and identify active or toxic compounds. Psoralea corylifolia L. (PCL) was selected as the subbject to establish a methodology for rapid screening and identification of hepatotoxic compounds. High-content imaging, ultra-performance liquid chromatography and high-resolution mass spectrometry were used in this study to detect the hepatotoxicity and identify unknown compounds in PCL samples. Then, putative toxic compounds which are highly related to hepatotoxicity were screened by spectrum-toxicity correlation analysis, and the toxicity intensity verified by high-content imaging. The maximum nontoxic dose of processed samples with good detoxification effect reduced more than 9 times compared with unprocessed raw medicinal materials. Spectrum-toxicity correlation analysis showed that bavachinin A, bavachin, isobavachalcone and neobavaisoflavone had high correlation with the hepatotoxicity of PCL, and psoralen and isopsoralen had low correlation with hepatotoxicity. This study verified the hepatotoxicity of these six putative compound monomers, proving the results of spectrum-toxicity correlation analysis. Based on the correlation analysis of high-resolution mass spectrometry of detection compounds and high-content imaging of hepatocyte toxicity data, the potential toxic compound of herbal and dietary supplement products can be quickly and accurately screened.


Assuntos
Suplementos Nutricionais/toxicidade , Medicamentos de Ervas Chinesas/toxicidade , Hepatócitos/efeitos dos fármacos , Psoralea/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ficusina/toxicidade , Flavonoides/toxicidade , Humanos , Isoflavonas/toxicidade , Espectrometria de Massas/métodos , Imagem Molecular/métodos
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