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The extraction of higher-value products from lignin degradations under mild conditions is a challenge. Previous research reported efficient two-step oxidation and reduction strategies for lignin degradation, which has great significance to lignin degradation. In this paper, the mechanism about the C-O bond cleavage of lignin with and without Cα oxidations has been studied systematically. Our calculation results show that the degradation of anionized lignin with Cα oxidations is kinetically and thermodynamically feasible. In addition, the calculations predict that the anionized lignin compounds without Cα oxidation also could be degraded under mild conditions. Moreover, we propose special lignin catalytic degradation systems containing the characteristic structure of "double hydrogen bonds." The double hydrogen bonds structure could further decrease the energy barriers of the C-O bond cleavage reaction. This provides a versatile strategy to design novel lignin degradation.
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BACKGROUND: Clinical practice guidelines aim to support clinicians in providing clinical care and should be supported by evidence. There is currently no information on whether clinical practice guidelines in laparoscopic surgery are supported by evidence. METHODS: We performed a systematic review and identified clinical practice guidelines of laparoscopic surgery published in PubMed and Embase between March 2016 and February 2019. We performed an independent assessment of the strength of recommendation based on the evidence provided by the guideline authors. We used the 'Appraisal of Guidelines for Research & Evaluation II' (AGREE-II) Tool's 'rigour of development', 'clarity of presentation', and 'editorial independence' domains to assess the quality of the guidelines. We performed a mixed-effects generalised linear regression modelling. RESULTS: We retrieved 63 guidelines containing 1905 guideline statements. The median proportion of 'difference in rating' of strength of recommendation between the guideline authors and independent assessment was 33.3% (quartiles: 18.3%, 55.8%). The 'rigour of development' domain score (odds ratio 0.06; 95% confidence intervals 0.01-0.48 per unit increase in rigour score; P value = 0.0071) and whether the strength of recommendation was 'strong' by independent evaluation (odds ratio 0.09 (95% confidence intervals 0.06-0.13; P value < 0.001) were the only determinants of difference in rating between the guideline authors and independent evaluation. CONCLUSION: A considerable proportion of guideline statements in clinical practice guidelines in laparoscopic surgery are not supported by evidence. Guideline authors systematically overrated the strength of the recommendation (i.e., even when the evidence points to weak recommendation, guideline authors made strong recommendations).
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Fragilidade , Laparoscopia , Humanos , Modelos Lineares , PubMed , ConfiançaRESUMO
GS-9669 is a non-nucleos(t)ide inhibitor (NNI) binding to the thumb site II of the Hepatitis C virus (HCV) NS5B polymerase and has advanced into phase II trials. To clarify the drug resistance mechanisms of GS-9669 caused by M423T/I/V, L419M, R422K, and I482L mutations of NS5B polymerase (GT1b) and the receptor-ligand interactions during the binding process, a series of molecular simulation methods including molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed for the wild-type (WT) and six mutant NS5B/GS-9669 complexes. The calculated results indicate that the binding free energies of the mutant systems are less negative than that of the WT system, indicating that these mutations will indeed cause NS5B to produce different degrees of resistance to GS-9669. The mutation-induced drug resistances are mainly caused by the loss of binding affinities of Leu419 and Trp528 with GS-9669 or the formation of multiple solvent bridges. Moreover, the ASMD calculations show that GS-9669 binds to the thumb II sites of the seven NS5B polymerases in distinct pathways without any obvious energy barriers. Although the recognition methods and binding pathways are distinct, the binding processes of GS-9669 with the WT and mutant NS5B polymerases are basically controlled thermodynamically. This study clearly reveals the resistance mechanisms of GS-9669 caused by M423T/I/V, L419M, R422K, and I482L mutations of HCV NS5B polymerase and provides some valuable clues for further optimization and design of novel NS5B inhibitors.
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KCNQ5 is suggestively associated with myopia, but its specific role in the myopic process has not been studied further. The aim of this study was to investigate the expression of potassium channel gene KCNQ5 and the changes of K+ microenvironment within the retina of form deprivation myopia (FDM) guinea pigs. A total of 60 guinea pigs were randomly divided into the normal control (NC) group, the self-control (SC) group, and the form-deprivation (FD) group for different treatments. Molecular assays and immunohistochemistry (IHC) were conducted to measure the expression and distribution of KCNQ5-related gene and protein in the retina. We determined the K+ concentration in the retina. In addition, the possible effects of form deprivation on potassium ionic currents and the pharmacological sensitivity of KCNQ5 activator Retigabine and inhibitor XE991 to the M-current in RPE cells were investigated using the patch-clamp technique. As a result, FD eyes exhibited more myopic refraction and longer AL. The mRNA and protein levels of KCNQ5 significantly decreased in the FD eyes, but the K+ concentration increased. In addition, the M-type K+ current [IK(M)] density decreased in FD RPE cells, and were activated or inhibited in a concentration-dependent manner due to the addition of Retigabine or XE991. Overall, KCNQ5 was significantly downregulated in the retina of FD guinea pigs, which may be associated with the increasing K+ concentration, decreasing IK(M) density, and elongating ocular axis. It suggested that KCNQ5 may play a role in the process of myopia, and the intervention of potassium channels may contribute to the prevention and control of myopia.
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Experimental studies have demonstrated statin-induced toxicity for ovary and uterus. However, the safety of statins on the functions of ovary and uterus in real-world clinical settings remains unknown. The aim of this study was to identify ovary and uterus related adverse events (AEs) associated with statin use by analyzing data from FDA Adverse Event Reporting System (FAERS). We used OpenVigil 2.1 to query FAERS database. Ovary and uterus related AEs were defined by 383 Preferred Terms, which could be classified into ten aspects. Disproportionality analysis was performed to assess the association between AEs and statin use. Our results suggest that statin use may be associated with a series of ovary and uterus related AEs. These AEs are involved in ovarian cysts and neoplasms, uterine neoplasms, cervix neoplasms, uterine disorders (excl neoplasms), cervix disorders (excl neoplasms), endocrine disorders of gonadal function, menstrual cycle and uterine bleeding disorders, menopause related conditions, and sexual function disorders. Moreover, there are variabilities in the types and signal strengths of ovary and uterus related AEs across individual statins. According to our findings, the potential ovary and uterus related AEs of statins should attract enough attention and be closely monitored in future clinical practice.
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Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Ovário/efeitos dos fármacos , Útero/efeitos dos fármacos , Adolescente , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Ovário/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estados Unidos , United States Food and Drug Administration , Útero/metabolismo , Adulto JovemRESUMO
Aim: The p21-activated kinases (PAKs) are involved in many important biological activity regulations. FRAX019, FRAX414, FRAX597, FRAX1036 and G-5555 were identified as PAKs inhibitors. Their detailed inhibitory mechanisms deserve further investigation. Results: Molecular dynamics simulations and further calculations for the PAK1/inhibitor and PAK4/inhibitor complexes indicate that their binding free energies are basically consistent with the trend of experimental activity data. Conclusion: The anchoring of residues Leu347PAK1 and Leu398PAK4 is the structural basis for designing Afraxis PAK inhibitors. This study discloses the inhibitory mechanisms of FRAX019, FRAX414, FRAX597, FRAX1036 and G-5555 toward PAK1 and PAK4 and some clues to enhance kinase activities and selectivities, which will provide valuable information to the development of more potent and selective PAK inhibitors.
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Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Simulação de Dinâmica Molecular , Estrutura Molecular , Termodinâmica , Quinases Ativadas por p21/metabolismoRESUMO
A novel cyclopentenone derivative, talarocyclopenta A (1), a new phenolicethers derivative, talarocyclopenta B (2) and a new itaconic acid derivative, talarocyclopenta C (3) together with four known itaconic acid derivatives (4-7) were isolated from the Talaromyces assiutensis JTY2. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. Among them, talarocyclopent (1) is the first represent an unusual type of cyclopentenone derivative, possessing a cyclopentenone unit, a 2-butanone unit and a 3-hydroxybutyric acid unit. All isolated compounds were evaluated for their anti-inflammatory and antibacterial activities. Compounds 1-4 showed inhibitory activities against the nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro. Compound 2 showed broad spectrum antibacterial against six terrestrial pathogenic bacteria.
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Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Talaromyces/química , Animais , Camundongos , Testes de Sensibilidade Microbiana , Células RAW 264.7RESUMO
OBJECTIVE: To determine the prevalence and associated factors of cognitive impairments in the community-dwelling elderly aged 60 years or older in Chengdu of Sichuan province. METHODS: A random cluster sampling strategy was adopted to select 621 community-dwelling elderly. Face-to-face interviews were conducted to assess the cognitive status of the participants. 2 tests and logistic regression analyses were performed to identify factors associated with cognitive impairments. RESULTS: About 40.9% of the participants had cognitive impairments. Those attended primary schools had a lower risk of cognitive impairments [odds ratio OR)=0.369, P<0.001] compared with the illiterate ones. Older age OR=1.505 for 70-79 years, P=0.042; OR=3.069 for ≥80 years, P<0.001), cerebrovascular disease OR=2.159, P=0.003) and smoking OR=2.388, P<0.001) were risk factors of cognitive impairments. Men had lower risk OR=0.489, P=0.005) of cognitive impairments than women. CONCLUSION: The prevalence of cognitive impairments in community-dwelling elderly in Chengdu is high in comparison with those in other cities. Illiteracy, older age (over 70 years), women, smoking, and cerebrovascular disease are risk factors of cognitive impairments.
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Disfunção Cognitiva/epidemiologia , Idoso , Transtornos Cerebrovasculares , China/epidemiologia , Escolaridade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Fatores de Risco , FumarRESUMO
A chemical investigation on the aerial parts of Hypericum perforatum resulted in the isolation of a new phloroglucinol derivatives (1), and seven known compounds (2-8). The structures of the compounds were elucidated by means of spectroscopic methods (MS, IR, 1D NMR, and 2D NMR) as 3-methyl-4,6-di (3- methyl-2-butenyl)-3-(4-methyl-3-pentenyl)-2-(2-ethyl-1-oxobutyl)-cyclohexanone (1),hyperforin (2),(2R,3R,4S,6)-3-methyl-4,6-di(3-methyl-2-butenyl)-2-(2-methyl-1-oxo-propyl)-3-(4-methyl-3-pentenyl)-cyclohexanone (3),hyperscabrin B (4),hyperscabrin C (5),furohyperforin isomer 1 (6),furoadhyperforin (7),and furohyperforin (8). Compound 1 was a new compound, and compounds 3-5 were obtained from H. perforatum for the first time.
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NS3 protease plays a vital role in the replication of the hepatitis C virus (HCV). BMS-605339 is a novel linear tetra-peptide α-ketoamide inhibitor of NS3 protease and shows specificity for HCV NS3 protease genotype 1a and genotype 1b. Mutation at the key site 168 of the HCV NS3 protease can induce resistance to BMS-605339, which greatly affects the antiviral therapy efficacy to hepatitis C. In the present study, we employed molecular dynamics simulations, free energy calculations, and free energy decomposition to explore the drug resistance mechanism of BMS-605339 due to the three representative mutations D168C/Y/V. The free energy decomposition analysis indicates that the decrease in the binding affinity is mainly attributed to the decrease in both van der Waals and electrostatic interactions. After detailed analysis of our calculated results, we observed that the break of the salt bridge between residues 155 and 168 caused by the mutations D168C/Y/V is the original reason for the decrease in the binding ability between BMS-605339 and the mutant NS3 proteases. The obtained results will reveal the drug resistance mechanism between BMS-605339 and the mutant NS3 proteases, and provide valuable clue for designing novel and more potent drugs to HCV NS3 protease.
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Resistência a Medicamentos/genética , Hepatite C/tratamento farmacológico , Inibidores de Proteases/química , Proteínas não Estruturais Virais/genética , Antivirais/química , Antivirais/uso terapêutico , Biologia Computacional , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepatite C/virologia , Humanos , Isoquinolinas/química , Isoquinolinas/uso terapêutico , Simulação de Dinâmica Molecular , Mutação , Inibidores de Proteases/uso terapêutico , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/químicaRESUMO
Objective To study and analyze the clinical effects of rhG-CSF combined with chemotherapy in the treatment of acute leukemia. Methods 60 patients with acute leukemia were selected as the study subjects (from February 2015 to April 2017). The control group was given routine chemotherapy, the experimental group was given rhG-CSF on the basis treatment of the control group. Clinical indicators of two groups of patients were compared and analyzed. Results After the corresponding treatment, the effective rate was 63.3% in the experimental group and 43.3% in the control group, and the difference was statistically significant (P<0.05). After treatment, the quality of life score of the control group (62.30±9.20) was significantly lower than the experimental group (76.88±10.90) with statistical difference (P<0.05). The number of neutrophils reduced from 0.1×109/L to 1.5×109/L in the experimental group took (11.23±1.65), and the time for the control group was (18.90±2.78), and the difference between the two groups was statistically significant (P<0.05). There were no serious adverse reactions in the two groups, and the incidence was 10% and 13.3%, which was not statistically significant. Conclusion rhG-CSF combined with chemotherapy in the treatment of acute leukemia has good clinical effect.
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Objective To discuss the feasibility of the establishment of a Y-shaped channel with windowing technique in treating the stent shunt obstruction occurring after transjugular intrahepatic portosystemic shunt (TIPS).Methods From February 2012 to December 2016,puncture windowing technique was employed in 7 patients to establish a Y-shaped channel in order to treat the stent shunt obstruction complicated by gastric varices bleeding or ascites due to recurrent portal hypertension.The preoperative Child-Pugh scores of liver function ranged from 5 to 10 points,with a mean of (6.85±1.56) points.The blood flow in both the portal vein and the shunt was determined before operation as well as at 5 days and 1,3,6months after operation;the post operative results were compared with preoperative ones.Results Y-shaped channel was successfully reconstructed in all 7 patients.The patients were followed up for a mean of 11months.Neither death nor hepatic encephalopathy occurred.Conclusion For the treatment of post-TIPS stent shunt obstruction,Y-shaped channel reconstruction within the occluded stent by using windowing technique is safe and effective,the operation is simple and easy.Therefore,this technique has certain clinical value.
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Objective To study and analyze the clinical effects of rhG-CSF combined with chemotherapy in the treatment of acute leukemia. Methods 60 patients with acute leukemia were selected as the study subjects (from February 2015 to April 2017). The control group was given routine chemotherapy, the experimental group was given rhG-CSF on the basis treatment of the control group. Clinical indicators of two groups of patients were compared and analyzed. Results After the corresponding treatment, the effective rate was 63.3% in the experimental group and 43.3% in the control group, and the difference was statistically significant (P<0.05). After treatment, the quality of life score of the control group (62.30±9.20) was significantly lower than the experimental group (76.88±10.90) with statistical difference (P<0.05). The number of neutrophils reduced from 0.1×109/L to 1.5×109/L in the experimental group took (11.23±1.65), and the time for the control group was (18.90±2.78), and the difference between the two groups was statistically significant (P<0.05). There were no serious adverse reactions in the two groups, and the incidence was 10% and 13.3%, which was not statistically significant. Conclusion rhG-CSF combined with chemotherapy in the treatment of acute leukemia has good clinical effect.
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Nanoemulsions (NEs) are used as transdermal drug delivery systems for systematic therapeutic purposes. We hypothesized that the skin permeation profile of an NE could be modulated by incorporating it into a hydrogel containing differing proportions of thickening agent. The objectives of this study were as follows: 1) to determine the stability and skin irritability of NE gels (NGs) containing 1%, 2%, and 3% (w/w) Carbopol® 934 (CP934) (termed NG1, NG2, and NG3, respectively); 2) to compare the skin permeation profiles and drug deposition patterns of the NGs; and 3) to visualize the drug delivery routes of the NGs. Terbinafine and citral were incorporated into the NGs as model drugs. Ex vivo skin permeation tests indicated that the percutaneous flux rates of terbinafine decreased in the order NE (215 µg/cm2) > NG1 (213 µg/cm2) > NG2 (123 µg/cm2) > NG3 (74.3 µg/cm2). The flux rates of citral decreased in the order NE (1,026 µg/cm2) > NG1 (1,021 µg/cm2) > NG2 (541 µg/cm2) > NG3 (353 µg/cm2). The NGs accumulated greater amounts of the drugs in the stratum corneum and less in the epidermis/dermis than did the NE (P<0.05) over a period of 12 h. Laser scanning confocal microscopy indicated that the NGs altered the main drug delivery routes from skin appendages to intercellular paths. Histological images suggested that perturbations to the skin structure, specifically the size of the epidermal intercellular spaces and the separation distance of dermal collagen bundles, could be significantly minimized by increasing the proportion of CP934. These results suggest that adjustments of the CP934 proportions can be used to modulate the skin permeation profiles of NGs for specific therapeutic purposes.
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Acrilatos/química , Acrilatos/metabolismo , Nanomedicina , Pele/metabolismo , Administração Cutânea , Administração Tópica , Animais , Emulsões , Géis , Cobaias , Masculino , Permeabilidade , Pele/citologia , Absorção CutâneaRESUMO
Urodynamic investigation in conscious rats is widely employed to explore functional bladder disorders of various etiologies and pathogeneses. Rats can be placed in restraining cages or wide cabinets where they are allowed to move freely during cystometry. However, the requirements of special devices hampered the application of urodynamic test in freely moving rats, and whether the restraint has any effects on urodynamic parameters in conscious rats remains obscure. In the present study, we described a novel approach for urodynamic investigation in both restrained and freely moving conscious rats. In addition, we for the first time systematically compared the urodynamic parameters of rats in the two conditions. With the current method, we successfully recorded stable and repeatable intravesical pressure traces and collected expected reliable data, which supported the idea that the restraint does not affect the activity of the micturition reflex in rats, provided sufficient and appropriate measures could be applied during cystometry. Fewer technique problems were encountered during urodynamic examination in restrained rats than in freely moving ones. Taken together, conscious cystometry in rats placed in restraining cages with proper managements is a reliable and practical approach for evaluating the detrusor activity and bladder function.
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Técnicas de Diagnóstico Urológico/instrumentação , Movimento , Bexiga Urinária/fisiologia , Urodinâmica , Vigília , Animais , Feminino , Ratos , Ratos Sprague-Dawley , Reflexo , Restrição FísicaRESUMO
NS5B polymerase plays an important role in viral replication machinery. TMC647055 (TMC) is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase. However, mutations that result in drug resistance to TMC have been reported. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations, and free energy decomposition to investigate the drug resistance mechanism of HCV to TMC resulting from L392I, P495T, P495S, and P495L mutations in NS5B polymerase. From the calculated results we determined that the decrease in the binding affinity between TMC and NS5B(L392I) polymerase is mainly caused by the extra methyl group at the CB atom of Ile. The polarity of the side-chain of residue 495 has no distinct influence on residue 495 binding with TMC, whereas the smaller size of the side-chain of residue 495 causes a substantial decrease in the van der Walls interaction between TMC and residue 495. Moreover, the longer length of the side-chain of residue 495 has a significant effect on the electrostatic interaction between TMC and Arg-503. Finally, we performed the same calculations and detailed analysis on other 3 mutations (L392V, P495V, and P495I). The results further confirmed our conclusions. The computational results not only reveal the drug resistance mechanism between TMC647055 and NS5B polymerase, but also provide valuable information for the rational design of more potent non-nucleoside inhibitors targeting HCV NS5B polymerase.
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Antivirais/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Modelos Moleculares , Mutação , Relação Estrutura-Atividade , Sulfonamidas/química , Termodinâmica , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismoRESUMO
Urodynamic investigation in conscious rats is widely employed to explore functional bladder disorders of various etiologies and pathogeneses. Rats can be placed in restraining cages or wide cabinets where they are allowed to move freely during cystometry. However, the requirements of special devices hampered the application of urodynamic test in freely moving rats, and whether the restraint has any effects on urodynamic parameters in conscious rats remains obscure. In the present study, we described a novel approach for urodynamic investigation in both restrained and freely moving conscious rats. In addition, we for the first time systematically compared the urodynamic parameters of rats in the two conditions. With the current method, we successfully recorded stable and repeatable intravesical pressure traces and collected expected reliable data, which supported the idea that the restraint does not affect the activity of the micturition reflex in rats, provided sufficient and appropriate measures could be applied during cystometry. Fewer technique problems were encountered during urodynamic examination in restrained rats than in freely moving ones. Taken together, conscious cystometry in rats placed in restraining cages with proper managements is a reliable and practical approach for evaluating the detrusor activity and bladder function.
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Animais , Feminino , Ratos , Técnicas de Diagnóstico Urológico , Movimento , Ratos Sprague-Dawley , Reflexo , Restrição Física , Bexiga Urinária , Fisiologia , Urodinâmica , VigíliaRESUMO
Urodynamic investigation in conscious rats is widely employed to explore functional bladder disorders of various etiologies and pathogeneses. Rats can be placed in restraining cages or wide cabinets where they are allowed to move freely during cystometry. However, the requirements of special devices hampered the application of urodynamic test in freely moving rats, and whether the restraint has any effects on urodynamic parameters in conscious rats remains obscure. In the present study, we described a novel approach for urodynamic investigation in both restrained and freely moving conscious rats. In addition, we for the first time systematically compared the urodynamic parameters of rats in the two conditions. With the current method, we successfully recorded stable and repeatable intravesical pressure traces and collected expected reliable data, which supported the idea that the restraint does not affect the activity of the micturition reflex in rats, provided sufficient and appropriate measures could be applied during cystometry. Fewer technique problems were encountered during urodynamic examination in restrained rats than in freely moving ones. Taken together, conscious cystometry in rats placed in restraining cages with proper managements is a reliable and practical approach for evaluating the detrusor activity and bladder function.