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Objective To study the antifungal activity of a new series of triazole compounds with n-propyl side chain and disubstituted benzyl structure. Methods Eleven target compounds were designed and synthesized. The structures were confirmed by 1H NMR, and some compounds were confirmed by 13C NMR or HRMS. Three fungal strains were selected as experimental strains, and the antifungal activity was tested in vitro according to the standardized antifungal sensitivity test method recommended by National Committee for Clinical Laboratory Standards (NCCLS). Results Compound B11 showed better activity against candida albicans SC5314 than fluconazole and was comparable to posaconazole; Compounds B10, B11 and B4 showed better activity against cryptococcus neoformanis H99 than fluconazole, while compounds B2, B3, B5, B6 and B7 showed similar activity to fluconazole against cryptococcus neoformanis H99; while all compounds showed poor activity against aspergillus fumigatus. Conclusion Some of the target compounds with n-propyl side chain and disubstituted benzyl group structure had certain antifungal activity and could be identified as potential lead antifungal drugs.
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Objective To study the antifungal activity of phenazines derivatives. Methods The anti-fungal activity of phenazine compounds was evaluated initially with micro-liquid dilution. No significant antifungal activity against Candida albicans was found. Then, with the combination of phenazine compounds and fluconazole, the anti-fungal activity against fluconazole-resistant C. albicans was detected. Results The phenazine-17 had significant antifungal activity when combined with fluconazole through the inhibition of hyphae formation. Conclusion This study provides a new idea for the development of antifungal drugs and the solution of antifungal drug resistance.
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Objective To detect the transcription factors of copper ion (Cu,2+) metabolism and oxidative stress by Candida albicans knocked down different transcription factors.Methods Spot assay, growth curve were used.Results The sensitivity to Cu,2+ in Cup2Δ/Δ was increasing and the growth of Cup2Δ/Δ was inhibited in 5 mmol /L Cu,2+ medium.The results showed that Cup2Δ/Δ also increased the sensitivity to H2O2, interestingly, Cu,2+and H2O2 played a synergistic antifungal effect.The tolerance of Cup2Δ/Δ and SN250 to H2O2 induced oxidative stress was increased after BCS chelating Cu,2+.In the fluconazole, miconazole and ketoconazole susceptibility experiments, Cup2Δ/Δ did not show susceptibility to azole drugs.Conclusion Knockout transcription factor Cup2, which could increase the sensitivity to Cu,2+ and H2O2in Candida albicans.Transcription factor Cup2 might be involved in the regulation and control of Candida albicansmetabolism on Cu,2+ and oxidative stress induced by H2O2, but not involved in the regulation and control of drug resistance to azole drugs.
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Objective Based on the structure-activity relationships on the reported antifungal agents bearing quinoline or thiophene moieties ,novel compounds bearing both quinoline and thiophene were designed ,synthesized ,and evaluated for in vitro antifungal activity against Candida albicans .Methods With 5-cyanothiophene-2-carbaldehyde or 5-cyanothiophene-3-car-baldehyde as starting materials ,13 compounds were synthesized via reductive amination ,reduction of cyano group and amida-tion of quinoline-or isoquinoline-carboxylic acid .Their chemical structures were characterized by 1 H NMR and MS . In vitro antifungal screening against Candida albicans SC5314 was performed with the microbroth dilution method .Results All the compounds exhibited potent antifungal activities against Candida albicans .Among them ,compound 6k showed the highest an-tifungal activity with MIC80 value of 0 .5 μg/ml ,which is same potent as fluconazole .Conclusion The designed compounds bearing both quinoline and thiophene exhibited potent antifungal activities ,and deserve further research .
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Objective 3,4-Methylenedioxyphenethylamine and caffeic acid derivatives have been proven previously in our group to produce activity against drug resistant fungi synergistic with fluconazole (FCZ).The two pharmacophores were cou-pled by amino acids as linkers in this project in order to design and synthesize the novel compounds and investigate the activity against drug resistant fungi in vitro.Methods 3,4-Methylenedioxyphenethylamine initially reacted with Boc-protected amino acids,following deprotection and coupling reaction with caffeic acid,to get nine title compounds.All title compounds as well as four intermediates were subjected to antifungal activity screening for fluconazole resistant Candida albicans in vitro.Results Nine title compounds showed synergistic antifungal activity for drug resistant Candida albicans with fluconazole at a concentra-tion range of 0.5-2.0μg/ml.Among them,compounds 3b,3f,3g and 3i showed the higher activity with the same MIC80 value of 0.5 μg/ml,which is comparable to those of the control compounds 7b and 5.Conclusion Linking 3,4-methylenedioxyphen-ethylamine and caffeic acid with piperidine-4-carboxylic acid (3b),valine (3g),leucine (3f) and isoleucine (3i) led to novel compounds with high synergistic antifungal activity against drug resistant Candida albicans combined with fluconazole.
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Pathogenic Candida albicans has a high degree of adaptability to environment,which is evidenced by its a-daptability to various conditions,including its symbiosis with the host,growth in host tissues during invasion,and survival un-der antifungal treatment.The growth and reproduction of C.albicans is accompanied with metabolism process.C.albicans can use a wide range of carbon and nitrogen sources,and it is sensitive to the alteration of nutrition.Recent studies reveal that the environment affects the metabolism of C.albicans,whilst C.albicans regulates its metabolism to adapt to the environment. Therefore,further study on the relationship between metabolism and high adaptability of C.albicans is helpful to discover no-vel antifungal targets.
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Inflammatory bowel disease is a chronic inflammation of the intestinal tract ,which comprises two primary forms of Crohn's disease(CD) and ulcerative colitis (UC) .Decades of studies have revealed that environmental factors ,suscepti-bility genes ,and gut microbiota are considered as the major determinants for the induction of IBD .The combination of factors has made IBD as an appropriate and a high-priority platform for studying host-microbiome interactions .More recently ,profiling studies of the intestinal microbe have associated pathogenesis of IBD with characteristic alterations in the composition of the in-testinal microbiota ,reinforcing the viewpoint that IBD results from the altered interplays between the host and intestinal mi-crobe .the studies of the gut flora in IBD were reviewed andthe multiple effects of intestinal microbiota-dysfunction on the IBD were described .The progress of intestinal microbiota alterations with different therapeutic methods in animal models and clinic trials were provided .
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Objective To explore the in vitro fungistasis of nanometer silvers made by different methods on Candida al-bicans .Methods The minimal inhibitory concentrations (MICs) of Candida albicans strains stimulated to silver nanoparticles were determined by microdilution method .The combination effects of silver nanoparticles with fluconazole were determined by chess board check assay .Results The inhabitation effect of two kinds of silver nanoparticles were different on the growth of Candida albicans .Silver nanoparticles had a synergistic effect with fluconazole on Candida albicans .Conclusion The two kinds of silver nanoparticles had various antifungal activities in vitro and had a synergistic effect with fluconazole on Candida albicans .
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The chemical constituents of Rosa chinensis Jacq were diverse ,mainly including flavonoids ,flavonoid glyco-sides ,phenolic acids ,aromatic oils ,tannins and pigments .Its extract and some chemical constituents had shown multiple phar-macological activities ,such as antitumor ,antifungal ,anti-viral ,anti-oxidation etc ..The advances in the study on chemical com-ponents and pharmacological actions of Rosa chinensis Jacq were reviewed and its application prospect was prospected .
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The incidence of systemic fungal infections have increased dramatically, moreover, drug resistance including either primary (intrinsic) or secondary (acquired) resistance, becomes one of the main reasons accounting for the failure of treating invasive fungal infections in the past decades. Nowadays, clinically available antifungal drugs are limited and their combination in antifungal therapy was not effective. It is expected to be a new strategy to synergistically sensitize antifungal drugs against drug-resistant fungi by using new small molecules. Based on the study in our research group and the reported work of others, we reviewed the research of the natural products which have synergistic effect with the antifungal agents against drug-resistant fungi. This review focused on the resource, structure, pharmacological activity, and action mechanism of the compounds, as well as somewhat in common, and would provide theoretical base for seeking new drug against drug-resistance fungi.
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Objective To investigate the protective effects and mechanism of TG 6 on myocardial ischemia/reperfusion injury . Methods the protective effects of TG 6 on myocardial ischemia/reperfusion was investigated by setting up models of ischemia and reperfusion of rats induced by ligating the left coronary anterior descending artery in vivo,isolated rat hearts through an improved Lange-ndorff device, and hypoxia /reoxygenation injury of neonatal rat cardiomyocytes , and the serum CK,LDH,T-SOD, MDA were taken as research markers .Results TG6 significantly reduced the myocardial infarct size , decreased the activity of CK and the content of MDA in serum, reduced the activity of LDH, and increased the activity of T-SOD in vivo;TG6 obviously increased the coronary blood flow after low rate perfusion and reperfusion , decreased the content of MDA and the leakage of CK , LDH in myocardial tissue , elevated the activity of T-SOD in vitro of isolated rat hearts;TG6 had no effects on cells in normal growth condition , raised the viability of cardio-myocytes significantly, and reduced the rate of CK leakage and the content of [Ca2+]i obviously in Na2S2O4 treated cells in vitro of neonatal rat cardiomyocytes .Conclusion TG6 could effectively protect myocardial ischemia/reperfusion injury .
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Hepatotoxicity is one of the most common adverse reactions during anti -hyperlipidemia treatment .Mechanisms of anti-hyperlipidemia drug-induced hepatotoxicity are not clear yet , but most of the toxic reactions are dose-related hypersensitivity and could be released after drug withdrawal .It is accepted that clinical risk factors for the development of hepatotoxicity during anti -hyper-lipidemia treatment are high age and chronic illnesses .Treatment of anti-hyperlipidemia drug-induced hepatotoxicity has not been uni-fied and most of the treatments are non-specific and symptomatic .Researching hypotoxicity and hepatoprotection antihyperlipidemia drug, especially TCM and pharmaceutics will become a promising direction .
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The target of rapamycin ( TOR) , a Ser/Thr protein kinase of PIKKs ( phosphatidylinositol kinase-related kinases ) , is the central factor of a highly conserved signaling pathway in eukaryotes , and regulates cell growth in response to nutrients , hor-mones, and stresses.It controls temporal growth by activating anabolic processes such as translation , ribosome biogenesis , protein syn-thesis, transportation of amino acid and metabolic enzymes .The advances in TOR pathway in the most pervasive human fungal patho-gen Candida albicans.
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Berberine was an isoquinoline type alkaloid extracted from Chinese herbs such as Coptis chinensis.Recently, as a great many berberine derivatives had been synthesized with comprehensive physiological functions , the structural modification and ap-plication of berberine showed great promising significance .Recent literatures had been systematically analyzed and summarized in this review.With abundant pharmacological activities of berberine different sites ′derivatives had been presented , systematical information of berberine structural modification as a lead compound and new drug R&D were provided in this article .
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Abstract: Our previous work revealed berberine can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, which suggested that berberine has synergistic antifungal activity with fluconazole. Preliminary SAR of berberine needs to be studied for the possibility of investigating its target and SAR, improving its drug-likeness, and exploring new scaffold. In this work, 13-substitutited benzyl berberine derivatives and N-benzyl isoquinoline analogues were synthesized and characterized by 1H NMR and MS. Their synergetic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The 13-substitutited benzyl berberine derivatives 1a-1e exhibited comparable activity to berberine, which suggested that the introduction of functional groups to C-13 can maintain its activity. The N-benzyl isoquinolines, which were designed as analogues of berberine with its D ring opened, exhibited lower activity than berberine. However, compound 2b, 2c, and 4b showed moderate activity, which indicated that berberine may be deconstructed to new scaffold with synergistic antifungal activity with fluconazole. The results of our research may be helpful to the SAR studies on its other biological activities.
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As the investments from the state and society in universities increased rapidly, the scientific and technological resources gained huge promotion. However, the efficiency of some instruments remained low, and the repeated purchases of some instruments occurred frequently. Here the authors discussed about building a practical, reasonable and efficient system for lab management.
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Gene mutation of Candida albicans is one of the main causes for azole drug resistance. Different types of variation play different roles in promoting the process of drug resistance. ERG series of gene mutations primarily affect the ergosterol synthesis pathway. When the regulatory factors TAC1 for CDR1 gene and Mrr1 for MDR1 gene generate mutations, the expression level of drug efflux pump protein in Candida albicans may be changed. In addition, gene copy number variation is also gaining attention. Therefore, the research of mutation resistance-associated genes has a positive meaning to explore the mechanism of drug resistance in Candida albicans.
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The Y118A、Y118F、Y118T、S378A、S378T、H310A、H310R mutants of Candida albicans sterol 14?-demethylase (CACYP51) were constructed and heterologously expressed in D12667, the reconstructed strain with the deletion of CYP51 gene of the Y12667. With the strains obtained and microsome enzymes separated, the western blot and the ultraviolet absorption spectrophotometry were used to qualitative and quantitative detect the expressed protein, the GC-MS was used to detect the metabolism activity of the protein. The results showed that, the target protein expressed successfully in the reconstructed strains, with the expression level up to 25% of the total microsome proteins. The results also showed that, the wild type protein had the catalytic activity to its nature substrate. While after alteration the wild gene with Y118A、Y118F、Y118T、S378A、S378T、H310A、H310R by a single base substitution, the catalytic activity of protein markedly decreased respectively. So the wild type and mutation CYP51 were expressed successfully in Saccharomyces cerevisiae and the expression products preserved the activity to metabolism their nature substrate.
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This paper combines the experience that university is in constructing center of experimental teaching.We thoroughly elaborated center of experimental teaching the guidelines of construction,develop process,and concrete conditions were introduced such as experiment resources integration,instruments management,network construction,personnel dispensation,model of managements establishment,laboratory open,and have obtained the obviously result.
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Objective:To introduce a "Four-step method" for extraction and separation of Candida albicans total proteins.Methods: Proteins of C.albicans were extracted step-by-step with 4 kinds of solutions with different solubilities.After quantification,the protein samples were separated by isoelectric focusing electrophoresis and then by SDS-PAGE.Results: Proteins with different solubilities were successfully extracted step-by-step from C.albicans and were separated by two-dimensional gel electrophoresis. Conclusion: The "Four-step method" for extraction of C.albicans proteins is an effective approach to study C.albicans membrane proteome and lays a foundation for further investigation of the mechanisms of antifungal agents and drug resistance in C.albicans.