scholarly journals Proteomic and Transcriptomic Analysis of Aspergillus fumigatus on Exposure to Amphotericin B

2008 ◽  
Vol 52 (12) ◽  
pp. 4220-4227 ◽  
Author(s):  
Poonam Gautam ◽  
Jata Shankar ◽  
Taruna Madan ◽  
Ravi Sirdeshmukh ◽  
Curam Sreenivasacharlu Sundaram ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Differential Expression ◽  
Amphotericin B ◽  
Stress Proteins ◽  
Fungal Infections ◽  
Antifungal Drug ◽  
Transcriptomic Analysis ◽  
Differentially Expressed ◽  
Specific Response ◽  
Expression Levels

ABSTRACT Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections, including invasive aspergillosis. It has been our aim to understand the molecular targets of AMB in Aspergillus fumigatus by genomic and proteomic approaches. In transcriptomic analysis, a total of 295 genes were found to be differentially expressed (165 upregulated and 130 downregulated), including many involving the ergosterol pathway, cell stress proteins, cell wall proteins, transport proteins, and hypothetical proteins. Proteomic profiles of A. fumigatus alone or A. fumigatus treated with AMB showed differential expression levels for 85 proteins (76 upregulated and 9 downregulated). Forty-eight of them were identified with high confidence and belonged to the above-mentioned categories. Differential expression levels for Rho-GDP dissociation inhibitor (Rho-GDI), secretory-pathway GDI, clathrin, Sec 31 (a subunit of the exocyst complex), and RAB GTPase Ypt51 in response to an antifungal drug are reported here for the first time and may represent a specific response of A. fumigatus to AMB. The expression of some of these genes was validated by real-time reverse transcription-PCR. The AMB responsive genes/proteins observed to be differentially expressed in A. fumigatus may be further explored for novel drug development.

scholarly journals High heterogeneity undermines generalization of differential expression results in RNA-Seq analysis

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Weitong Cui ◽  
Huaru Xue ◽  
Lei Wei ◽  
Jinghua Jin ◽  
Xuewen Tian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Small Sample ◽  
Differentially Expressed ◽  
Cancer Type ◽  
Rna Seq ◽  
Sample Sizes ◽  
Large Sample ◽  
Expression Levels ◽  
Gene Expression Levels

Abstract Background RNA sequencing (RNA-Seq) has been widely applied in oncology for monitoring transcriptome changes. However, the emerging problem that high variation of gene expression levels caused by tumor heterogeneity may affect the reproducibility of differential expression (DE) results has rarely been studied. Here, we investigated the reproducibility of DE results for any given number of biological replicates between 3 and 24 and explored why a great many differentially expressed genes (DEGs) were not reproducible. Results Our findings demonstrate that poor reproducibility of DE results exists not only for small sample sizes, but also for relatively large sample sizes. Quite a few of the DEGs detected are specific to the samples in use, rather than genuinely differentially expressed under different conditions. Poor reproducibility of DE results is mainly caused by high variation of gene expression levels for the same gene in different samples. Even though biological variation may account for much of the high variation of gene expression levels, the effect of outlier count data also needs to be treated seriously, as outlier data severely interfere with DE analysis. Conclusions High heterogeneity exists not only in tumor tissue samples of each cancer type studied, but also in normal samples. High heterogeneity leads to poor reproducibility of DEGs, undermining generalization of differential expression results. Therefore, it is necessary to use large sample sizes (at least 10 if possible) in RNA-Seq experimental designs to reduce the impact of biological variability and DE results should be interpreted cautiously unless soundly validated.

Reducing the toxicity of amphotericin B by encapsulation using methoxy poly(ethylene glycol)-b-poly(l-glutamic acid-co-l-phenylalanine)

2018 ◽  
Vol 6 (8) ◽  
pp. 2189-2196 ◽  
Author(s):  
Chenguang Yang ◽  
Baiji Xue ◽  
Wantong Song ◽  
Bo Kan ◽  
Dawei Zhang ◽  
...  
Keyword(s):  
Ethylene Glycol ◽  
Glutamic Acid ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Antifungal Drug ◽  
Poly Ethylene Glycol ◽  
Poly Ethylene

Amphotericin B (AmB) is an antifungal drug used for serious fungal infections and leishmaniosis.

scholarly journals Comparative Genome Sequence Analyses of Geographic Samples of Aspergillus fumigatus—Relevance for Amphotericin B Resistance

2020 ◽  
Vol 8 (11) ◽  
pp. 1673
Author(s):  
Yuying Fan ◽  
Yue Wang ◽  
Jianping Xu
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
High Rate ◽  
Whole Genome ◽  
Nucleotide Polymorphisms ◽  
Genome Sequences ◽  
Resistant Strains

Amphotericin B (AMB) is a major fungicidal polyene agent that has a broad spectrum of action against invasive fungal infections. AMB is typically used as the last-line drug against serious and life-threatening infections when other drugs have failed to eliminate the fungal pathogens. Recently, AMB resistance in Aspergillus fumigatus has become more evident. For example, a high rate of AMB resistance (96%) was noted in the A. fumigatus population in Hamilton, Ontario, Canada. AMB-resistant strains have also been found in other countries. However, the mechanism of AMB resistance remains largely unknown. Here, we investigated the potential genes and mutations associated with AMB resistance using whole-genome sequences and examined AMB resistance distribution among genetic populations. A total of 196 whole-genome sequences representing strains from 11 countries were examined. Analyses of single nucleotide polymorphisms (SNPs) at the whole-genome level revealed that these strains belonged to three divergent genetic clusters, with the majority (90%) of AMB resistant strains located in one of the three clusters, Cluster 2. Our analyses identified over 60 SNPs significantly associated with AMB resistance. Together, these SNPs represent promising candidates from which to investigate the putative molecular mechanisms of AMB resistance and for their potential use in developing rapid diagnostic markers for clinical screening of AMB resistance in A. fumigatus.

Amphotericin B-Associated Hypertension

1996 ◽  
Vol 30 (7-8) ◽  
pp. 765-767 ◽  
Author(s):  
Ysa Le ◽  
Khurram Z Rana ◽  
Michael N Dudley
Keyword(s):  
Blood Pressure ◽  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Causal Relationship ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Acute Hypertension ◽  
Case Summary ◽  
Para Determinar

OBJECTIVE: To report two cases of hypertension related to amphotericin B infusion. CASE SUMMARY: A 63-year-old woman with Candida albicans bacteremia and an 84-year-old man with Aspergillus fumigatus pneumonia developed hypertension within minutes of amphotericin B administration. Both patients' blood pressure returned to baseline soon after the infusion of amphotericin B was stopped. Neither patient was rechallenged. DISCUSSION: A causal relationship may exist between the administration of amphotericin B and these hypertensive episodes. Blood pressure in both patients normalized without treatment on discontinuation of the infusion. The mechanism of amphotericin B-associated hypertension is unclear but could include vasoconstricting properties of the drug or the administration of intravenous NaCl 0.9% prior to amphotericin B infusion. We recommend that intravenous NaCl 0.9% be administered following amphotericin B infusion and that the infusion be stopped if hypertensive episodes arise. CONCLUSIONS: Both acute hypertension and hypotension can occur in patients receiving amphotericin B for systemic fungal infections. OBJETIVO: Reportar dos casos de hipertensión relacionados a la infusión de anfotericina B. RESUMEN DEL CASO: Una paciente de 63 años de edad con bacteremia debida a la Candida albicans y un paciente de 84 años de edad con neumonía debida al Aspergillus fumigatus desarrollaron hipertensión a los pocos minutos de comenzar la administración de anfotericina B. La presión sanguínea de ambos pacientes retornó a la línea de base tan pronto como se detuvo la infusión de anfortericina B. Ninguno de los dos pacientes fue reexpuesto a la anfotericina B para determinar si el evento se repeatía. DISCUSIÓN: Puede existir una relación causal entre la adminstración de anfotericina B y estos episodios de hipertensión reportados, ya que la presión sanguínea se normalizó en ambos pacientes sin necesidad de tratamiento adicional después de que se suspendió la infusión de anfotericina B. El mecanismo por el cual anfotericina está asociada al desarrollo de hipertensión no está claro pero se especula que se debe a las propiedades vasoconstrictoras del medicamento o a la administración de cloruro de sodio intravenosamente antes de comenzar la infusión de anfotericina B. Por consiguiente, los autores recomiendan que el cloruro de sodio sea administrado después de que se haya concluido la infusión de anfotericina B. En el caso de que se reporten episodios hipertensivos, la infusión de anfotericina B debería ser suspendida inmediatamente. CONCLUSIONES: Casos de hipertensión o hipotensión pueden ocurrir en pacientes que reciben anfotericina B para el tratamiento de infecciones fungosas sistémicas.

Antifúngicos poliénicos. Mecanismo de acción y aplicaciones

2020 ◽  
Vol 63 (2) ◽  
pp. 7-17
Author(s):  
Evelyn Rivera-Toledo ◽  
Alan Uriel Jiménez-Delgadillo ◽  
Patricia Manzano-Gayosso
Keyword(s):  
Antifungal Activity ◽  
Key Words ◽  
Secondary Metabolism ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Variable Number ◽  
Therapeutic Failure ◽  
Morbidity And Mortality ◽  
Clinical Use

The first compounds with specific antifungal activity were identified in the middle of the last century as a product of the secondary metabolism of bacteria of the order Actinomycetales, and their clinical use significantly diminished the morbidity and mortality associated with severe fungal infections. Many of such biosynthetic compounds are characterized by a chemical polygenic structure, with a variable number of carbon-carbon double bonds. Currently, besides polygenic antimycotics, there are other antifungal agents, such as the azole compounds, that have less toxicity in patients; however, cases of therapeutic failure with such compounds have been documented, therefore, the use of polygenics is still the best alternative in such cases. This review presents data about the properties and applications of antifungal-polygenic compounds using amphotericin B as a model. Key words: Amphotericin B; antifungal polyenes; ergosterol

scholarly journals Differential Gene Expression between Fungal Mating Types Is Associated with Sequence Degeneration

2020 ◽  
Vol 12 (4) ◽  
pp. 243-258 ◽  
Author(s):  
Wen-Juan Ma ◽  
Fantin Carpentier ◽  
Tatiana Giraud ◽  
Michael E Hood
Keyword(s):  
Differential Expression ◽  
Differentially Expressed Genes ◽  
Mating Type ◽  
Sex Chromosomes ◽  
Sex Chromosome ◽  
Gc Content ◽  
Differentially Expressed ◽  
Mating Types ◽  
Sexual Antagonism ◽  
Recombination Suppression

Abstract Degenerative mutations in non-recombining regions, such as in sex chromosomes, may lead to differential expression between alleles if mutations occur stochastically in one or the other allele. Reduced allelic expression due to degeneration has indeed been suggested to occur in various sex-chromosome systems. However, whether an association occurs between specific signatures of degeneration and differential expression between alleles has not been extensively tested, and sexual antagonism can also cause differential expression on sex chromosomes. The anther-smut fungus Microbotryum lychnidis-dioicae is ideal for testing associations between specific degenerative signatures and differential expression because 1) there are multiple evolutionary strata on the mating-type chromosomes, reflecting successive recombination suppression linked to mating-type loci; 2) separate haploid cultures of opposite mating types help identify differential expression between alleles; and 3) there is no sexual antagonism as a confounding factor accounting for differential expression. We found that differentially expressed genes were enriched in the four oldest evolutionary strata compared with other genomic compartments, and that, within compartments, several signatures of sequence degeneration were greater for differentially expressed than non-differentially expressed genes. Two particular degenerative signatures were significantly associated with lower expression levels within differentially expressed allele pairs: upstream insertion of transposable elements and mutations truncating the protein length. Other degenerative mutations associated with differential expression included nonsynonymous substitutions and altered intron or GC content. The association between differential expression and allele degeneration is relevant for a broad range of taxa where mating compatibility or sex is determined by genes located in large regions where recombination is suppressed.

scholarly journals Genome-wide analysis of changes in miRNA and target gene expression reveals key roles in heterosis for Chinese cabbage biomass

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Peirong Li ◽  
Tongbing Su ◽  
Deshuang Zhang ◽  
Weihong Wang ◽  
Xiaoyun Xin ◽  
...  
Keyword(s):  
Chinese Cabbage ◽  
Leaf Development ◽  
Target Genes ◽  
Expression Patterns ◽  
Seedling Stage ◽  
Differentially Expressed ◽  
Small Rna Sequencing ◽  
Leaf Morphogenesis ◽  
Expression Levels ◽  
Parental Lines

AbstractHeterosis is a complex phenomenon in which hybrids show better phenotypic characteristics than their parents do. Chinese cabbage (Brassica rapa L. spp. pekinensis) is a popular leafy crop species, hybrids of which are widely used in commercial production; however, the molecular basis of heterosis for biomass of Chinese cabbage is poorly understood. We characterized heterosis in a Chinese cabbage F1 hybrid cultivar and its parental lines from the seedling stage to the heading stage; marked heterosis of leaf weight and biomass yield were observed. Small RNA sequencing revealed 63 and 50 differentially expressed microRNAs (DEMs) at the seedling and early-heading stages, respectively. The expression levels of the majority of miRNA clusters in the F1 hybrid were lower than the mid-parent values (MPVs). Using degradome sequencing, we identified 1,819 miRNA target genes. Gene ontology (GO) analyses demonstrated that the target genes of the MPV-DEMs and low parental expression level dominance (ELD) miRNAs were significantly enriched in leaf morphogenesis, leaf development, and leaf shaping. Transcriptome analysis revealed that the expression levels of photosynthesis and chlorophyll synthesis-related MPV-DEGs (differentially expressed genes) were significantly different in the F1 hybrid compared to the parental lines, resulting in increased photosynthesis capacity and chlorophyll content in the former. Furthermore, expression of genes known to regulate leaf development was also observed at the seedling stage. Arabidopsis plants overexpressing BrGRF4.2 and bra-miR396 presented increased and decreased leaf sizes, respectively. These results provide new insight into the regulation of target genes and miRNA expression patterns in leaf size and heterosis for biomass of B. rapa.

scholarly journals Understanding Rice-Magnaporthe Oryzae Interaction in Resistant and Susceptible Cultivars of Rice under Panicle Blast Infection Using a Time-Course Transcriptome Analysis

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 301
Author(s):  
Vishesh Kumar ◽  
Priyanka Jain ◽  
Sureshkumar Venkadesan ◽  
Suhas Gorakh Karkute ◽  
Jyotika Bhati ◽  
...  
Keyword(s):  
Cell Wall ◽  
Secondary Metabolites ◽  
Magnaporthe Oryzae ◽  
Transcriptome Analysis ◽  
Hormonal Regulation ◽  
Rice Blast ◽  
Blast Resistance ◽  
Differentially Expressed ◽  
Specific Response ◽  
Panicle Blast

Rice blast is a global threat to food security with up to 50% yield losses. Panicle blast is a more severe form of rice blast and the response of rice plant to leaf and panicle blast is distinct in different genotypes. To understand the specific response of rice in panicle blast, transcriptome analysis of blast resistant cultivar Tetep, and susceptible cultivar HP2216 was carried out using RNA-Seq approach after 48, 72 and 96 h of infection with Magnaporthe oryzae along with mock inoculation. Transcriptome data analysis of infected panicle tissues revealed that 3553 genes differentially expressed in HP2216 and 2491 genes in Tetep, which must be the responsible factor behind the differential disease response. The defense responsive genes are involved mainly in defense pathways namely, hormonal regulation, synthesis of reactive oxygen species, secondary metabolites and cell wall modification. The common differentially expressed genes in both the cultivars were defense responsive transcription factors, NBS-LRR genes, kinases, pathogenesis related genes and peroxidases. In Tetep, cell wall strengthening pathway represented by PMR5, dirigent, tubulin, cell wall proteins, chitinases, and proteases was found to be specifically enriched. Additionally, many novel genes having DOMON, VWF, and PCaP1 domains which are specific to cell membrane were highly expressed only in Tetep post infection, suggesting their role in panicle blast resistance. Thus, our study shows that panicle blast resistance is a complex phenomenon contributed by early defense response through ROS production and detoxification, MAPK and LRR signaling, accumulation of antimicrobial compounds and secondary metabolites, and cell wall strengthening to prevent the entry and spread of the fungi. The present investigation provided valuable candidate genes that can unravel the mechanisms of panicle blast resistance and help in the rice blast breeding program.

scholarly journals Dectin-2-Targeted Antifungal Liposomes Exhibit Enhanced Efficacy

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Suresh Ambati ◽  
Emma C. Ellis ◽  
Jianfeng Lin ◽  
Xiaorong Lin ◽  
Zachary A. Lewis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Effective Dose ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Drugs ◽  
Extracellular Matrices ◽  
Content Type ◽  
Order Of Magnitude ◽  
Life Threatening

ABSTRACT Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus cause life-threatening candidiasis, cryptococcosis, and aspergillosis, resulting in several hundred thousand deaths annually. The patients at the greatest risk of developing these life-threatening invasive fungal infections have weakened immune systems. The vulnerable population is increasing due to rising numbers of immunocompromised individuals as a result of HIV infection or immunosuppressed individuals receiving anticancer therapies and/or stem cell or organ transplants. While patients are treated with antifungals such as amphotericin B, all antifungals have serious limitations due to lack of sufficient fungicidal effect and/or host toxicity. Even with treatment, 1-year survival rates are low. We explored methods of increasing drug effectiveness by designing fungicide-loaded liposomes specifically targeted to fungal cells. Most pathogenic fungi are encased in cell walls and exopolysaccharide matrices rich in mannans. Dectin-2 is a mammalian innate immune membrane receptor that binds as a dimer to mannans and signals fungal infection. We coated amphotericin-loaded liposomes with monomers of Dectin-2’s mannan-binding domain, sDectin-2. sDectin monomers were free to float in the lipid membrane and form dimers that bind mannan substrates. sDectin-2-coated liposomes bound orders of magnitude more efficiently to the extracellular matrices of several developmental stages of C. albicans, C. neoformans, and A. fumigatus than untargeted control liposomes. Dectin-2-coated amphotericin B-loaded liposomes reduced the growth and viability of all three species more than an order of magnitude more efficiently than untargeted control liposomes and dramatically decreased the effective dose. Future efforts focus on examining pan-antifungal targeted liposomal drugs in animal models of fungal diseases. IMPORTANCE Invasive fungal diseases caused by Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have mortality rates ranging from 10 to 95%. Individual patient costs may exceed $100,000 in the United States. All antifungals in current use have serious limitations due to host toxicity and/or insufficient fungal cell killing that results in recurrent infections. Few new antifungal drugs have been introduced in the last 2 decades. Hence, there is a critical need for improved antifungal therapeutics. By targeting antifungal-loaded liposomes to α-mannans in the extracellular matrices secreted by these fungi, we dramatically reduced the effective dose of drug. Dectin-2-coated liposomes loaded with amphotericin B bound 50- to 150-fold more strongly to C. albicans, C. neoformans, and A. fumigatus than untargeted liposomes and killed these fungi more than an order of magnitude more efficiently. Targeting drug-loaded liposomes specifically to fungal cells has the potential to greatly enhance the efficacy of most antifungal drugs.

Two-year Longitudinal Evaluation of Amphotericin B Lipid Complex Injection in a Tertiary Care Medical Center

2000 ◽  
Vol 35 (2) ◽  
pp. 176-181 ◽  
Author(s):  
Leanne D. Kennedy ◽  
Julie F. Connelly ◽  
Kevin M. Kuzma
Keyword(s):  
Serum Creatinine ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Tertiary Care ◽  
Serum Creatinine Concentration ◽  
Creatinine Concentration ◽  
Lipid Complex ◽  
Tertiary Care Medical Center ◽  
Amphotericin B Lipid Complex ◽  
The Mean

A 2-year concurrent drug use evaluation was conducted in 156 patients to determine whether Abelcet (amphotericin B lipid complex injection) was being prescribed according to institution-approved guidelines and to characterize the patient population receiving Abelcet. Eighty-nine patients (57%) had fungal infections documented by chest x-ray, computed tomography, or fungal cultures. Sixty-seven (43%) had clinically suspected fungal infections. The Abelcet mean dose by weight was 5 mg/kg/day (actual body weight). Seventy-one patients (46%) met the established guidelines for use; 85 (54%) did not. Premedication was given to 64% of the patients; only 15 patients (10%) experienced documented fever and chills. A total of 72 patients (46%) died during therapy. Of the 75 patients who completed therapy in the hospital, 41 were switched to conventional amphotericin B, fluconazole, or itraconazole following a decrease in serum creatinine concentration, and 34 did not receive further antifungal therapy. The mean length of Abelcet therapy was 11 days. The mean increase in serum creatinine concentration at discontinuation of therapy was 0.2 mg/dL. Continued monitoring of Abelcet use was recommended and established guidelines were reaffirmed. Hydration with normal saline before and after dosing was suggested to help improve renal function, and dopamine was recommended to increase renal blood flow.

Sign in / Sign up

Export Citation Format

Share Document