scholarly journals Broad-Spectrum Antifungal Activities and Mechanism of Drimane Sesquiterpenoids

2019 ◽  
Author(s):  
Edruce Edouarzin ◽  
Connor Horn ◽  
Anuja Paduyal ◽  
Cunli Zhang ◽  
Jianyu Lu ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Gene Products ◽  
High Concentration ◽  
Fungal Cell ◽  
Strong Activity ◽  
Antifungal Activities ◽  
Drimane Sesquiterpenoids ◽  
Genome Wide ◽  
Resistant Strains ◽  
Insertion Mutants

ABSTRACTEight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, (+)-albicanol, and (1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1-carbaldehyde (4) showed strong activity against C. albicans. (-)-Drimenol, the strongest inhibitor of the three, (at concentrations of 8 – 64 μg/ml, causing 100% death of fungi), acts not only against C. albicans as a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, Pneumocystis, Blastomyces, Fusarium, Rhizopus, Saksenaea and FLU resistant strains of C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest drimenol is a broad-spectrum antifungal agent. At high concentration (100 μg/ml), drimenol caused a rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol rescued the worms from C. albicans-mediated death, indicating drimenol is tolerable and bioactive in a metazoan. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections revealed putative genes and pathways affected by drimenol. Using a C. albicans mutants spot assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and novel putative targets orf19.759, orf19.1672, and orf19.4382 were revealed to be the potential targets of drimenol. Further, computational modeling results suggest possible modification of the structure of drimenol including the A ring for improving antifungal activity.

scholarly journals Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids

2020 ◽  
Vol 7 (6) ◽  
pp. 146-159
Author(s):  
Edruce Edouarzin ◽  
Connor Horn ◽  
Anuja Paudyal ◽  
Cunli Zhang ◽  
Jianyu Lu ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antifungal Activities ◽  
Drimane Sesquiterpenoids

scholarly journals A Genome-Wide Screen in Saccharomyces cerevisiae Reveals a Critical Role for Oxidative Phosphorylation in Cellular Tolerance to Lithium Hexafluorophosphate

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 888
Author(s):  
Xuejiao Jin ◽  
Jie Zhang ◽  
Tingting An ◽  
Huihui Zhao ◽  
Wenhao Fu ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Oxidative Phosphorylation ◽  
Cellular Response ◽  
Critical Role ◽  
Lithium Ion ◽  
Deletion Mutants ◽  
High Concentration ◽  
Genome Wide ◽  
A Genome ◽  
Lithium Hexafluorophosphate

Lithium hexafluorophosphate (LiPF6) is one of the leading electrolytes in lithium-ion batteries, and its usage has increased tremendously in the past few years. Little is known, however, about its potential environmental and biological impacts. In order to improve our understanding of the cytotoxicity of LiPF6 and the specific cellular response mechanisms to it, we performed a genome-wide screen using a yeast (Saccharomyces cerevisiae) deletion mutant collection and identified 75 gene deletion mutants that showed LiPF6 sensitivity. Among these, genes associated with mitochondria showed the most enrichment. We also found that LiPF6 is more toxic to yeast than lithium chloride (LiCl) or sodium hexafluorophosphate (NaPF6). Physiological analysis showed that a high concentration of LiPF6 caused mitochondrial damage, reactive oxygen species (ROS) accumulation, and ATP content changes. Compared with the results of previous genome-wide screening for LiCl-sensitive mutants, we found that oxidative phosphorylation-related mutants were specifically hypersensitive to LiPF6. In these deletion mutants, LiPF6 treatment resulted in higher ROS production and reduced ATP levels, suggesting that oxidative phosphorylation-related genes were important for counteracting LiPF6-induced toxicity. Taken together, our results identified genes specifically involved in LiPF6-modulated toxicity, and demonstrated that oxidative stress and ATP imbalance maybe the driving factors in governing LiPF6-induced toxicity.

Antifungal Activities of Some Indole Derivatives

2010 ◽  
Vol 65 (7-8) ◽  
pp. 437-439 ◽  
Author(s):  
Hui Xu ◽  
Qin Wang ◽  
Wen-Bin Yang
Keyword(s):  
Fusarium Oxysporum ◽  
Fusarium Graminearum ◽  
Broad Spectrum ◽  
Alternaria Alternata ◽  
Phytopathogenic Fungi ◽  
Pyricularia Oryzae ◽  
Indole Derivatives ◽  
Alternaria Brassicae ◽  
Antifungal Activities

Nine indole derivatives were evaluated in vitro against Fusarium graminearum, Alternaria alternata, Helminthosporium sorokinianum, Pyricularia oryzae, Fusarium oxysporum f. sp. vasinfectum, Fusarium oxysporum f. sp. cucumarinum, and Alternaria brassicae. Most of the compounds were found to possess antifungal activities. Especially compounds 2, 5, 8, and 9 exhibited broad-spectrum antifungal activities against the above-mentioned seven phytopathogenic fungi, and showed more potent activities than hymexazole, a commercial agricultural fungicide.

Input-output properties of hand-related cells in the ventral cingulate cortex in the monkey

1995 ◽  
Vol 73 (6) ◽  
pp. 2584-2590 ◽  
Author(s):  
G. Cadoret ◽  
A. M. Smith
Keyword(s):  
Index Finger ◽  
Receptive Fields ◽  
Sensory Cortex ◽  
Cellular Activity ◽  
Finger Force ◽  
Input Output ◽  
High Concentration ◽  
Strong Activity ◽  
Excitatory Responses ◽  
Rostral Part

1. Neurons with proprioceptive or cutaneous receptive fields associated with the hand were identified in the ventral bank of the cingulate sulcus in the monkey. Cells with proprioceptive fields outnumbered cells receiving cutaneous afferents by more than three to one. No cells were encountered that received convergent proprioceptive and cutaneous input. The high concentration of these neurons in the lateral depth of the cingulate sulcus establishes that a distinct hand representation exists within the rostral part of area 23c. 2. Hand-related neurons in area 23c exhibited strong activity modulations during grasping, lifting, and holding an object with the contralateral thumb and index finger. Force pulse perturbations applied to the object elicited excitatory responses at latencies of approximately 45 ms. The modulation of the cellular activity and the input-output properties of these cingulate neurons suggest that, like neurons of primary motor and sensory cortex, these cingulate neurons are also involved in the sensorimotor control of finger movements.

scholarly journals Development of Novel Anti-influenza Thiazolides with Relatively Broad-Spectrum Antiviral Potentials

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Lei Zhao ◽  
Yunzheng Yan ◽  
Qingsong Dai ◽  
Xingzhou Li ◽  
Ke Xu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Broad Spectrum ◽  
Late Phase ◽  
Influenza Virus Infection ◽  
Oseltamivir Carboxylate ◽  
Cellular Genes ◽  
Action Analysis ◽  
Antiviral Activities ◽  
Resistant Strains ◽  
Entity Discovery

ABSTRACT Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug resistance to specific anti-influenza virus drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug, nitazoxanide, with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza virus potentials, with 10-fold improvement compared to results with nitazoxanide, and were effective against a variety of influenza virus subtypes including oseltamivir-resistant strains. Notably, the combination using compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effects against oseltamivir-resistant strains. Mode-of-action analysis demonstrated that compounds 4a/4d acted at the late phase of the viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of upregulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, the results of our study indicated the direction to optimize nitazoxanide as an anti-influenza drug and discovered two candidates with novel structures, compounds 4a/4d, that have relatively broad-spectrum antiviral potentials.

scholarly journals Genome-wide screen uncovers novel pathways for tRNA processing and nuclear–cytoplasmic dynamics

2015 ◽  
Vol 29 (24) ◽  
pp. 2633-2644 ◽  
Author(s):  
Jingyan Wu ◽  
Alicia Bao ◽  
Kunal Chatterjee ◽  
Yao Wan ◽  
Anita K. Hopper
Keyword(s):  
Nuclear Export ◽  
Outer Membrane Proteins ◽  
Chromatin Modification ◽  
Mitochondrial Outer Membrane ◽  
Cell Physiology ◽  
Gene Products ◽  
Ribonucleic Acids ◽  
Trna Processing ◽  
Genome Wide ◽  
Genes Encoding

Transfer ribonucleic acids (tRNAs) are essential for protein synthesis. However, key gene products involved in tRNA biogenesis and subcellular movement remain to be discovered. We conducted the first comprehensive unbiased analysis of the role of nearly an entire proteome in tRNA biology and describe 162 novel and 12 previously known Saccharomyces cerevisiae gene products that function in tRNA processing, turnover, and subcellular movement. tRNA nuclear export is of particular interest because it is essential, but the known tRNA exporters (Los1 [exportin-t] and Msn5 [exportin-5]) are unessential. We report that mutations of CRM1 (Exportin-1), MEX67/MTR2 (TAP/p15), and five nucleoporins cause accumulation of unspliced tRNA, a hallmark of defective tRNA nuclear export. CRM1 mutation genetically interacts with los1Δ and causes altered tRNA nuclear–cytoplasmic distribution. The data implicate roles for the protein and mRNA nuclear export machineries in tRNA nuclear export. Mutations of genes encoding actin cytoskeleton components and mitochondrial outer membrane proteins also cause accumulation of unspliced tRNA, likely due to defective splicing on mitochondria. Additional gene products, such as chromatin modification enzymes, have unanticipated effects on pre-tRNA end processing. Thus, this genome-wide screen uncovered putative novel pathways for tRNA nuclear export and extensive links between tRNA biology and other aspects of cell physiology.

scholarly journals Treatment of murine Candida krusei or Candida glabrata infection with L-743,872.

1997 ◽  
Vol 41 (9) ◽  
pp. 1937-1939 ◽  
Author(s):  
J R Graybill ◽  
R Bocanegra ◽  
M Luther ◽  
A Fothergill ◽  
M J Rinaldi
Keyword(s):  
Body Weight ◽  
Broad Spectrum ◽  
Candida Glabrata ◽  
Clinical Development ◽  
Candida Krusei ◽  
Murine Models ◽  
Fungal Cell ◽  
Significant Potential ◽  
Cell Counts

L-743,872 is a broad-spectrum pneumocandin antifungal drug developed by Merck Research Co., and in the present work it was evaluated in vivo in murine models of Candida krusei and Candida glabrata infection. Mice were infected intravenously with two isolates of C. krusei and treated with fluconazole or L-743,872. Fluconazole was beneficial only in immune-competent mice infected with isolate 94-2696. At > 0.5 mg/kg of body weight/day, L-743,872 was effective against both infecting isolates in immune-competent and immune-suppressed mice. Against C. glabrata, L-743,872 was effective, at doses > or = 0.5 mg/kg, in reducing fungal cell counts in the kidneys but not in the spleen. L-743,872 has significant potential for clinical development.

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