JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Xu Renle,Chai Pengfan,Cheng Lei,Sun Yongde,Miao Tongzhou,Niu Quanrui,Gao Yanqing,Li Jian
Based on the excellent fungicidal activity of the rosin-based
Schiff
derivative, compound 3c (Co. 3c), against Rhizoctonia solani , this study further investigated its action
mechanism via multiomics, computer-aided drug design, phenotype, and
physiological indicators. Transcriptomic and proteomic analyses identified
2010 differentially expressed genes (DEGs) and 311 differentially
expressed proteins (DEPs), respectively. Steroid biosynthesis was
the most significantly enriched pathway, and the DEGs and DEPs involved
in sterol biosynthesis were simultaneously upregulated. DFT calculations
revealed that Co. 3c exhibited high chemical reactivity, enabling
stable noncovalent interactions with biomacromolecules. Mycelial phenotypic
observations and physiological measurements confirmed that Co. 3c
disrupted mycelial cellular structures, induced lipid peroxidation,
and reduced the intracellular ergosterol content by 45.0%. Molecular
docking suggested that Co. 3c bound to the active pockets of C-8 sterol
isomerase and sterol 22-desaturase through hydrogen bonds and hydrophobic
interactions. Collectively, these findings provide a theoretical basis
for the development of rosin-derived fungicides.
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Biochimica et Biophysica Acta-Gene Regulatory Mechanisms
·
2023
·
IF 4.7
Xinying Sui,Xinyu Cheng,Zhaodi Li,Yonghong Wang,Zhenpeng Zhang,Ruyue Yan,Lei Chang,Yanchang Li,Ping Xu,Changzhu Duan
Fungal infections and antifungal resistance are the increasing global public health concerns. Mechanisms of fungal resistance include alterations in drug-target interactions, detoxification by high expression of drug efflux transporters, and permeability barriers associated with biofilms. However, the systematic panorama and dynamic changes of the relevant biological processes of fungal drug resistance acquisition remain limited. In this study, we developed a yeast model of resistance to prolonged fluconazole treatment and utilized the isobaric labels TMT (tandem mass tag)-based quantitative proteomics to analyze the proteome composition and changes in native, short-time fluconazole stimulated and drug-resistant strains. The proteome exhibited significant dynamic range at the beginning of treatment but returned to normal condition upon acquisition drug resistance. The sterol pathway responded strongly under a short time of fluconazole treatment, with increased transcript levels of most enzymes facilitating greater protein expression . With the drug resistance acquisition, the sterol pathway returned to normal state, while the expression of efflux pump proteins increased obviously on the transcription level. Finally, multiple efflux pump proteins showed high expression in drug-resistant strain. Thus, families of sterol pathway and efflux pump proteins, which are closely associated with drug resistance mechanisms, may play different roles at different nodes in the process of drug resistance acquisition. Our findings uncover the relatively important role of efflux pump proteins in the acquisition of fluconazole resistance and highlight its potential as the vital antifungal targets.
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Antibiotics-Basel
·
2023
·Vol. 12
·期 12
·1675
·
IF 4.8
Ting Fang,Juan Xiong,Li Wang,Zhe Feng,Sijin Hang,Jinhua Yu,Wanqian Li,Yanru Feng,Hui Lu,Yuanying Jiang
Candida albicansfilamentation plays a significant role in developing both mucosal and invasive candidiasis, making it a crucial virulence factor. Consequently, exploring and identifying inhibitors that impede fungal hyphal formation presents an intriguing approach toward antifungal strategies. In line with this anti-filamentation strategy, we conducted a comprehensive screening of a library of FDA-approved drugs to identify compounds that possess inhibitory properties against hyphal growth. The compound octenidine dihydrochloride (OCT) exhibits potent inhibition of hyphal growth inC. albicansacross different hyphae-inducing media at concentrations below or equal to 3.125 μM. This remarkable inhibitory effect extends to biofilm formation and the disruption of mature biofilm. The mechanism underlying OCT’s inhibition of hyphal growth is likely attributed to its capacity to impede ergosterol biosynthesis and induce the generation of reactive oxygen species (ROS), compromising the integrity of the cell membrane. Furthermore, it has been observed that OCT demonstrates protective attributes against invasive candidiasis inGalleria mellonellalarvae through its proficient eradication ofC. albicanscolonization in infectedG. mellonellalarvae by impeding hyphal formation. Although additional investigation is required to mitigate the toxicity of OCT in mammals, it possesses considerable promise as a potent filamentation inhibitor against invasive candidiasis.Keywords:octenidine dihydrochloride;anti-filamentation;Candida albicans;ergosterol biosynthesis
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CLINICAL SCIENCE
·
2019
·Vol. 133
·期 13
·1523-1536
·
IF 5.237
Sun Xiao,Feng Xiuli,Zheng Dandan,Li Ang,Li Chunyan,Li Siying,Zhao Zhongxi
Cigarette smoke (CS) is the major cause of chronic obstructive pulmonary disease (COPD). CS heightens inflammation, oxidative stress and apoptosis. Ergosterol is the main bioactive ingredient in Cordyceps sinensis (C. sinensis), a traditional medicinal herb for various diseases. The objective of this work was to investigate the effects of ergosterol on anti-inflammatory and antioxidative stress as well as anti-apoptosis in a cigarette smoke extract (CSE)-induced COPD model both in vitro and in vivo. Our results demonstrate that CSE induced inflammatory and oxidative stress and apoptosis with the involvement of the Bcl-2 family proteins via the nuclear factor kappa B (NF-κB)/p65 pathway in both 16HBE cells and Balb/c mice. CSE induced epithelial cell death and increased the expression of nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), malondialdehyde (MAD) and the apoptosis-related proteins cleaved caspase 3/7/9 and cleaved-poly-(ADP)-ribose polymerase (PARP) both in vitro and in vivo, whereas decreased the levels of superoxide dismutase (SOD) and catalase (CAT). Treatment of 16HBE cells and Balb/c mice with ergosterol inhibited CSE-induced inflammatory and oxidative stress and apoptosis by inhibiting the activation of NF-κB/p65. Ergosterol suppressed apoptosis by inhibiting the expression of the apoptosis-related proteins both in vitro and in vivo. Moreover, the usage of QNZ (an inhibitor of NF-κB) also partly demonstrated that NF-κB/p65 pathway was involved in the ergosterol protective progress. These results show that ergosterol suppressed COPD inflammatory and oxidative stress and apoptosis through the NF-κB/p65 pathway, suggesting that ergosterol may be partially responsible for the therapeutic effects of cultured C. sinensis on COPD patients.
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Advanced Science
·
2024
·
IF 14.3
Cheng Zhen,Li Wang,Yanru Feng,Malcolm Whiteway,Sijin Hang,Jinhua Yu,Hui Lu,Yuanying Jiang
Candidiasis, which presents a substantial risk to human well-being, is frequently treated with azoles. However, drug-drug interactions caused by azoles inhibiting the human CYP3A4 enzyme, together with increasing resistance of Candida species to azoles, represent serious issues with this class of drug, making it imperative to develop innovative antifungal drugs to tackle this growing clinical challenge. A drug repurposing approach is used to examine a library of Food and Drug Administration (FDA)-approved drugs, ultimately identifying otilonium bromide (OTB) as an exceptionally encouraging antifungal agent. Mechanistically, OTB impairs vesicle-mediated trafficking by targeting Sec31, thereby impeding the plasma membrane (PM) localization of the ergosterol transporters, such as Sip3. Consequently, OTB obstructs the movement of ergosterol across membranes and triggers cytotoxic autophagy. It is noteworthy that C. albicans encounters challenges in developing resistance to OTB because it is not a substrate for drug transporters. This study opens a new door for antifungal therapy, wherein OTB disrupts ergosterol subcellular distribution and induces cytotoxic autophagy. Additionally, it circumvents the hepatotoxicity associated with azole-mediated liver enzyme inhibition and avoids export-mediated drug resistance in C. albicans .
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Jing Wang,Lizi Zuo,Ziqi Lu,Muhammad Noman,Chenwen Xiao,Haiping Qiu,Zhongna Hao,Yingying Cai,Zhen Zhang,Rongyao Chai,Yanli Wang,Jianping Lu,Xuping Shentu,Jiaoyu Wang,Fucheng Lin
Rice blast, caused by the fungal pathogen Magnaporthe oryzae ( M. oryzae ), leads to substantial global reductions in crop yield. Clotrimazole (CLZ), a synthetic imidazole derivative with broad-spectrum antifungal properties, is widely employed in clinical and veterinary applications for fungal infections treatment. However, limited information exists regarding its antifungal efficacy and mechanisms against phytopathogenic fungi. This study systematically elucidates the antifungal effects and underlying mechanisms of CLZ against M. oryzae . CLZ exhibits potent inhibitory effects on hyphal growth, conidiation, appressorium development, and pathogenicity. CLZ treatment disrupts cellular membrane integrity and significant depletion of ergosterol content. Molecular analysis reveals that the pharmacophore ring of CLZ directly interacts with the key sterol 14α-demethylase enzymes MoCyp51A and MoCyp51B in the ergosterol biosynthetic pathway. Deletion of MoCYP51A or MoCYP51B exhibits enhanced susceptibility to CLZ, confirming that CLZ effectively suppresses ergosterol biosynthesis to impair membrane integrity in M. oryzae . Additionally, CLZ treatment triggers multiple cytological alterations including enhanced cell wall deposition, mitochondrial ultrastructural defects, dysregulated mitophagy, and excessive reactive oxygen species (ROS) accumulation. These data collectively reveal that CLZ inhibits fungal virulence of M. oryzae by simultaneously targeting structural and functional damage to the cell wall, cell membrane, and organelles. Safety assessments further confirmed that CLZ exhibits minimal toxicity to both insects and crops. This evidence collectively proves the potential application of CLZ as a promising fungicide for the management of rice blast.
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Marine Drugs
·
2025
·Vol. 23
·期 11
·445
·
IF 5.4
Junming Zhang,Jiangming Zhong,Yi Li,Qi Zhou,Zhiyun Du,Li Lin,Peng Shu,Ling Jiang,Wei Zhou
Background: Ultraviolet B (UVB) radiation induces oxidative stress, inflammation, and collagen degradation in skin, leading to photodamage. Ergosterol (ERG)—a sterol widely distributed in fungi and algae, including numerous marine species—possesses antioxidant and anti-inflammatory activities, but its photoprotective mechanisms remain unclear. Methods: Using integratedin vitro(UVB-irradiated human keratinocytes) andin vivo(topical ERG in a murine UVB model) approaches, combined with transcriptomic and network pharmacology analyses, we evaluated ERG’s effects on oxidative stress, inflammation, and extracellular matrix integrity. Results: ERG treatment preserved keratinocyte viability, reduced reactive oxygen species, and suppressed pro-inflammatory mediators after UVB exposure. In mice, topical ERG significantly attenuated epidermal hyperplasia, maintained tight-junction integrity, and inhibited collagen matrix degradation. Mechanistically, ERG exerted dual inhibition of the nuclear factor kappa B (NF-κB) pathway, which mediates inflammation, and the mitogen-activated protein kinase (MAPK) pathway, which regulates collagen degradation. Conclusions: These findings identify ERG as a marine-derived sterol with potent photoprotective activity that simultaneously targets oxidative stress, inflammation, and extracellular matrix damage, highlighting its promise as a natural compound for dermatological applications and aligning with ongoing efforts to explore marine-derived agents against skin oxidative stress and inflammation.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2019
·
IF 3.361
Xiao Sun,Yan Liu,Xiuli Feng,Chunyan Li,Siying Li,Zhongxi Zhao
Macrophages are the most abundant immune cells in the lung, which play an important role in COPD. The anti-inflammatory and anti-oxidation of ergosterol are well documented. However, the effect of ergosterol on macrophage polarization has not been studied. The objective of this work was to investigate the effect of ergosterol on macrophage polarization in CSE-induced RAW264.7 cells and Sprague-Dawley (SD) rats COPD model. Our results demonstrate that CSE-induced macrophages tend to the M1 polarization via increasing ROS, IL-6 and TNF-α, as well as increasing MMP-9 to destroy the lung construction in both RAW264.7 cells and SD rats. However, treatment of RAW264.7 cells and SD rats with ergosterol inhibited CSE-induced inflammatory by decreasing ROS, IL-6 and TNF-α, and increasing IL-10 and TGF-β, shuffling the dynamic polarization of macrophages from M1 to M2 both in vitro and in vivo . Ergosterol also decreased the expression of M1 marker CD40, while increased that of M2 marker CD163. Moreover, ergosterol improved the lung characters in rats by decreasing MMP-9. Furthermore, ergosterol elevated HDAC3 activation and suppressed P300/CBP and PCAF activation as well as acetyl NF-κB/p65 and IKKβ, demonstrating that HDAC3 deacetylation was involved in the effect of ergosterol on macrophage polarization. These results also provide a proof in immunoregulation of ergosterol for therapeutic effects of cultured C. sinensis on COPD patients.
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MOLECULES
·
2024
·Vol. 29
·期 18
·4375
·
IF 4.2
Ran Luo,Haoyi Zhao,Siqi Deng,Jiale Wu,Haijun Wang,Xiaoshan Guo,Cuicui Han,Wenkang Ren,Yinglong Han,Jianwen Zhou,Yu Lin,Ming Bu
In this study, novel ergosterol peroxide (EP) derivatives were synthesized and evaluated to assess their antiproliferative activity against four human cancer cell lines (A549, HepG2, MCF-7, and MDA-MB-231). Compound3gexhibited the most potent antiproliferative activity, with an IC50value of 3.20 µM against MDA-MB-231. This value was 5.4-fold higher than that of the parental EP. Bioassay optimization further identified3gas a novel glutaminase 1 (GLS1) inhibitor (IC50= 3.77 µM). In MDA-MB-231 cells,3greduced the cellular glutamate levels by blocking the glutamine hydrolysis pathway, which triggered reactive oxygen species production and induced caspase-dependent apoptosis. Molecular docking indicated that3ginteracts with the reaction site of the variable binding pocket by forming multiple interactions with GLS1. In a mouse model of breast cancer,3gshowed remarkable therapeutic effects at a dose of 50 mg/kg, with no apparent toxicity. Based on these results,3gcould be further evaluated as a novel GLS1 inhibitor for triple-negative breast cancer (TNBC) therapy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症研究
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MEDICINE
·
2018
·
IF 2.028
Meijia Wu,Ting Huang,Juan Wang,Ping Chen,Wanwan Mi,Yuanyuan Ying,Hangli Wang,Dandan Zhao,Shengwu Huang
Supplemental Digital Content is available in the text
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FEMS MICROBIOLOGY LETTERS
·
2018
·Vol. 365
·期 5
·
IF 1.735
Ke Xia,Xia Xiao-Yuan,Zheng Ren-Chao,Zheng Yu-Guo
The Erg28p protein is localized to the endoplasmic reticulum, where it acts as a scaffold to tether the C-4 demethylase complex involved in the sterol biosynthesis pathway of Saccharomyces cerevisiae. However, due to the challenges involved in characterizing the interactions of membrane proteins, the precise region of Erg28p that is responsible for the assembly of this enzyme complex remains unknown. To address this question, mutants with serial truncations in the C-terminus of Erg28p were constructed based on a topology prediction of its transmembrane domain. Sterol profiles demonstrated that intermediates involved in the stepwise removal of the two C-4 methyl groups from the tetracyclic sterol ring were accumulated in the ERG28Δ135-447 strain. Homologous alignment of Erg28p further identified a highly conserved 10-amino acid sequence (63LS/QARTFGT/LWT72) within the truncated region of ERG28Δ136-273. Complementation of the BY4741/erg28 strain with the ScERG28Δ175-204 plasmid resulted both in a significant growth inhibition and a reduction of ergosterol biosynthesis compared with the plasmid without the Δ175-204 truncation. Furthermore, homology modeling of the Erg28p mutant indicated that the deletion of residues 63–72 significantly disrupted the 3D structure of the four parallel helices in Erg28p. Taken together, the data indicate that the region spanning amino acids 63–72 constitutes a key consensus motif within Erg28p that is required for sterol C-4 demethylation during ergosterol biosynthesis in S. cerevisiae.
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ARCHIV DER PHARMAZIE
·
2025
·Vol. 358
·期 11
·e70121
·
IF 3.6
Ling Jiang,Jiangming Zhong,Huixiong Chen,Yi Li,Qi Zhou,Miaohong Yang,Li Lin,Peng Shu,Zhiyun Du
Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is one of the nuclear receptor transcription factors that plays a key role in the differentiation of pro-inflammatory IL-17 + T helper cells. Recently, RORγt has attracted increasing attention as a potential drug target for the treatment of several human inflammatory diseases, including psoriasis and Crohn's disease. In this study, we revealed that ergosterol (ERG) was a novel RORγt inverse agonist, which decreased RORγt transcriptional activity, to regulate collagen fiber deposition and to inhibit pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-17, IL-22, and IL-23 in the skin lesions of IMQ-induced mice with psoriasis. Furthermore, ERG could repair the epidermal barrier function by upregulating tight junction proteins, such as claudin, occludin, and ZO-1, thereby alleviating psoriasis symptoms. These findings suggested that ERG might be used as a promising novel RORγt inverse agonist in the management of psoriasis.
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