Publications by authors named "Huan Mei"

39 Publications

Absence of CG methylation alters the long noncoding transcriptome landscape in multiple species.

FEBS Lett 2021 May 5. Epub 2021 May 5.

Zhejiang Provincial Key Laboratory of Crop Genetic Resources, Institute of Crop Science, Plant Precision Breeding Academy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China.

The noncoding regions throughout the genome are in large part comprised of transposable elements (TEs), some of which are functionalized with long intergenic noncoding RNAs (lincRNAs). DNA methylation is predominantly associated with TEs, but little is known about its contribution to the transcription of lincRNAs. Here, we examine the lincRNA profiles of DNA methylation-related mutants of five species, Arabidopsis, rice, tomato, maize, and mouse, to elucidate patterns in lincRNA regulation under altered DNA methylation status. Significant activation of lincRNAs was observed in the absence of CG DNA methylation rather than non-CG. Our study establishes a working model of the contribution of DNA methylation to regulation of the dynamic activity of lincRNA transcription.
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http://dx.doi.org/10.1002/1873-3468.14100DOI Listing
May 2021

Fungal co-infection in COVID-19 patients: evidence from a systematic review and meta-analysis.

Aging (Albany NY) 2021 03 19;13(6):7745-7757. Epub 2021 Mar 19.

Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing 210042, Jiangsu, China.

Coronavirus disease 2019 (COVID-19) has infected tens of millions of people worldwide within the last year. However, the incidence of fungal co-infection in COVID-19 patients remains unclear. To investigate the association between fungal co-infection and mortality due to COVID-19, we systematically searched Medline, Embase, MedRxiv and Cochrane Library for eligible studies published in the period from 1 January to 1 December 2020. We performed a meta-analysis of nine studies that met the inclusion criteria. In total, data from 2780 patients and 426 patients were included who were admitted to the ICU. In eight of the articles, 211 participants died due to COVID-19 infection, which means an overall mortality rate of 10.9%. The overall pooled proportion of fungal co-infection in COVID-19 patients was 0.12 (95% CI = 0.07-0.16, n = 2780, = 96.8%). In terms of mortality in COVID-19 patients with fungal infection, the overall pooled proportion of mortality was 0.17 (95% CI = 0.10-0.24, n = 1944, = 95.6%). These findings provide evidence suggesting a favorable use for empirical antibiotics in the majority of patients when COVID-19 infection is diagnosed. Our analysis is investigating the use of antifungal therapy to treat COVID-19 can serve as a comprehensive reference for COVID-19 treatment.
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http://dx.doi.org/10.18632/aging.202742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034918PMC
March 2021

Comprehensive genome and transcriptome analysis of the dermatophyte Trichophyton schoenleinii reveals the candidate pathogenic genes.

Mycoses 2021 Jun 11;64(6):624-633. Epub 2021 Mar 11.

Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.

Background: Trichophyton schoenleinii is an anthropophilic dermatophyte that causes tinea favosa. Nowadays, it remains an important pathogen in some regions of the world, mainly epidemic in Africa and West Asia. Despite the medical importance of T. schoenleinii infections, a high-quality reference genome for T. schoenleinii is still unavailable, neither its transcriptomic profile.

Objectives: The aim of the current study was to improve understanding of the underlying pathogenic mechanism of T. schoenleinii, and to define the candidate pathogenic genes of T. schoenleinii.

Methods: Comprehensive genomic analysis of T. schoenleinii was carried out by Illumina and PacBio sequencing platforms. Transcriptome profiles of T. schoenleinii cultured in vitro in two media containing either keratin or soy protein were determined using RNA sequencing (RNA-seq) technology.

Results: Here, we present the first draft genome sequence of T. schoenleinii strain T2s, which consists of 11 scaffolds containing 7474 predicted genes. Transcriptome analysis showed that genes involved in keratin hydrolysis have higher expression in T. schoenleinii grown in keratin medium, including genes encoding proteases, cysteine dioxygenase and acetamidase. Other genes with higher expression include genes encoding the components of the pH-responsive signal transduction pathways and transcription factors, many of which may play a role in pathogenicity.

Conclusion: In summary, this study provides new insights into the pathogenic mechanism of T. schoenleinii and highlights candidate genes for further development of novel targets in disease diagnosis and treatment of tinea favosa.
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http://dx.doi.org/10.1111/myc.13257DOI Listing
June 2021

Proteome-Wide Analysis of Lysine 2-Hydroxyisobutyrylation in Candida albicans.

mSystems 2021 Feb 2;6(1). Epub 2021 Feb 2.

Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, Jiangsu, People's Republic of China

is the most common human fungal pathogen, causing diseases ranging from mucosal to systemic infections for both immunocompetent and immunocompromised individuals. Lysine 2-hydroxyisobutyrylation is a highly conserved posttranslational modification found in a wide variety of organisms. In this study, we surveyed the biological impact of 2-hydroxyisobutyrylation on lysine residuals (Khib) in Using an antibody enrichment approach along with the traditional liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, we analyzed the pattern of Khib-modified proteins and sites in one wild-type strain of We identified 1,438 Khib-modified proteins with 6,659 modified sites in this strain, and a more detailed bioinformatics analysis indicated that the Khib-modified proteins are involved in a wide range of cellular functions with diverse subcellular locations. Functional enrichment analysis featured several prominent functional pathways, including ribosome, biosynthesis of antibiotics, biosynthesis of secondary metabolites, biosynthesis of amino acids and carbon metabolism, of which the ribosome pathway is the most affected pathway. Even compared with the reported numbers of lysine acetylation (Kac) and succinylation (Ksuc) sites, the numbers of Khib-modified sites on ribosomal proteins remained the highest for These bioinformatic results suggest that 2-hydroxyisobutyrylation may play an indispensable role in the regulation of the ribosomal biogenesis and protein translation. Findings in this study may provide new insights for studying posttranslational modification (PTM)-associated mechanisms in fungal development and pathogenicity. is one of the most commonly reported fungal pathogens in mucosal and systemic infections. A better understanding of its growth habits and metabolic processes in the host should help improve defense strategies. The newly discovered protein posttranslational modification (PTM) on histones is one epigenetic mechanism which has been linked to many pathogenic events, including cancers. The types of PTM and their pathogenic roles in are still somewhat poorly understood, even though studies of based on acetylation inhibitors have shed some light on their function, and it seems that PTMs regulate pathogenic adhesion factors. Here, we quantified and analyzed the occurrence of lysine 2-hydroxyisobutyrylation (Khib) in The Khib-modified proteins are enriched with respect to carbon metabolism, ribosomal biogenesis, and protein translation in .
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http://dx.doi.org/10.1128/mSystems.01129-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857534PMC
February 2021

Divergent improvement of two cultivated allotetraploid cotton species.

Plant Biotechnol J 2021 Jan 14. Epub 2021 Jan 14.

Zhejiang Provincial Key Laboratory of Crop Genetic Resources, Institute of Crop Science, Plant Precision Breeding Academy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China.

Interspecific genomic variation can provide a genetic basis for local adaptation and domestication. A series of studies have presented its role of interspecific haplotypes and introgressions in adaptive traits, but few studies have addressed their role in improving agronomic character. Two allotetraploid Gossypium species, Gossypium barbadense (Gb) and G. hirsutum (Gh) originating from the Americas, are cultivated independently. Here, through sequencing and the comparison of one GWAS panel in 229 Gb accessions and two GWAS panels in 491 Gh accessions, we found that most associated loci or functional haplotypes for agronomic traits were highly divergent, representing the strong divergent improvement between Gb and Gh. Using a comprehensive interspecific haplotype map, we revealed that six interspecific introgressions from Gh to Gb were significantly associated with the phenotypic performance of Gb, which could explain 5%-40% of phenotypic variation in yield and fibre qualities. In addition, three introgressions overlapped with six associated loci in Gb, indicating that these introgression regions were under further selection and stabilized during improvement. A single interspecific introgression often possessed yield-increasing potential but decreased fibre qualities, or the opposite, making it difficult to simultaneously improve yield and fibre qualities. Our study not only has proved the importance of interspecific functional haplotypes or introgressions in the divergent improvement of Gb and Gh, but also supports their potential value in further human-mediated hybridization or precision breeding.
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http://dx.doi.org/10.1111/pbi.13547DOI Listing
January 2021

Efficacy and prognosis of surgical treatment in ARMM and its effects on immune and inflammatory profiles.

Exp Ther Med 2020 Dec 27;20(6):277. Epub 2020 Oct 27.

Department of Breast Surgery, Linyi Cancer Hospital, Linyi, Shandong 276000, P.R. China.

The aim of the present study was to investigate the efficacy and prognosis of surgical treatment in anorectal malignant melanoma (ARMM) as well as its effects on immune and inflammatory profiles. A total of 64 patients with ARMM were enrolled and divided into control group (n=32) and observation group (n=32) based on different therapeutic methods. Patients in the observation group underwent wide local excision, while those in the control group were given non-surgical treatment. The immune function was compared between the two groups after treatment. The expression levels of serum IL-17, IL-23 and vascular endothelial growth factor (VEGF) were compared between the groups before and after treatment. Patients were followed up for 5 years to observe the recurrence and survival rates in the two groups. Compared with those in the control group, the levels of cluster of differentiation (CD)3, CD4 and CD4/CD8 were increased, while the level of CD8 was reduced in the observation group (P<0.05). The levels of serum IL-17, IL-23 and VEGF were significantly lower in both groups at 4, 6 and 8 weeks after treatment than those before treatment, and the decrease was more obvious in the observation group (P<0.05). The observation group exhibited a notably elevated 5-year survival rate and a remarkably decreased recurrence rate in comparison with the control group (P<0.05). For ARMM, surgical treatment is more effective than non-surgical treatment, which has less effect on immune function, is able to reduce serum IL-17, IL-23 and VEGF levels, lower recurrence rate, improve patient survival rate, and plays a certain positive role in prolonging the survival time of ARMM patients.
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http://dx.doi.org/10.3892/etm.2020.9407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664591PMC
December 2020

Activities of Ravuconazole and Isavuconazole against Dematiaceous Fungi.

Antimicrob Agents Chemother 2020 08 20;64(9). Epub 2020 Aug 20.

Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, Jiangsu, People's Republic of China

The activities of 11 antifungals against 84 dematiaceous fungi were tested. For most tested fungal species, the MIC values of ravuconazole and isavuconazole were lower than those obtained with itraconazole, voriconazole, and posaconazole. Ravuconazole and isavuconazole appear to be more efficient against most dematiaceous fungal infections than the other triazoles. However, some pigmented fungi, such as and , remain more susceptible to other triazoles or to echinocandins.
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http://dx.doi.org/10.1128/AAC.00643-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449202PMC
August 2020

Molecular Identification and In Vitro Antifungal Susceptibility of Aspergillus Isolates Recovered from Otomycosis Patients in Western China.

Mycopathologia 2020 Jun 28;185(3):527-535. Epub 2020 Apr 28.

Microbiology Department, People's Hospital of Suzhou National New & Hi-Tech Industrial Development Zone, Suzhou, Jiangsu, China.

Aspergillus species are the most common causative agents involved in otomycosis. In this study, 45 Aspergillus isolates were obtained from patients with otomycosis in western China during 2013-2016. The aim of this study is to identify the Aspergillus isolates to the species level by using β-tubulin gene sequencing and to evaluate their in vitro susceptibility to nine antifungal drugs: amphotericin B, itraconazole, voriconazole, posaconazole, ravuconazole, isavuconazole, caspofungin, micafungin and anidulafungin according to CLSI M38-A2. Our results indicate that A. tubingensis (18/45) is the predominant Aspergillus species causing ear infections in western China, which is three times more than its sibling species A. niger (6/45) and A. welwitschiae (2/45). Other detected species were A. fumigatus (n = 8), A. terreus (n = 7) and A. flavus (n = 4). Antifungal susceptibility data indicate that triazoles and echinocandins are active against the most Aspergillus isolates. There are no significant differences in the susceptibility among A. niger, A. tubingensis and A. welwitschiae to each of the antifungals tested. One azole-resistant A. fumigatus isolate with a TR34/L98H mutation in the CYP51A gene and one posaconazole-resistant A. terreus isolate presented among the studied isolates. In conclusion, A. tubingensis is the most prevalent Aspergillus species causing otomycosis in western China. Posaconazole and echinocandins are potential drugs for treatment of otomycosis due to Aspergillus; however, in vivo efficacy remains to be determined.
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http://dx.doi.org/10.1007/s11046-020-00448-7DOI Listing
June 2020

Assembly and analysis of the whole genome of Arthroderma uncinatum strain T10, compared with Microsporum canis and Trichophyton rubrum.

Mycoses 2020 Jul 3;63(7):683-693. Epub 2020 Jun 3.

Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, China.

Background: Arthroderma uncinatum is a geophilic dermatophyte that occasionally causes superficial infections in humans leading to skin diseases.

Objectives: To better understand the ecology and potential pathogenicity of A uncinatum, we analysed its whole genome. We compared A uncinatum with the genome of the zoophilic dermatophyte Microsporum canis and with the anthropophilic species Trichophyton rubrum. The compared species differ significantly in the frequency of human infection.

Methods: We reported the genome sequence of strain T10 of A uncinatum based on SMRT (single-molecule real-time) technology (PacBio).

Results: We obtained a near-complete 23.56 Mb genome, with 7153 predicted gene models and ~20% repetitive sequences. We subsequently determined the specific genetic differences between A uncinatum, M canis and T rubrum. The functional enrichment analysis suggests that A uncinatum is particularly enriched in specific virulence genes. This suggests that the ancestral condition in dermatophytes is with high virulence, which has decreased in the course of evolution to enhance coexistence with animal or human hosts.
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http://dx.doi.org/10.1111/myc.13079DOI Listing
July 2020

Onychomycosis caused by : A case report and mini-review.

Med Mycol Case Rep 2020 Mar 8;27:72-76. Epub 2020 Feb 8.

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences, Peking Union Medical College, 12th JiangWangMiao Street, Nanjing, Jiangsu, 210029, China.

Onychomycosis has been reported to be mainly caused by dermatophytes. Recently, more attention has been paid to yeast for its increasing morbidity, especially the candida specices. Here we reported a fingernail infection caused by , the sexual reproduction period of . Itraconazole was used for three courses, and the patient achieved improvement without any significant side-effects. This might be the first onychomycosis case of .
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http://dx.doi.org/10.1016/j.mmcr.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016335PMC
March 2020

Auxotrophic mutations of Trichophyton rubrum created by in vitro synthesized Cas9 ribonucleoprotein.

BMC Biotechnol 2020 01 20;20(1). Epub 2020 Jan 20.

Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, Jiangsu, 210042, People's Republic of China.

Background: Trichophyton rubrum is an obligate human parasitic fungus and responsible for approximately 80-90% of dermatomycosis in human. Molecular genetic manipulations of this pathogen are challenging and available tools and protocols are only rudimentary. We adapt molecular genetics methods of well established fungal model organism, to knock out genes in T. rubrum. For the adaptation, crucial modifications are necessary. With the implementation of in vitro synthesized Cas9-sgRNA ribonucleoprotein complex, it is possible to adapt molecular genetic methods, to knock out genes in T. rubrum.

Results: The gene knock-out method is based on integration of a selection marker into the target site, to interrupt the gene translation. The target gene gets preassigned by the homologous sequence of the in vitro synthesized Cas9-sgRNA ribonucleoprotein complex. To develop the method, we first isolated and characterized a T. rubrum strain with a high amount of microconidia. Next, we developed a transformation protocol, whereby the Cas9-sgRNA ribonucleoprotein gets delivered into the fungal protoplast by the PEG method. We knocked out the URA3 gene and resulted, as predicted, uracil auxotrophic strains. These strains can be used for specific gene knock-outs by reintegrating the URA3 fragment and selection on uracil lacking cultivation media. Exemplary, we knocked out the TRP3 gene and got the predicted phenotype, tryptophan auxotrophic strains. The mutation had been verified by sequencing.

Conclusions: We developed a method, based on in vitro synthesized Cas9-sgRNA ribonucleoprotein complex, for target specific gene knock-outs in T. rubrum. We knocked out the Ura3 gene and resulted uracil auxotrophic strains. These strains were used for target specific gene knock-outs by reintegrating the Ura3 fragment into the target gene site to interrupt the gene transcription. The developed method allows to adapt sophisticate gene manipulation methods of model fungal species to non-model species.
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http://dx.doi.org/10.1186/s12896-020-0601-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971929PMC
January 2020

Whole-genome resequencing of Trichophyton rubrum provides insights into population differentiation and drug resistance.

Mycopathologia 2020 Feb 19;185(1):103-112. Epub 2019 Sep 19.

Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, 210042, Jiangsu, People's Republic of China.

Trichophyton rubrum (T. rubrum) is anthropophilic fungus and thus a very common cause of dermatophyte infections around the world. Infection of T. rubrum could result in conditions such as tinea capitis, tinea corporis, tinea inguinalis, tinea manus, tinea unguium, or tinea pedis. Because of this, the resistance of T. rubrum to antifungal therapies has drawn extensive research interest. However, the pathogenic characteristics of T. rubrum, such as site of infections, geographic location and host groups, have yet to be explored. In this study, the whole genome of 48 strains from different regions is resequenced and the population structure and association of single nucleotide polymorphism with resistance to six widely used antifungal drugs are analyzed. A total of 23,394 genomic variations are detected, which cover 2165 genes with only 15.14% of the variations located in exons. The population structure of T. rubrum is monomorphic, and genetic diversity is very low. Population structure analysis shows that the 48 sampled strains can be divided into two sub-populations. The gene TERG_08771 harboring the highest SNPs density is found to be associated with resistance to voriconazole. Although many proteins have yet to be identified and explored, association studies could still be useful to identify drug resistance or drug-susceptible loci, which would warrant further insightful investigations.
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http://dx.doi.org/10.1007/s11046-019-00384-1DOI Listing
February 2020

Different toenail onychomycosis due to and in an immunocompetent young adult.

Med Mycol Case Rep 2019 Jun 28;24:69-71. Epub 2019 Apr 28.

Department of Dermatology & Laboratory of Medical Mycology, Jining No. 1 People's Hospital, Shandong, PR China.

() and () have emerged as a potential pathogen in immunosuppressed hosts; they rarely induce onychomycosis in immunocompetent hosts without assistance from other pathogens. Here we present onychomycosis induced by two strains on different toenails in an immunocompetent young adult. The patient presented with onychomycosis on left and right first toenails due to and , respectively. Based on the diagnosis, he had been orally treated with itraconazole 200 twice daily for one week every four weeks that repeated 7 times; however, the toenails did not respond satisfactorily to the treatment. After two months of drug cessation, we confirmed that the two toenails were infected with different fungi. was isolated from the left first toenail, and was isolated from the right first toenail. Identifications were confirmed by morphological and cultural characteristics as well as by DNA molecular analysis. After determining in vitro drug susceptibility, the patient was successfully treated with a topical application of ketoconazole cream on the left toenail and oral itraconazole. It is the rare known case of different nails being infected by and respectively.
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http://dx.doi.org/10.1016/j.mmcr.2019.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503208PMC
June 2019

Hyperpigmentation on the Palm in a Three-year-old Girl: A Quiz.

Acta Derm Venereol 2019 Jun;99(7):715-716

Department of Dermatology, the Fifth Hospital of Jinhua city, 321000 Jinhua, China.

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http://dx.doi.org/10.2340/00015555-3190DOI Listing
June 2019

SOCS3 ablation enhances DC-derived Th17 immune response against Candida albicans by activating IL-6/STAT3 in vitro.

Life Sci 2019 Apr 6;222:183-194. Epub 2019 Mar 6.

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, PR China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, PR China. Electronic address:

Aims: Enhancing the potency of dendritic cells (DCs) by downregulating negative immunoregulatory pathways may provide immunotherapeutic possibilities against candidiasis.

Main Methods: In this study, a si-RNA method is used to repress expression of the cytokine signaling-3 suppressor (SOCS3) in murine bone marrow-DCs, and then the maturation of DCs and the subsequent T-cell response after exposure to C. albicans are monitored in vitro.

Key Findings: Along with a higher expression of the DC maturation markers CD40, CD86 and MHC-II, IL-6/STAT3 is markedly upregulated in the SOCS3 siRNA-treated DCs after exposure to C. albicans as compared with control DCs. In response to DCs maturation, CD4 T cells have an increased expression of Th17 cell markers -- including the retinoic acid-related orphan nuclear hormone receptors γt (RORγt), IL-17A and IL-23R -- and increased release of IL-17. We note that this enhanced Th17 cell differentiation induced by siSOCS3-treated DCs in presence of C. albicans can be partly offset when anti-IL-6 antibody is added into the co-culture.

Significance: As with SOCS1 in our previous report, suppression of SOCS3 alone also has the potential to fully activate DCs maturation. However, while SOCS1 knockdown in DCs during C. albicans infection specifically augments Th1 differentiation, SOCS3 silencing particularly increases Th17 differentiation.
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http://dx.doi.org/10.1016/j.lfs.2019.03.009DOI Listing
April 2019

In vitro susceptibility of dematiaceous fungi to nine antifungal agents determined by two different methods.

Mycoses 2019 Apr 20;62(4):384-390. Epub 2019 Feb 20.

Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, Jiangsu, China.

Background: The infection rate for dematiaceous fungi has increased rapidly over the most recent decades. However, the treatment for such infections has been lacking in empirical support with oral antifungal agents.

Objectives: To provide a better regimen for dematiaceous infections in future, the Sensititre YeastOne® colorimetric antifungal panels were used and compared with Laboratory Standards Institute (CLSI) M38-A2 reference broth microdilution method.

Methods: Two methods were used for nine antifungals against 67 dematiaceous fungi.

Results: Via two methods, we found that the MICs of itraconazole, voriconazole, posaconazole and amphotericin B were lower than fluconazole. The values obtained with CLSI method for four triazoles, 5-flucytosine and amphotericin B were in high essential agreements with those observed by YeastOne® method. The results of echinocandins across the two methods showed some divergence, which might be attributed to the methodology itself, particularly when sensitivity was determined in the lowest concentration of the drug. In YeastOne® method, the results were defined as MICs, but as MECs in CLSI method.

Conclusions: The YeastOne® method appeared to be both easier and more efficient for dematiaceous fungi when compared with the CLSI method, and the agreement between the two methods was good for most common antifungals.
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http://dx.doi.org/10.1111/myc.12895DOI Listing
April 2019

Silencing SOCS1 in dendritic cells promote survival of mice with systemic Candida albicans infection via inducing Th1-cell differentiation.

Immunol Lett 2018 05 23;197:53-62. Epub 2018 Mar 23.

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, PR China. Electronic address:

Enhancing the immunity conferred by dendritic cells (DCs) to fungal infection represents a promising strategy in the number of immunocompromised individuals. In a previous study, we demonstrated that suppressor of cytokine signaling 1 (SOCS1) silencing can promote the maturation of DCs and induce an immune response against Candida albicans (C. albicans) in vitro. Herein, the effectiveness of SOCS1 suppression administered by SOCS1-siRNA-treated DCs is further evaluated in systemic candidiasis mouse model. The SOCS1-silenced DCs increase mouse survival and significantly decrease fungal colonization in the kidneys. We confirm that the serum IFN-γ levels in SOCS1-siRNA-treated mice are higher than in all other infected groups at the early stages of infection, which correlates with a higher differentiation of IFN-γCD4 T cells (Th1) in the spleen. Meanwhile, the differentiation of IL-4-producing CD4 T (Th2) or IL-17-producing CD4 T cells (Th17 cells) remain unaffected under the same treatment, suggesting that SOCS1-silenced DCs significantly affect the IFN-γ-producing CD4 T cells (Th1). However, at the late stages of infection when the differentiation of Th1, Th2 and Th17 cells decreases in SOCS1-silenced-DCs-treated mice, all the serum cytokines (IFN-γ, IL-4 and IL-17) are also reduced. In summary, treatment of mice with SOCS1-silenced DCs can protect mice from systemic infection during the early stages and thereby increase overall survival. We conclude that the increase in Th1 response in early stages avoids the cascade inflammatory response in later stages that is known to place such a large fungal load on the kidneys and cause subsequent death.
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http://dx.doi.org/10.1016/j.imlet.2018.03.009DOI Listing
May 2018

Transcriptional profile of the human skin pathogenic fungus Mucor irregularis in response to low oxygen.

Med Mycol 2018 Jul;56(5):631-644

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, Jiangsu, People's Republic of China.

Mucormycosis is one of the most invasive mycosis and has caused global concern in public health. Cutaneous mucormycosis caused by Mucor irregularis (formerly Rhizomucor variabilis) is an emerging disease in China. To survive in the human body, M. irregularis must overcome the hypoxic (low oxygen) host microenvironment. However, the exact molecular mechanism of its pathogenicity and adaptation to low oxygen stress environment is relatively unexplored. In this study, we used Illumina HiSeq technology (RNA-Seq) to determine and compare the transcriptome profile of M. irregularis CBS103.93 under normal growth condition and hypoxic stress. Our analyses demonstrated a series of genes involved in TCA, glyoxylate cycle, pentose phosphate pathway, and GABA shunt were down-regulated under hypoxic condition, while certain genes in the lipid/fatty acid metabolism and endocytosis were up-regulated, indicating that lipid metabolism was more active under hypoxia. Comparing the data with other important human pathogenic fungi such as Aspergillus spp., we found that the gene expression pattern and metabolism in responses to hypoxia in M. irregularis were unique and different. We proposed that these metabolic changes can represent a species-specific hypoxic adaptation in M. irregularis, and we hypothesized that M. irregularis could use the intra-lipid pool and lipid secreted in the infection region, as an extracellular nutrient source to support its hypoxic growth. Characterizing the significant differential gene expression in this species could be beneficial to uncover their role in hypoxia adaptation and fungalpathogenesis and further facilitate the development of novel targets in disease diagnosis and treatment against mucormycosis.
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http://dx.doi.org/10.1093/mmy/myx081DOI Listing
July 2018

Coccidioidomycosis: Imported and possible domestic cases in China: A case report and review, 1958-2017.

Mycoses 2018 Jul 19;61(7):506-513. Epub 2018 Feb 19.

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.

We report a case of imported pulmonary coccidioidomycosis caused by Coccidioides posadasii in a patient who was misdiagnosed as tuberculosis and mistreated with antituberculosis medications for 18 months. The symptoms were not relieved until antifungal treatment was started. An extensive review of the coccidioidomycosis cases occurring in China reveals 38 cases, 16 of which had no associated history of travel to any traditional endemic areas. We speculate that some factors may drive Coccidioides spp. transference to China, which then causes those domestic infections. Moreover, we indicate the first, to the best of our knowledge, possible endemic areas in China.
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http://dx.doi.org/10.1111/myc.12750DOI Listing
July 2018

Transcriptional profile of the human skin pathogenic fungus Mucor irregularis in response to low oxygen.

Med Mycol 2018 10;56(7):e2

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, Jiangsu, People's Republic of China.

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http://dx.doi.org/10.1093/mmy/myx132DOI Listing
October 2018

Successful Treatment by Surgery of a Primary Cutaneous Mucormycosis Caused by Mucor irregularis.

Mycopathologia 2018 Apr 30;183(2):445-449. Epub 2017 Oct 30.

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.

We report a case of primary cutaneous mucormycosis caused by Mucor irregularis. A 66-year-old man was presented to our hospital with a history of gradually enlarging plaque on the right leg for about a year. The identification of pathogen based on the fungus morphology and DNA sequencing revealed M. irregularis as the responsible fungus for skin lesion. The lesion was removed incidentally by a surgery procedure, and no recrudescence was seen during a follow-up of 24-month observation.
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http://dx.doi.org/10.1007/s11046-017-0219-4DOI Listing
April 2018

The influence of the mating type on virulence of Mucor irregularis.

Sci Rep 2017 09 6;7(1):10629. Epub 2017 Sep 6.

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical, Sciences and Peking Union Medical College, No. 12 Jiang Wangmiao Street, Nanjing, 210042, Jiangsu, People's Republic of China.

Mucor irregularis is an emerging fungal pathogen that cause cutaneous infection and could cause death. However, little is known about its mechanism of pathogenesis. There is evidence suggesting virulence vary with mating types in fungi, including the Mucorales. Here, we characterized the mating type locus of M. irregularis and the mating type ratio of 17 clinical isolates in China. Genomic data indicated M. irregularis is heterothallic having two mating types - bearing either SexP or SexM allele. Also, we employed a mice model to study the inflammation and pathological effects of different mating types. The comparison of the inflammatory response, cytokine profiles and Th-1, Th-2 and Th-17 cells numbers in each mating type treated mice showed that the severity and disease progress were enhanced in (+) mating type treated mice. One (+/0) mutant strain, with multiple mutations at the mating locus, had defects in sexual mating ability but appeared to be more virulent than the (-) mating type. Although (+) mating type appeared to be more virulent, most of our clinical isolates presented belonged to (-) mating type. Our findings support the involvement of MAT genes in sexual fertility, and the influence of mating type on the severity of cutaneous infection.
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http://dx.doi.org/10.1038/s41598-017-10954-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587739PMC
September 2017

Itraconazole exerts its anti-melanoma effect by suppressing Hedgehog, Wnt, and PI3K/mTOR signaling pathways.

Oncotarget 2017 Apr;8(17):28510-28525

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.

Malignant melanoma is the deadliest form of all skin cancers. Itraconazole, a commonly used systemic antifungal drug, has been tested for its anti-tumor effects on basal cell carcinoma, prostate cancer, and non-small cell lung cancer. Whether itraconazole has any specific anti-tumor effect on melanoma remains unknown. However, the goal of this study is to investigate the effect of itraconazole on melanoma and to reveal some details of its underlying mechanism. In the in vivo xenograft mouse model, we find that itraconazole can inhibit melanoma growth and extend the survival of melanoma xenograft mice, compared to non-itraconazole-treated mice. Also, itraconazole can significantly inhibit cell proliferation, as demonstrated by Ki-67 staining in itraconazole-treated tumor tissues. In in vitro, we show that itraconazole inhibits the proliferation and colony formation of both SK-MEL-28 and A375 human melanoma cells. Moreover, we demonstrate that itraconazole significantly down-regulates Gli-1, Gli-2, Wnt3A, β-catenin and cyclin D1, while it up-regulates Gli-3 and Axin-1, indicating potent inhibitory effects of itraconazole on Hedgehog (Hh) and Wnt signaling pathways. Furthermore, itraconazole significantly suppresses the PI3K/mTOR signaling pathway - indicated by the down-regulated phosphorylation of p70S6K, 4E-BP1 and AKT - but has no effect on the phosphorylation of MEK or ERK. Our data suggest that itraconazole inhibits melanoma growth through an interacting regulatory network that includes Hh, Wnt, and PI3K/mTOR signaling pathways. These results suggest that this agent has several potent anti-melanoma features and may be useful in the synergesis of other anti-cancer drugs via blockage of the Hh, Wnt and PI3K/mTOR signaling pathways.
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http://dx.doi.org/10.18632/oncotarget.15324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438669PMC
April 2017

Onychomycosis due to with yellowish black discoloration and periungual inflammation.

Med Mycol Case Rep 2016 Sep 14;13:12-16. Epub 2016 Sep 14.

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, PR China.

Onychomycosis is usually caused by dermatophytes, although also other filamentous and yeast-like fungi are associated with nail invasion. is an environmental genus of ascomycetes exhibiting a certain degree of extremotolerance. We report the first case of onychomycosis in a 46-year-old woman in China caused by . The patient showed yellowish black discoloration with periungual inflammation on the left first toenail. We confirmed the causative agent, by KOH mount, culture, micromorphology and DNA sequence analysis.
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http://dx.doi.org/10.1016/j.mmcr.2016.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035348PMC
September 2016

Formononetin exhibits anti-hyperglycemic activity in alloxan-induced type 1 diabetic mice.

Exp Biol Med (Maywood) 2017 01 24;242(2):223-230. Epub 2016 Jul 24.

4 Department of Ophthalmology, Linyi People's Hospital of Shandong University, Linyi 276003, Shandong Province, China.

The aim of this study was to investigate the anti-hyperglycemic activity and mechanism of formononetin in alloxan-induced type 1 diabetic mice by determining its effect on some diabetes-related indices as described below. Body weight, fasting blood glucose, hepatic glycogen, serum insulin, and serum glucagon were determined by electronic scales, glucometer, and ELISA kits. Fas, Caspase-3, pancreatic and duodenal homeobox-1 , insulin receptor substrate 2, glucokinase and glucose transporter 2, mRNA and proteins levels in pancreas tissue, and glucokinase and glucose-6-phosphatase mRNA, and proteins levels in liver tissue were detected by fluorogenic quantitative-polymerase chain reaction and Western blot assays. The results indicated that formononetin (5, 10, and 20 mg/kg; oral administration) reversed the alloxan-induced increase of some indices (fasting blood glucose level and Fas and Caspase-3 mRNA and proteins levels in pancreas tissue) and reduction of some indices (body weight gain, oral glucose tolerance, insulin activity, hepatic glycogen level, pancreatic and duodenal homeobox-1, insulin receptor substrate 2, glucokinase and glucose transporter 2, mRNA and proteins levels in pancreas tissue, and glucokinase mRNA and protein levels in liver tissue). The glucagon level and glucose-6-phosphatase mRNA and protein levels in liver tissue were not affected by the drugs administration. In conclusion, formononetin exhibited anti-hyperglycemic activity in alloxan-induced type 1 diabetic mice by inhibiting islet B cell apoptosis and promoting islet B cell regeneration, insulin secretion, hepatic glycogen synthesis, and hepatic glycolysis.
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http://dx.doi.org/10.1177/1535370216657445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167112PMC
January 2017

Chromoblastomycosis due to Fonsecaea monophora misdiagnosed as sporotrichosis and cutaneous tuberculosis in a pulmonary tuberculosis patient.

Med Mycol Case Rep 2016 Mar 10;11:57-60. Epub 2016 May 10.

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, PR China.

Chromoblastomycosis is caused by dematiaceous fungi. It develops after inoculation of the organism into the skin. We report a case of chromoblastomycosis in a pulmonary tuberculosis patient without known history of trauma. The lesions were initially diagnosed as sporotrichosis and skin tuberculosis. Histopathology of scales and skin biopsy specimen revealed sclerotic bodies, the hallmark of chromoblastomycosis. The causative organism was identified as Fonsecaea monophora by rDNA ITS sequencing. The lesions recovered markedly after two month treatment with oral terbinafine 250 mg daily according to drug sensitive test in vitro in combination with local thermotherapy.
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http://dx.doi.org/10.1016/j.mmcr.2016.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907037PMC
March 2016

Paeoniflorin suppresses IL-6/Stat3 pathway via upregulation of Socs3 in dendritic cells in response to 1-chloro-2,4-dinitrobenze.

Int Immunopharmacol 2016 Sep 26;38:45-53. Epub 2016 May 26.

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, PR China. Electronic address:

Mounting evidence has suggested that inflammation is associated with IL-6/Stat3 pathway in dendritic cells (DCs) and Th17 cells, which are critical for development of allergic contact dermatitis (ACD). Paeoniflorin (PF) has been clinically proved to be effective in the treatment of inflammatory skin diseases such as ACD. We have previously demonstrated the effect of PF on DCs stimulated with 1-chloro-2,4-dinitrobenze (DNCB) and naïve CD4(+)CD45RA(+) T cells for Th17 cell differentiation. However, whether PF down-regulates IL-6/Stat3 in DCs and Th17 cells remains to be explored. In this study, we show clearly that PF markedly decreases IL-6/Stat3 in DCs stimulated with DNCB at both gene and protein levels compared with control DCs in vitro. Meanwhile, PF up-regulates suppressor of cytokine signaling 3 (Socs3). Such decreased expression of IL-6/Stat3 is abolished in DCs that were transfected with Socs3 short interfering RNA (siRNA). When mice CD4(+)CD45 RA(+) T cells were co-cultured with PF-treated DCs stimulated with/without DNCB, the gene expression of the Th17 cell markers such as retinoic acid-related orphan nuclear hormone receptor γt (RORγt), IL-17A, and IL-23R decreased, in accordance with the less secretions of IL-17 and IL-23 in vitro and in vivo. Finally, the suppressed Th17 differentiation induced by PF can be abolished by additional recombinant mouse IL-6. Our results suggest that the anti-inflammatory mechanisms introduced by depletion of Socs3 expression or inactivation of the negative regulator such as Socs3 may represent a promising strategy for the prevention of ACD.
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http://dx.doi.org/10.1016/j.intimp.2016.05.013DOI Listing
September 2016

Subcutaneous infection by Ochroconis mirabilis in an immunocompetent patient.

Med Mycol Case Rep 2016 Mar 26;11:44-7. Epub 2016 Apr 26.

Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, China.

Recently, the taxonomy of Ochroconis (Ascomycota, Pezizomycotina, Venturiales, Sympoventuriaceae) has been revised with the recognition of an additional genus, Verruconis. Ochroconis comprises mesophilic saprobes that occasionally infect vertebrates which mostly are cold-blooded, while Verruconis contains thermophilic species which is a neurotrope in humans and birds. On the basis of molecular data it is noted that only a single Ochroconis species regularly infects immunocompetent human hosts. Here we report a subcutaneous infection due to Ochroconis mirabilis in a 50-year-old immunocompetent female patient. In vitro antifungal susceptibility tests revealed that terbinafine was the most effective drug. The patient was successfully cured with oral administration of terbinafine 250 mg daily in combination with 3 times of topical ALA-photodynamic therapy for 9 months.
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http://dx.doi.org/10.1016/j.mmcr.2016.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857222PMC
March 2016

Antifungal effects of undecylenic acid on the biofilm formation of Candida albicans.

Int J Clin Pharmacol Ther 2016 May;54(5):343-53

Undecylenic acid can effectively control skin fungal infection, but the mechanism of its fungal inhibition is unclear. Hyphal growth of Candida albicans (C. albicans) and biofilm formation have been well recognized as important virulence factors for the initiation of skin infection and late development of disseminated infection. In this study, we seek to investigate antifungal mechanisms of undecylenic acid by evaluating the virulence factors of C. albicans during biofilm formation. We found that undecylenic acid inhibits biofilm formation of C. albicans effectively with optimal concentration above 3 mM. In the presence of this compound, the morphological transition from yeast to filamentous phase is abolished ultimately when the concentration of undecylenic acid is above 4 mM. Meanwhile, the cell surface is crumpled, and cells display an atrophic appearance under scanning electron microscopy even with low concentration of drug treatment. On the other hand, the drug treatment decreases the transcriptions of hydrolytic enzymes such as secreted aspartic protease, lipase, and phospholipase. Hyphal formation related genes, like HWP1, are significantly reduced in transcriptional level in drug-treated biofilm condition as well. The down-regulated profile of these genes leads to a poorly organized biofilm in undecylenic acid treated environment.
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http://dx.doi.org/10.5414/CP202460DOI Listing
May 2016

Microsatellite analysis of genotype distribution patterns of Candida albicans vulvovaginal candidiasis in Nanjing, China and its association with pregnancy, age and clinical presentation.

Arch Gynecol Obstet 2016 08 10;294(2):291-7. Epub 2016 Feb 10.

Institute of Dermatology, Chinese Academy of Medical Science and Peaking Union Medical College and Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, No 12 Jiangwangmiao St., Nanjing, 210042, China.

Purpose: To characterize the genotype distribution pattern of Candida albicans associated with vulvovaginal candidiasis (VVC) in Nanjing, China by microsatellite genotyping.

Methods: A questionnaire was completed by each patient diagnosed with VVC. A total of 208 independent C. albicans was isolated from 208 patients. Microsatellite genotyping characterized the genotype distribution by analysis of the CAI locus marker.

Results: PCR of CAI fragments showed the three major genotypes contained 30:45, 21:21 and 32:46 alleles among the 51 genotypes detected, accounting for 29.3, 13.0 and 12.0 % of 208 clinical isolates. Genotype distributions had a similar pattern among different clinical presentations (P = 0.219). In both groups of the (21-30) and (31-40) years, 30:45 was the most frequent genotype allele detected. In the (21-30) year females, 16.5 % of the isolated strains had the genotype 21:21, while the same genotype in the group of (31-40) years was 6.9 %. Genotype distributions were significant difference between the pregnant and non-pregnant women (P < 0.001). 30:45 was detected only one in the 23 pregnant women.

Conclusions: The results indicated a unique genotype distribution of C. albicans associated with VVC in Nanjing, eastern China and a different distribution pattern was also detected in pregnant women compared to non-pregnant women.
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http://dx.doi.org/10.1007/s00404-016-4029-6DOI Listing
August 2016