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1.
Virulence ; 12(1): 1091-1110, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33843471

RESUMO

In eukaryotes, calcium not only is an essential mineral nutrient but also serves as an intracellular second messenger that is necessary for many physiological processes. Previous studies showed that the protein phosphatase-calcineurin protects fungi from toxicity caused by the extracellular calcium; however, little is known about how calcineurin mediates the cellular physiology process for this function. In this study, by monitoring intracellular calcium, particularly by tracking vacuolar calcium dynamics in living cells through a novel procedure using modified aequorin, we found that calcineurin dysfunction systematically caused abnormal intracellular calcium homeostasis in cytosol, mitochondria, and vacuole, leading to drastic autophagy, global organelle fragmentation accompanied with the increased expression of cell death-related enzymes, and cell death upon extracellular calcium stimuli. Notably, all detectable defective phenotypes seen with calcineurin mutants can be significantly suppressed by alleviating a cytosolic calcium overload or increasing vacuolar calcium storage capacity, suggesting toxicity of exogenous calcium to calcineurin mutants is tightly associated with abnormal cytosolic calcium accumulation and vacuolar calcium storage capacity deficiency. Our findings provide insights into how the original recognized antifungal drug target-calcineurin regulates intracellular calcium homeostasis for cell survival and may have important implications for antifungal therapy and clinical drug administration.

2.
Food Chem ; 356: 129704, 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33831827

RESUMO

The postharvest senescence accompanied by yellowing limited the shelf-life of broccoli. In this study, we developed a novel W/O/W double emulsion co-delivering brassinolide and cinnamon essential oil and applied it to broccoli for preservation. Results showed that double emulsion prepared by whey protein concentrate-high methoxyl pectin (1:3) exhibited best storage stability with largest particle size (581.30 nm), lowest PDI (0.23) and zeta potential (-40.31 mV). This double emulsion also exhibited highest encapsulation efficiency of brassinolide (92%) and cinnamon essential oil (88%). The broccoli coated with double emulsion maintained higher chlorophyll contents and activities of chlorophyllase and magnesium-dechelatase were reduced by 9% and 24%, respectively. The energy metabolic enzymes (SDH, CCO, H+-ATPase, Ca2+-ATPase) were also activated, inducing higher level of ATP and energy charge. These results demonstrated W/O/W double emulsion co-delivering brassinolide and cinnamon essential delayed the senescence of broccoli via regulating chlorophyll degradation and energy metabolism.

3.
Acta Biochim Pol ; 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33829718

RESUMO

Temporal lobe epilepsy (TLE) is a chronic disease of the nervous system, associated with increased proliferation in the hippocampus. Urothcarcinoma associated 1 (UCA1) is a long long non-coding RNA that was shown to regulate proliferation and differentiation of neural progenitors in vitro. We hypothesised that TLE-associated abnormal proliferation is a consequence of the downregulation of UCA1. This hypothesis was tested in mice with kainic acid (KA)-induced seizures, and then the potential mechanism was explored in vitro and in vivo. Result showed that the expression of UCA1 and Secreted Frizzled Related Protein 1 (SFRP1) were significantly reduced in hippocampal tissues of epileptic mice, while miR-375 was increased compared with the control group. Pearson correlation analysis showed that UCA1 was positively correlated with SFRP1, while miR-375 was negatively correlated with UCA1 and SFRP1. Besides, UCA1 was overexpressed in mice and the overexpression of UCA1 significantly reversed the abnormal proliferation of hippocampal neurons in epilepsy mice. In vitro Luciferase assay showed that UCA1 and Sfrp1 are both the targets of miR-375, and UCA1 promotes the expression of Sfrp1 by competitively adsorbing miR-375, thereby inhibiting the activation of the WNT/ß-catenin pathway. The inactivation of the WNT/ß-catenin pathway prevented the abnormal proliferation of neural progenitors in the epileptic hippocampus. In conclusion, our findings provide a theoretical basis for the clinical application of UCA1.

4.
Iran J Kidney Dis ; 1(2): 109-115, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33764321

RESUMO

INTRODUCTION: Steroid-dependent (SD)/frequently relapsing (FR) nephrotic syndrome (NS) follows a relapsing and remitting course. It is also characterized by proteinuria and edema, which can significantly affect health-related quality of life (HRQOL) in children. This study evaluated the effectiveness and safety of a single dose of rituximab (RTX) as well as the impact of RTX on HRQOL in children with SDFRNS. METHODS: Sixteen children with SDFRNS were enrolled in the study. Each patient was administered a single intravenous dose of RTX (375 mg/m2). Effectiveness was defined as remission of proteinuria. The side effects of RTX were monitored. HRQOL was assessed using PedsQL™ 4.0 Generic Core Scales. RESULTS: All the patients completed the study. Three SDNS patients and three FRNS patients discontinued treatment over 1 to 3.25 years of follow-up. Additionally, three SDNS patients and three FRNS patients experienced 1 to 2 relapses. The mean relapse-free period was 79.0 ± 77.6 days. The mean dosages of prednisolone and other immunosuppressants required were significantly lower (P < .05, < .001) six months after treatment with RTX compared with six months before treatment. Relapse rate was significantly reduced (P < .001) after treatment with RTX. Skin rash, hypotension, and fever were observed in one child. Total health score and physical, emotional, and school functioning were significantly higher six months after treatment with RTX (P < .001). CONCLUSION: A single dose of RTX is effective and safe for children with SDFRNS and can improve HRQOL, especially physical, emotional, and school functioning.

5.
Arch Microbiol ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674952

RESUMO

A polyphosphate-producing bacterium, YG09T, was isolated from the rhizosphere of Salvia miltiorrhiza. Its colonies were 2.0-3.0 mm in diameter, smooth, circular, convex and yellow after growth on R2A at 28 °C for 72 h, with aerobic, Gram-stain-negative, non-motile and rod-shaped bacteria. The strain was found to grow at 10-40 °C (optimum 37 °C), pH 5.5-8.0 (optimum 6.0), with 0-0.6% (w/v) NaCl (optimum 0). Chemotaxonomic analysis showed menaquinone-7 as the only quinone present; C15: 1 iso G, C15: 1 iso, C16: 0, C16: 0 3OH, C17: 0 iso 3OH, summed feature 3 (C16:1 ω7c and/or C16:1 ω6c) as the major fatty acids (> 5%), and phosphatidylethanolamine, three unidentified phospholipids, four unidentified polar lipids, three unidentified aminolipids, and one unidentified amino phospholipid as the polar lipids. The DNA G + C content was 44.6 mol%. The 16S rRNA gene sequences of the isolate showed highest similarities to Panacibacter ginsenosidivorans Gsoil 1550T (93.6%), Filimonas endophytica SR2-06T (93.4%), Parasegetibacter terrae SGM2-10T (92.8%), and Arvibacter flaviflagrans C-1-16T (92.7%), within the family Chitinophagaceae of the phylum Bacteroidetes. The ANI values between strain YG09T and Panacibacter ginsenosidivoran Gsoil 1550T, Filimonas endophytica SR2-06T and Filimonas lacunae YT21T were 69.4, 68.3 and 68.7%, respectively. Based on phenotypic, genotypic and phylogenetic analyses, strain YG09T represents a novel genus in the family Chitinophagaceae, for which the name Foetidibacter luteolus gen. sp. nov. is proposed. The type strain is Foetidibacter luteolus YG09T (= MCCC 1K04042T = KCTC 72595T).

6.
J Magn Reson Imaging ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33590944

RESUMO

BACKGROUND: Myocardial injury has been found using magnetic resonance imaging in recovered coronavirus disease 2019 (COVID-19) patients unselected or with ongoing cardiac symptoms. PURPOSE: To evaluate for the presence of myocardial involvement in recovered COVID-19 patients without cardiovascular symptoms and abnormal serologic markers during hospitalization. STUDY TYPE: Prospective. POPULATION: Twenty-one recovered COVID-19 patients and 20 healthy controls (HC). FIELD STRENGTH/SEQUENCE: 3.0 T, cine, T2-weighted imaging, T1 mapping, and T2 mapping. ASSESSMENT: Cardiac ventricular function includes end-diastolic volume, end-systolic volume, stroke volume, cardiac output, left ventricle (LV) mass, and ejection fraction (EF) of LV and right ventricle (RV), and segmental myocardial T1 and T2 values were measured. STATISTICAL TESTS: Student's t-test, univariate general linear model test, and chi-square test were used for analyses between two groups. Ordinary one-way analyses of variance or Kruskal-Wallis H test were used for analyses between three groups, followed by post-hoc analyses. RESULTS: Fifteen (71.43%) COVID-19 patients had abnormal magnetic resonance findings, including raised myocardial native T1 (5, 23.81%) and T2 values (10, 47.62%), decreased LVEF (1, 4.76%), and RVEF (2, 9.52%). The segmental myocardial T2 value of COVID-19 patients (49.20 [46.1, 54.6] msec) was significantly higher than HC (48.3 [45.2, 51.7] msec) (P < 0.001), while the myocardial native T1 value showed no significant difference between COVID-19 patients and HC. The myocardial T2 value of serious COVID-19 patients (52.5 [48.1, 57.1] msec) was significantly higher than unserious COVID-19 patients (48.8 [45.9, 53.8] msec) and HC (48.3 [45.2, 51.7]) (P < 0.001). COVID-19 patients with abnormally elevated D-dimer, C-reactive protein, or lymphopenia showed higher myocardial T2 values than without (all P < 0.05). DATA CONCLUSION: Cardiac involvement was observed in recovered COVID-19 patients with no preexisting cardiovascular disease, no cardiovascular symptoms, and elevated serologic markers of myocardial injury during the whole course of COVID-19. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 5.

7.
Mol Oncol ; 15(4): 1054-1068, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33540470

RESUMO

Epidermal growth factor receptor (EGFR) is often overexpressed in head and neck squamous cell carcinoma (HNSCC) and represents a top candidate for targeted HNSCC therapy. However, the clinical effectiveness of current Food and Drug Administration (FDA)-approved drugs targeting EGFR is moderate, and the overall survival rate for HNSCC patients remains low. Therefore, more effective treatments are urgently needed. In this study, we generated a novel diphtheria toxin-based bivalent human epidermal growth factor fusion toxin (bi-EGF-IT) to treat EGFR-expressing HNSCC. Bi-EGF-IT was tested for in vitro binding affinity, cytotoxicity, and specificity using 14 human EGFR-expressing HNSCC cell lines and three human EGFR-negative cancer cell lines. Bi-EGF-IT had increased binding affinity for EGFR-expressing HNSCC compared with the monovalent version (mono-EGF-IT), and both versions specifically depleted EGFR-positive HNSCC, but not EGFR-negative cell lines, in vitro. Bi-EGF-IT exhibited a comparable potency to that of the FDA-approved EGFR inhibitor, erlotinib, for inhibiting HNSCC tumor growth in vivo using both subcutaneous and orthotopic HNSCC xenograft mouse models. When tested in an experimental metastasis model, survival was significantly longer in the bi-EGF-IT treatment group than the erlotinib treatment group, with a significantly reduced number of metastases compared with mono-EGF-IT. In addition, in vivo off-target toxicities were significantly reduced in the bi-EGF-IT treatment group compared with the mono-EGF-IT group. These results demonstrate that bi-EGF-IT is more effective and markedly less toxic at inhibiting primary HNSCC tumor growth and metastasis than mono-EGF-IT and erlotinib. Thus, the novel bi-EGF-IT is a promising drug candidate for further development.

9.
Hepatol Int ; 15(1): 202-212, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33548030

RESUMO

BACKGROUND: Infection with SARS-CoV-2 has been associated with liver dysfunction, aggravation of liver burden, and liver injury. This study aimed to assess the effects of liver injuries on the clinical outcomes of patients with COVID-19. METHODS: A total of 1520 patients with severe or critical COVID-19 from Huoshenshan Hospital, Wuhan, were enrolled. Chronic liver disease (CLD) was confirmed by consensus diagnostic criteria. Laboratory test results were compared between different groups. scRNA-seq data and bulk gene expression profiles were used to identify cell types associated with liver injury. RESULTS: A total of 10.98% of patients with severe or critical COVID-19 developed liver injury after admission that was associated with significantly higher rates of mortality (21.74%, p < 0.001) and intensive care unit admission (26.71%, p < 0.001). Pre-existing CLDs were not associated with a higher risk. However, fatty liver disease and cirrhosis were associated with higher risks, supported by evidences from single cell and bulk transcriptome analysis that showed more TMPRSS2+ cells in these tissues. By generating a model, we were able to predict the risk and severity of liver injury during hospitalization. CONCLUSION: We demonstrate that liver injury occurring during therapy as well as pre-existing CLDs like fatty liver disease and cirrhosis in patients with COVID-19 is significantly associated with the severity of disease and mortality, but the presence of other CLD is not associated. We provide a risk-score model that can predict whether patients with COVID-19 will develop liver injury or proceed to higher-risk stages during subsequent hospitalizations.


Assuntos
/complicações , Hepatopatias/diagnóstico , Hepatopatias/virologia , Adulto , Idoso , China , Cuidados Críticos , Oxigenação por Membrana Extracorpórea , Feminino , Hospitalização , Humanos , Hepatopatias/mortalidade , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Respiração Artificial , Fatores de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida
10.
Fungal Genet Biol ; 149: 103531, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33581364

RESUMO

Fungi activate corresponding metabolic pathways in response to different carbon sources to adapt to different environments. Previous studies have shown that the glycerol kinase GlcA that phosphorylates glycerol to the intermediate glycerol-3-phosphate (G3P) is required for the growth of Aspergillus fumigatus when glycerol is used as the sole carbon source. The present study identified there were two putative glycerol kinases, GlcA and GlcB, in A. fumigatus but glycerol activated only glcA promoter but not glcB promoter, although both glcA and glcB could encode glycerol kinase. Under normal culture conditions, the absence of glcA caused no detectable colony phenotypes on glucose and other tested carbon sources except glycerol, indicating dissimilation of glucose and these tested carbon sources bypassed requirement of glcA. Notably, the oxidative stress agent H2O2 on the background of glucose medium clearly induced GlcA expression and promoted G3P synthesis. Deletion and overexpression of glcA elicited sensitivity and resistance to oxidative stress agent H2O2, respectively, accompanied by decrease and increase of G3P production. In addition, the sensitivity to oxidative stress in the glcA mutant was probably associated with dysfunction of mitochondria with a decreased mitochondrial membrane potential and an abnormal accumulation of the cellular reactive oxygen species (ROS). Furthermore, overexpressing the glycerol-3-phosphate dehydrogenase GfdA thatcatalyzes the reduction of dihydroxyacetone phosphate (DHAP) to G3P rescued phenotypes of the glcA null mutant to H2O2. Therefore, the present study suggests that GlcA-involved G3P synthesis participates in oxidative stress tolerance of A. fumigatus via regulating the cellular ROS level.

11.
Mol Microbiol ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33629421

RESUMO

Aspergillus fumigatus is an opportunistic mold responsible for severe life-threatening fungal infections in immunocompromised patients. The cell wall, an essential structure composed of glucan, chitin, and galactomannan, is considered to be a target for the development of antifungal drugs. The nucleotide sugar donor GDP-mannose (GDP-Man) is required for the biosynthesis of galactomannan, glycosylphosphatidylinositol (GPI) anchors, glycolipid, and protein glycosylation. Starting from fructose-6-phosphate, GDP-Man is produced by the sequential action of the enzymes phosphomannose isomerase, phosphomannomutase (Pmm), and GDP-mannose pyrophosphorylase. Here, using heterokaryon rescue and gene knockdown approaches we demonstrate that the phosphomannomutase encoding gene in A. fumigatus (pmmA) is essential for survival. Reduced expression of pmmA is associated with significant morphological defects including retarded germination, growth, reduced conidiation, and abnormal polarity. Moreover, the knockdown strain exhibited an altered cell wall organization and sensitivity toward cell wall perturbing agents. By solving the first crystal structure of A. fumigatus phosphomannomutase (AfPmmA) we identified non-conservative substitutions near the active site when compared to the human orthologues. Taken together, this work provides a genetic and structural foundation for the exploitation of AfPmmA as a potential antifungal target.

12.
Appl Microbiol Biotechnol ; 105(3): 1253-1268, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33475797

RESUMO

Ergosterol, a major lipid present in the fungal cell membrane, is considered as an effective antifungal drug target. A rational strategy for increasing drug reservoir relies on functionally validation of essential enzymes involved in fungal key biological pathway. Current knowledge regarding the essential genes in the ergosterol biosynthesis pathway is still limited in the opportunistic human pathogen Aspergillus fumigatus. In this study, we characterized two endoplasmic reticulum-localized sterol C-14 reductases encoded by both erg24A and erg24B homologs that are essential for the viability of A. fumigatus despite the fact that neither paralog is essential individually. Loss of one homolog of Erg24 impairs hyphal growth, conidiation, and virulence but has no effect on ergosterol biosynthesis. To investigate the functional significance of erg24, a conditional double mutant (Δerg24B niiA::erg24A) was constructed in the Δerg24B background. Strikingly, the conditional erg24 double mutant exhibited severe growth defects and accumulation of sterol intermediate. Moreover, the addition of metal ions and the overexpression of the corresponding ion transporters could rescue the growth defects of the erg24 double mutant in A. fumigatus, implying that the defective phenotype of the erg24 double mutant is tightly associated with dysregulation of ion homeostasis. Taken together, our results demonstrate the critical role of Erg24 in ergosterol biosynthesis and ion homeostasis in A. fumigatus, which may have important implications for antifungal discovery. KEY POINTS: • We characterized two endoplasmic reticulum-localized sterol C-14 reductases Erg24A and Erg24B in A. fumigatus. • Erg24A and Erg24B in combination, but not individually, are required for the viability of A. fumigatus. • Inactivation of Erg24 leads to the disruption of ion homeostasis and affects ergosterol biosynthesis.

13.
Theranostics ; 11(4): 1732-1752, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33408778

RESUMO

Estrogen and estrogen receptor (ER)-regulated gene transcriptional events have been well known to be involved in ER-positive breast carcinogenesis. Meanwhile, circular RNAs (circRNAs) are emerging as a new family of functional non-coding RNAs (ncRNAs) with implications in a variety of pathological processes, such as cancer. However, the estrogen-regulated circRNA program and the function of such program remain uncharacterized. Methods: CircRNA sequencing (circRNA-seq) was performed to identify circRNAs induced by estrogen, and cell proliferation, colony formation, wound healing, transwell and tumor xenograft experiments were applied to examine the function of estrogen-induced circRNA, circPGR. RNA sequencing (RNA-seq) and ceRNA network analysis wereperformed to identify circPGR's target genes and the microRNA (miRNA) bound to circPGR. Anti-sense oligonucleotide (ASO) was used to assess circPGR's effects on ER-positive breast cancer cell growth. Results: Genome-wide circRNA profiling by circRNA sequencing (circRNA-seq) revealed that a large number of circRNAs were induced by estrogen, and further functional screening for the several circRNAs originated from PGR revealed that one of them, which we named as circPGR, was required for ER-positive breast cancer cell growth and tumorigenesis. CircPGR was found to be localized in the cytosol of cells and functioned as a competing endogenous RNA (ceRNA) to sponge miR-301a-5p to regulate the expression of multiple cell cycle genes. The clinical relevance of circPGR was underscored by its high and specific expression in ER-positive breast cancer cell lines and clinical breast cancer tissue samples. Accordingly, anti-sense oligonucleotide (ASO) targeting circPGR was proven to be effective in suppressing ER-positive breast cancer cell growth. Conclusions: These findings reveled that, besides the well-known messenger RNA (mRNA), microRNA (miRNA), long non-coding RNA (lncRNA) and enhancer RNA (eRNA) programs, estrogen also induced a circRNA program, and exemplified by circPGR, these estrogen-induced circRNAs were required for ER-positive breast cancer cell growth, providing a new class of therapeutic targets for ER-positive breast cancer.

14.
Fungal Genet Biol ; 147: 103509, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33400990

RESUMO

For decades, the edible mushroom Pleurotus eryngii (P. eryngii) has been cultivated as important raw materials for food and pharmaceutical industries in most of Asian countries, especially in China. Unfortunately, the generation and improvement of new cultivars are very difficult since there are many barriers which have not been solved thoroughly by gene editing tools, even though the CRISPR-Cas9 technique has been widely applied in other species. In this study, we identified the point-mutated variant of the endogenous sdhB gene (cbxr) as a more stable selection marker than hygromycin B resistance gene (hph) in P. eryngii. Furthermore, using a codon-optimized Cas9, a predicted native U6 promoter-guided sgRNA, as well as an optimized protoplast transformation system, a highly efficient pyrG gene editing system was established in P. eryngii, that incorporated varied insertions and deletions (indels) by non-homologous end joining (NHEJ) and homology-directed repair (HDR). Findings for a successful targeted gene editing strategy in the edible mushroom P. eryngii may open a new chapter for the improvement of edible mushroom cultivars.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33431412

RESUMO

The emergence of azole-resistant fungal pathogens has posed a great threat to public health worldwide. Although the molecular mechanism of azole resistance has been extensively investigated, the potential regulators of azole resistance remain largely unexplored. In this study, we identified a new function of the fungal specific C2H2 zinc finger transcription factor SltA (involved in the salt tolerance pathway) in the regulation of azole resistance of the human fungal pathogen Aspergillus fumigatus A lack of SltA results in an itraconazole hypersusceptibility phenotype. Transcriptional profiling combined with LacZ reporter analysis and electrophoretic mobility shift assays (EMSA) demonstrated that SltA is involved in its own transcriptional regulation and also regulates the expression of genes related to ergosterol biosynthesis (erg11A, erg13A, and erg24A) and drug efflux pumps (mdr1, mfsC, and abcE) by directly binding to the conserved 5'-AGGCA-3' motif in their promoter regions, and this binding is dependent on the conserved cysteine and histidine within the C2H2 DNA binding domain of SltA. Moreover, overexpression of erg11A or mdr1 rescues sltA deletion defects under itraconazole conditions, suggesting that erg11A and mdr1 are related to sltA-mediated itraconazole resistance. Most importantly, deletion of SltA in laboratory-derived and clinical azole-resistant isolates significantly attenuates drug resistance. Collectively, we have identified a new function of the transcription factor SltA in regulating azole resistance by coordinately mediating the key azole target Erg11A and the drug efflux pump Mdr1, and targeting SltA may provide a potential strategy for intervention of clinical azole-resistant isolates to improve the efficiency of currently approved antifungal drugs.

16.
Eur J Gastroenterol Hepatol ; 33(1): 107-113, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32243344

RESUMO

OBJECTIVES: Hepatitis B virus reactivation in patients on immunosuppressive therapy is a critical issue. We aimed to verify the monitoring strategies of hepatitis B virus DNA and quantitative hepatitis B surface antigen in patients receiving therapies with moderate risk. METHODS: We enrolled 25 patients with autoimmune diseases receiving immunosuppressive therapy. Liver function, hepatitis B virus DNA, and quantitative hepatitis B surface antigen were followed-up every 2 months for 24 months. The hepatitis B virus reactivation was defined as hepatitis B virus DNA reappearance or increase of >1 log IU/mL. RESULTS: Patients who were hepatitis B surface antigen positive with (n = 12) or without (n = 6) antiviral prophylaxis and hepatitis B surface antigen negative (n = 7) were analyzed, and the reactivation rates were 0%, 50% and 14%, respectively. Antiviral prophylaxis prevented hepatitis B virus reactivation in hepatitis B surface antigen-positive patients (P = 0.025). Administration of high-risk steroid doses was the sole factor related to the sign of quantitative hepatitis B surface antigen increase of >0.5 log IU/mL in the first 12 months (P = 0.035, risk ratio = 0.098, 95% confidence interval = 0.011-0.847). Furthermore, no patient experienced hepatic decompensation or failure. CONCLUSION: Monitoring hepatitis B virus DNA and quantitative hepatitis B surface antigen every 2 months is safe. However, antiviral prophylaxis can prevent hepatitis B virus reactivation. For patients under steroid therapy in high-risk doses, quantitative hepatitis B surface antigen increase of >0.5 log IU/mL may signify hepatitis B virus reactivation.

17.
Cell Death Discov ; 6(1): 116, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33298860

RESUMO

Ischemia/reperfusion (I/R) injury is responsible for liver injury during hepatic resection and liver transplantation. The plasma membrane-bound G protein-coupled bile acid receptor (TGR5) could regulate immune response in multiple liver diseases. Nevertheless, the underlying role of TGR5 in hepatic I/R injury remains largely unknown. This study aimed to investigate the potential mechanism of TGR5 in hepatic I/R injury. Wild-type (WT) and TGR5 knockout (TGR5KO) mice were used to perform hepatic I/R, and macrophages were isolated from mice for in vitro experiments. The results demonstrated that knockout of TGR5 in mice significantly exacerbated liver injury and inflammatory response. TGR5KO mice infused with WT macrophages showed relieved liver injury. Further study revealed that TGR5 knockout inhibited sirtuin 3 (SIRT3) and forkhead box O3 (FOXO3) expression. In vitro experiments indicated that SIRT3 inhibited acetylation, ubiquitination and degradation of FOXO3. FOXO3 inhibited HIF-1α transcription by binding to its promoter. TGR5 knockout inhibited SIRT3 expression, thus promoted the acetylation, ubiquitination, and degradation of FOXO3, which resulted in increased HIF-1α transcription and macrophages proinflammatory response. Collectively, TGR5 plays a critical protective role in hepatic I/R injury. FOXO3 deacetylation mediated by SIRT3 can attenuate hepatic I/R injury. TGR5 deficiency aggravates hepatic I/R injury via inhibiting SIRT3/FOXO3/HIF-1α pathway.

18.
Mol Microbiol ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300219

RESUMO

In eukaryotes, histone acetylation catalyzed by histone acetyltransferase (HAT) has been demonstrated to be critical for various physiological processes. However, the biological functions of HAT and the underlying mechanism by which HAT-regulated processes are involved in fungal development and virulence in the human opportunistic pathogen Aspergillus fumigatus remain largely unexplored. Here, we functionally characterized the roles of Rtt109 in A. fumigatus, an orthologue of Saccharomyces cerevisiae histone acetyltransferase Rtt109. In vivo and vitro HAT assays revealed that AfRtt109 functions as a canonical histone acetyltransferase, acetylating lysines 9 and 56 of histone H3. Deletion of Afrtt109 leads to severe defects in vegetative growth, conidiation and causes reduced virulence in the Galleria mellonella model, as well as hypersensitivity to genotoxic agents. Moreover, site-directed mutagenesis revealed that the conserved arginine residues R265 and R306 of Rtt109 are required for the H3K9 and H3K56 acetylation and virulence of A. fumigatus. Unexpectedly, R265E and R306E mutants did not exhibit any detectable phenotypic defects, implying that A. fumigatus Rtt109 regulates fungal development via histone acetylation-independent mechanisms. Together, our results revealed the critical role of fungal-specific HAT Rtt109 in regulating fungal development and virulence, and suggested that it may serve as a unique target for antifungal therapies.

19.
Artigo em Inglês | MEDLINE | ID: mdl-33257310

RESUMO

The electron donor cytochrome b5 (CybE/Cyb5) fuels the activity of the ergosterol biosynthesis-related P450 enzymes/P450s by providing electrons to P450s to promote ergosterol biosynthesis. Previous studies reported that lack of Aspergillus fumigatus (A. fumigatus) CybE reduces the proportion of ergosterol in total sterols and induces severe growth defects. However, the molecular characteristics of CybE and the underlying mechanism for CybE maintaining A. fumigatus growth remain poorly understood. Here, we found that CybE locates at the endoplasmic reticulum by its C-terminus with two transmembrane regions. Therefore, lack of the C-terminus of CybE is able to phenocopy a cybE deletion. Notably, cybE deletion reduced the accumulation of the sterol-rich plasma membrane domains (SRDs, the assembly platform of polarity factors/cell end markers and growth machinery) in hyphal tips and decreased membrane fluidity, which correspond to tardiness of hyphal extension and hypersensitivity to low temperature in cybE deletion mutant. Additionally, overexpressing another electron donor-heme-independent P450 reductase (CPR) significantly rescued growth defects and recovered SRD accumulation in deletion of cybE almost to the wild-type level, suggesting CybE maintaining the growth and deposition of SRDs in hyphal tips attributes to its nature as an electron donor. Protein pull-down assays revealed that CybE probably participates in metabolism and transfer of lipids, construction of cytoskeleton and mitochondria-associated energy metabolism to maintain the SRD accumulation in hyphal tips, membrane fluidity and hyphal extension. Findings in this study give a hint that inhibition of CybE may be an effective strategy for resisting the infection of the human pathogen A. fumigatus Importance Investigating the knowledge of the growth regulation in the human opportunistic pathogen A. fumigatus is conducive to design new antifungal approach. The electron donor cytochrome b5 (CybE) plays a crucial role in maintaining the normal growth of A. fumigatus, however, the potential mechanism remains elusive. Herein, we characterized the molecular features of CybE and found the C-terminus with two transmembrane domains are required for its ER localization and functions. In addition, we demonstrated that CprA, an electron donor-heme-independent P450 reductase, provides a reciprocal function for the missing cytochrome b5 protein-CybE in A. fumigatus CybE maintains the normal growth probably via supporting two crucial physiological processes, the SRD accumulation in hyphal tips and membrane fluidity. Therefore, our finding reveals the mechanisms underlying the regulatory effect of CybE on A. fumigatus growth and indicates that inhibition of CybE might be an effective approach for alleviating A. fumigatus infection.

20.
Hematology ; 25(1): 457-463, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33250014

RESUMO

Objectives: Bone destruction and renal impairment are two frequent complications of multiple myeloma (MM). Cystatin C, an extracellular cysteine proteinase inhibitor, is encoded by the housekeeping gene CST3 and associated with human tumors. The role of cystatin C in multiple myeloma has been revealed recently. The purpose of this study was to explore the role of cystatin C as a proteasome inhibitor in multiple myeloma. Methods : A comprehensive literature review was conducted through Pubmed to summarize the published evidence on cystatin C in multiple myeloma. English literature sources since 1999 were searched, using the terms cystatin C, multiple myeloma. Results: cystatin C is a sensitive indicator for the diagnosis of myeloma nephropathy and has a dual role in myeloma bone disease. Also, cystatin C reflects tumor burden and is strongly associated with prognosis in patients with multiple myeloma. Conclusion: Cystatin C have great diagnostic and prognostic value in multiple myeloma. It can provide a new treatment direction for MM by designing and searching for antagonists of cystatin C or cysteine protease agonists using cystatin C as a therapeutic target.

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