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1.
ChemMedChem ; 15(5): 404-410, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020724

RESUMO

Mitochondrial oxidative damage and dysfunction contribute to a wide range of human diseases. Considering the limitation of conventional antioxidants and that mitochondria are the main source of reactive oxygen species (ROS) which induce oxidative damage, mitochondria-targeted antioxidants which can selectively block mitochondrial oxidative damage and prevent various types of cell death have been widely developed. As a lipophilic cation, triphenylphosphonium (TPP) has been commonly used in designing mitochondria-targeted antioxidants. Conjugated with the TPP moiety, antioxidants can achieve more than 1000-fold higher mitochondrial concentration depending on cell membrane potentials and mitochondrial membrane potentials. Herein we discuss the deficiencies of conventional antioxidants and the advantages of mitochondrial targeting, and review various types of TPP-based mitochondria-targeted antioxidants. These provide theoretical and background support for the design of new anti-oxidant.

3.
Cancer Med ; 9(2): 586-594, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31788986

RESUMO

OBJECTIVES: To present the perioperative, functional, and oncological outcomes of robot-assisted partial nephrectomy (RPN) compared with laparoscopic partial nephrectomy (LPN) for anatomically complex T1b renal tumors with RENAL nephrometry scores ≥7. PATIENTS AND METHODS: One hundred and seventy patients, during the study period, were retrospectively reviewed in our analysis according to inclusion criteria. Propensity score matching (PSM) (1:1) method was applied to impose restrictions on the potential baseline confounders. The comparisons of perioperative and functional outcomes between the RPN and LPN groups were conducted and analyzed after PSM, Kaplan-Meier analyses were performed to assess the differences about oncological outcomes between the two groups before and after PSM. RESULTS: One hundred and nine and 61 T1b renal tumors with RENAL scores ≥7 were identified in the LPN and RPN groups, respectively. All significant differences in baseline characteristics disappeared after PSM. Except for 3 patients missing an appropriate pair, all the patients in the RPN group were successfully matched to 58 patients in the LPN group in a 1:1 ratio. Within the matched cohort, the RPN group was related to a significantly shorter mean operating time (OT) (P = .040), shorter mean warm ischemia time (WIT) (P = .023), and shorter median postoperative hospital stay (P = .023). The possibilities of surgical conversion, postoperative complication, and positive surgical margin were similar in the LPN and RPN groups. And there was also no significant difference in the pathological, renal functional, and oncological outcomes between the two series. CONCLUSIONS: For patients with anatomically complex T1b renal tumors with a RENAL nephrometry score ≥7, RPN had an advantage over LPN in reducing OT, WIT, and postoperative hospital stay length without increasing the risk of complications and weakening the oncological control, while the two surgical methods were similar in renal functional preservation.

5.
Br J Haematol ; 188(2): 321-331, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31418854

RESUMO

Hepcidin (HAMP) synthesis is suppressed by erythropoiesis to increase iron availability for red blood cell production. This effect is thought to result from factors secreted by erythroid precursors. Growth differentiation factor 11 (GDF11) expression was recently shown to increase in erythroid cells of ß-thalassaemia, and decrease with improvement in anaemia. Whether GDF11 regulates hepatic HAMP production has never been experimentally studied. Here, we explore GDF11 function during erythropoiesis-triggered HAMP suppression. Our results confirm that exogenous erythropoietin significantly increases Gdf11 as well as Erfe (erythroferrone) expression, and Gdf11 is also increased, albeit at a lower degree than Erfe, in phlebotomized wild type and ß-thalassaemic mice. GDF11 is expressed predominantly in erythroid burst forming unit- and erythroid colony-forming unit- cells during erythropoiesis. Exogeneous GDF11 administration results in HAMP suppression in vivo and in vitro. Furthermore, exogenous GDF11 decreases BMP-SMAD signalling, enhances SMAD ubiquitin regulatory factor 1 (SMURF1) expression and induces ERK1/2 (MAPK3/1) signalling. ERK1/2 signalling activation is required for GDF11 or SMURF1-mediated suppression in BMP-SMAD signalling and HAMP expression. This research newly characterizes GDF11 in erythropoiesis-mediated HAMP suppression, in addition to ERFE.

6.
Environ Int ; 135: 105338, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31841806

RESUMO

Fine particulate matter (PM2.5) has an adverse effect on reproductive function, in particular causing reduced male reproductive function, but relatively few studies have directly targeted its effects on female reproduction. To investigate the effects of PM2.5 exposure on female reproduction, we exposed female mice to PM2.5 by intratracheal instillation for 28 days, and evaluated apoptosis of ovarian granulosa cells and oocytes and the quality embryos after insemination. Our results showed increased numbers of apoptotic granulosa cells and oocytes after exposure to elevated concentrations of PM2.5, which had adverse effects on female fertility via compromising embryo development and quality. We conclude that PM2.5 induced apoptosis of ovarian granulosa cells and oocytes leading to disrupted embryo development and female fertility in mice.

7.
J Endourol ; 34(3): 281-288, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31885280

RESUMO

Objective: The aim of this study was to introduce the "ultrathin parenchyma" resection in a robot-assisted partial nephrectomy (RAPN) via the retroperitoneal approach, and to assess the feasibility, security, and effectiveness of this technique. Methods: We collected and retrospectively reviewed the clinical data of patients with renal tumors who underwent ultrathin parenchyma resections in RAPNs via the retroperitoneal approach or traditional sharp dissection in RAPNs via the retroperitoneal approach from February 2015 to August 2018. The general data and other parameters, such as the operation time, blood loss (BL), warm ischemia time (WIT), positive surgical margin (PSM), glomerular filtration rate (GFR), and postoperative recurrence, were compared and analyzed between the two surgical techniques. Results: In ultrathin parenchyma resection groups, one case was converted to an open surgery, while the other cases were completed effectively. There were no significant differences in the general data, operation time, intraoperative BL, WIT, intraoperative complications, transfusion rate, PSM rate, hospital stay, and recurrence rate after the operation between the two groups (p > 0.05). The postoperative residual kidney volume percentage and the GFR (6 months postoperatively) were significantly higher in the ultrathin parenchyma resection group when compared with the traditional sharp dissection group (p < 0.05). Conclusion: The ultrathin parenchyma resection during robotic partial nephrectomy (RPN) is a safe and effective surgical technique for the resection of cT1 renal tumors. It can preserve the renal function under the premise of ensuring effective tumor control.

8.
Biomed Res Int ; 2019: 3917982, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828101

RESUMO

Background and Objectives: Bladder cancer (BC) is a complex tumor associated with high recurrence and mortality. To discover key molecular changes in BC, we analyzed next-generation sequencing data of BC and surrounding tissue samples from clinical specimens. Methods. Gene expression profiling datasets of bladder cancer were analyzed online. The Database for Annotation, Visualization, and Integrated Discovery (DAVID, https://david.ncifcrf.gov/) was used to perform Gene Ontology (GO) functional and KEGG pathway enrichment analyses. Molecular Complex Detection (MCODE) in Cytoscape software (Cytoscape_v3.6.1) was applied to identify hub genes. Protein expression and survival data were downloaded from OncoLnc (http://www.oncolnc.org/). Gene expression data were obtained from the ONCOMINE website (https://www.oncomine.org/). Results. We identified 4211 differentially expressed genes (DEGs) by analysis of surrounding tissue vs. cancer tissue (SC analysis) and 410 DEGs by analysis of cancer tissue vs. recurrent tissue cluster (CR analysis). GO function analysis revealed enrichment of DEGs in genes related to the cytoplasm and nucleoplasm for both clusters, and KEGG pathway analysis showed enrichment of DEGs in the PI3K-Akt signaling pathway. We defined the 20 genes with the highest degree of connectivity as the hub genes. Cox regression revealed CCNB1, ESPL1, CENPM, BLM, and ASPM were related to overall survival. The expression levels of CCNB1, ESPL1, CENPM, BLM, and ASPM were 4.795-, 5.028-, 8.691-, 2.083-, and 3.725-fold higher in BC than the levels in normal tissues, respectively. Conclusions. The results suggested that the functions of CCNB1, ESPL1, CENPM, BLM, and ASPM may contribute to BC development and the functions of CCNB1, ESPL1, CENPM, and BLM may also contribute to BC recurrence.

9.
Eur J Surg Oncol ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31864825

RESUMO

INTRODUCTION: To assess the safety and efficiency of retroperitoneal laparoscopic partial nephrectomy (RLPN) and retroperitoneal laparoscopic radical nephrectomy (RLRN) for large (≥4 cm) renal tumors with a RENAL nephrometry score ≥7. MATERIALS AND METHODS: We retrospectively identified and analyzed the data of 254 patients who underwent RLPN or RLRN for large (≥4 cm) and anatomically complex renal tumors between 2008 and 2017. Propensity score matching (PSM) (1:1) method was conducted to adjust for preoperative clinical characteristics. Preoperative, renal functional, and oncological outcomes were compared. RESULTS: Finally, no significant differences in the baseline characteristics existed between the two groups after PSM. Within the well-balanced matched cohort, longer operating time (OT) and higher estimated blood loss (EBL) were found in RLPN group (p = 0.015 and p = 0.019, respectively), and RLPN trended to protect renal function better at a higher risk of low-grade complications (-10.9 vs -16.8 ml/min, p = 0.001; 23.0% vs 10.8%, p = 0.048, respectively). The patients in the RLPN group had a better overall survival (OS) than those in RLRN group, but cancer-specific survival and progression-free survival didn't differ significantly between the two groups. CONCLUSION: For patients with large (≥4 cm) and anatomically complex renal tumors, RLPN by highly experienced hands has an evident tendency to a better protection of renal function and a longer OS without waiving oncological control in comparison with RLRN, but at the expense of longer OT, a higher EBL and a higher risk of low-grade complications.

10.
Strabismus ; : 1-3, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566469

RESUMO

Purpose: To describe Optical Coherence Tomography (OCT) findings of the macula in patients with nystagmus, mainly the relationship between spectral-domain OCT (SD-OCT) images and nystagmus in macular dysplasia.Methods: In this study, 17 cases (29 eyes) of the congenital macular abnormalities in patients with albinism, macular heterotopias, congenital aniridia, foveal hypoplasia, congenital macular coloboma, and congenital retinoschisis were retrospectively analyzed. Patients underwent multimodal retinal imaging examinations including ultra-widefield fundus imaging, SD-OCT, autofluorescence, and visual field. When the pit was not clearly presented, SD-OCT imaging was centered at the expected foveal center.Results: Oculocutaneous albinism showed the absence of foveal pit and increased foveal thickness with nystagmus. Fundus revealed a lack of pigment in retinal pigment epithelium with visible large choroidal vessels. Congenital aniridia showed a planar fovea in the macula with the lack of a foveal pit and nystagmus. The SD-OCT section showed the absence of foveal pit in foveal hypoplasia with nystagmus. For monocular macular heterotopias, no nystagmus was found, especially fellow eye has good vision, and the real macular morphology is usually normal. Nystagmus was not found in patients with congenital macular coloboma and congenital retinoschisis in this study.Conclusion: SD-OCT plays roles in the diagnosis and prognosis of macular dysplasia in patients with nystagmus. Absence of normal foveal pit is an OCT imaging characteristic of macular dysplasia associated with nystagmus.

11.
Medicine (Baltimore) ; 98(38): e17263, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31568002

RESUMO

To discuss the feasibility, safety, and effectiveness of off-clamp robotic partial nephrectomy via retroperitoneal approach and provide data for evidence based medicine in the surgical treatment of renal tumor.The clinical data was documented and compared between robotic retroperitoneal partial nephrectomy with and without hilar occlusion (clamp group and off-clamp group) performed between January 1, 2015 and December 31, 2017.Six-months post-operative renal function was superior in the off-clamp group compared with clamp group, while long-term results remained to be elucidated. No significant difference in post-operative hospital stay was found between the 2 groups. Estimated blood loss in off-clamp group was significantly higher than clamp group, while no significant difference was found in transfusion rate.Off-clamp robotic partial nephrectomy via retroperitoneal approach is a safe and effective technique for the removal of renal tumor while the indication of surgery is strictly limited to small (<4 cm) and exophytic renal tumor.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Laparoscopia , Nefrectomia/métodos , Procedimentos Cirúrgicos Robóticos , Feminino , Humanos , Neoplasias Renais/cirurgia , Laparoscopia/métodos , Masculino , Pessoa de Meia-Idade , Espaço Retroperitoneal/cirurgia , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/métodos , Resultado do Tratamento
12.
J Cancer ; 10(20): 4998-5006, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598172

RESUMO

Objective: The study aims to assess the prognostic impact of pathological T3a upstaging in clinical T1 renal cell carcinoma (RCC) on clinical outcomes. Methods: We performed a systematic literature search of PMC, Embase, Web of Science, and Cochrane library from inception to April 2019 for studies that investigated the prognostic significance of pathological T3a upstaging in clinical T1 RCC after surgery and conducted a standard meta-analysis on survival outcomes. Results: Overall, nine studies including 101,505 clinical T1 RCC patients were identified, in which 5,560 (5.5%) patients were upstaged to T3a after surgical treatment. Meta-analysis results showed that pT3a upstaging from clinical T1 RCC was significantly associated with poor recurrence-free survival (RFS; pooled hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.70-2.75; P<0.001), overall survival (OS; pooled HR 1.36, 95% CI 1.24-1.50; P<0.001), and cancer-specific survival (CSS; pooled HR 2.11, 95% CI 1.58-2.83; P<0.001). Subgroup analyses by surgical type demonstrated that pT3a upstaging remains a significant prognostic factor for RFS and OS in RCC patients who underwent different surgical treatments. Conclusions: Current available evidence strongly supported that postoperative pT3a upstaging has a significant negative impact on RFS, OS, and CSS in clinical T1 RCC patients. Clinical T1 RCC patients with pT3a upstaging after surgery should be closely monitored by clinician and should receive close follow-up for their poor prognosis.

13.
Mol Med Rep ; 20(4): 3917-3923, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485665

RESUMO

Multiple studies have shown that HOX antisense intergenic RNA (HOTAIR), an oncogenic long non­coding RNA (lncRNA), is dysregulated in leukemia and is involved in tumor progression. The aim of the present study was to determine whether HOTAIR could serve as a novel biomarker for the diagnosis of multiple myeloma (MM), and to investigate its role in regards to MM cell viability and chemoresistance to dexamethasone (DEX). The results revealed that the expression of HOTAIR was significantly upregulated in serum, bone marrow and primary CD138+ cells from MM patients compared with those from normal controls as determined by qPCR. HOTAIR expression was obviously increased in MM cell lines compared to that in normal plasma cells. ROC curve analysis showed that the serum level of HOTAIR exhibited a higher diagnostic value for MM. Furthermore, loss­of­functional assays indicated that HOTAIR inhibition suppressed MM cell viability by arresting the cell cycle at the G0/G1 phase as determined by cell viability assay and flow cytometry. An in­depth study revealed that knockdown of HOTAIR led to decreased chemoresistance of DEX in MM cells by regulating the JAK2/STAT3 signaling pathway. Taken together, our findings suggest that upregulation of serum HOTAIR may prove to be a novel biomarker for the diagnosis of MM. HOTAIR promoted MM cell viability and increased chemoresistance of MM to DEX via the JAK2/STAT3 signaling pathway, indicating HOTAIR may also serve as a potential therapeutic target for MM.


Assuntos
Antineoplásicos Hormonais/farmacologia , Dexametasona/farmacologia , Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo/tratamento farmacológico , RNA Longo não Codificante/genética , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
14.
Biosci Rep ; 39(10)2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31427482

RESUMO

BACKGROUND: Regulatory T (Treg) cells are of critical functionality in immune activation and inflammation in uremic patients undergoing hemodialysis (HD). A disruption in balance of Treg cells has potency to elicit infectious disease progression. Here, we examined possible association between ratio imbalance of Th22/Treg cells and microinflammation in uremic patients undergoing HD. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated to allow measurement of the percentage of Th22 cells and Treg cells using flow cytometry. Subsequently, serum levels of related cytokines, interleukin (IL) 22 (IL-22) and IL-10 and inflammatory factors, C-reactive protein (CRP), (TNF-α), IL-6 were determined via enzyme-linked immunosorbent assay (ELISA). Then relationships among dialysis time, microinflammation status (CRP) and dialysis adequacy (immunoreactive parathyroid hormone (iPTH), urea clearance index (Kt/V), ß2-MG, serum calcium, and serum phosphorus) were evaluated. Finally, correlation between microinflammation status and dialysis adequacy was analyzed with Pearson's correlation coefficient. RESULTS: An increased percentage of Th22 and a decreased percentage of Treg cells were evident in uremic patients undergoing HD. Serum levels of IL-22, CRP, TNF-α, and IL-6 were increased, while IL-10 serum level was reduced. An imbalance of Th22/Treg cells was associated with microinflammation status in uremic patients undergoing HD. Furthermore, prolongation of the dialysis time, the microinflammation status and dialysis adequacy were changed. Increased dialysis adequacy was observed to correlate with alleviated microinflammation of uremic patients undergoing HD. CONCLUSIONS: Conjointly, an imbalance of Th22/Treg cells may be a potential cause responsible for uremia occurrence, which in turn indicates that uremia could be effectively alleviated by altering the ratio of Th22/Treg cells.

16.
Clin Exp Metastasis ; 36(6): 499-509, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446521

RESUMO

Ureteral metastases from other primary cancers are very rare. Treatment of these metastases is difficult and outcomes are poor. A thorough literature review was done with the aim of finding characteristics that may influence survival rates of patients with ureteral metastases. Systematic literature searches of PubMed and Web of Science were performed in Jan 2019. A total of 79 papers that included 265 patients with cancer metastases to their ureters were finally considered for evidence synthesis. Prostate, bladder, breast, gut cancer and lymphoma were the predominant primary tumors. The median interval time from primary tumor diagnosis to ureter metastasis was 28.5 months. The median survival time after diagnosis of ureter metastasis was 18 months. Risk factors of survival were analyzed. Age, sex, hydronephrosis, ureter side, and segment were not associated with survival. Interval time and treatment were associated with overall survival. Further analysis indicated that patients who underwent surgery had better outcomes.

17.
Microorganisms ; 7(9)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443515

RESUMO

Chinese Cordyceps is a well-known medicinal larva-fungus symbiote distributed in the Qinghai-Tibetan Plateau and adjacent areas. Previous studies have involved its artificial cultivation but commercial cultivation is difficult to perform because the crucial factors triggering the occurrence of Chinese Cordyceps are not quite clear. The occurrence of Chinese Cordyceps is greatly affected by the soil environment, including the soil's physicochemical and microecological properties. In this study, the effects of these soil properties on the occurrence of Chinese Cordyceps were investigated. The results show that the physicochemical properties, including easily oxidizable organic carbon (EOC), soil organic carbon (SOC), humic acid carbon (HAC), humin carbon (HMC), and pH, might be negatively related to the occurrence of Chinese Cordyceps, and soil water content (SWC) might be positively related. Several soil physicochemical parameters (pH, SOC, HMC, HAC, available potassium (APO), available phosphorus (APH), microbial biomass carbon (MBC), and the ratio of NH4+ to NO3- (NH4+/NO3-)) and microbial properties interact and mix together, which might affect the occurrence of Chinese Cordyceps. Soil microbial community structure was also a possible factor, and a low level of bacterial and fungal diversity was suitable for the occurrence of Chinese Cordyceps. The intra-kingdom network revealed that a closer correlation of the bacterial community might help the occurrence of Chinese Cordyceps, while a closer correlation of the fungal community might suppress it. The inter-kingdom network revealed that the occurrence rate of Chinese Cordyceps might be negatively correlated with the stability of the correlation state of the soil habitat. In conclusion, this study shows that soil physicochemical properties and microbial communities could be greatly related with the occurrence of Chinese Cordyceps. In addition, soil physicochemical properties, the level of bacterial and fungal diversity, and correlations of bacterial and fungal communities should be controlled to a certain level to increase the production of Chinese Cordyceps in artificial cultivation.

18.
J Org Chem ; 84(15): 9497-9508, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31268718

RESUMO

Pd-catalyzed reactions of azides with CO to access an isocynate intermediate have been developed extensively in recent years. However, the catalytic carbonylation of sensitive acyl azides has not been reported. Herein, we report a simple Pd-catalyzed carbonylation reaction of acyl azides with broad substrate scope, high efficiency, and simple operation under mild conditions, which provides facile access to acyl ureas. In addition, a mechanistic study was carried out by both experiment and DFT calculation. Control experiments and kinetic study revealed that the real active palladium species were Pd(0). The result of kinetic study suggested that palladium catalyst, azide, and CO were all involved in the turnover-limiting step except for amine. Further DFT study suggested that an unprecedented five-membered palladacycle intermediate was the key intermediate in the carbonylation reaction.

19.
J Cell Physiol ; 234(11): 20322-20328, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31344987

RESUMO

The glutamine amino acid transporter solute carrier family 38 member 1 (SLC38A1) is associated with the occurrence and progression of solid tumors. However, it has not yet been assessed in patients with hematologic malignancy. Herein, we investigated SLC38A1 expression and explored its clinical implications in acute myeloid leukemia (AML). The results showed that patients with high SLC38A1 expression had a lower mutation rate of NPM1 gene and higher incidence of adverse-risk karyotype (p = 0.0010 and 0.0051, respectively). Patients with a high level of SLC38A1 expression presented significantly shorter overall survival in whole-cohort, chemotherapy-only, and non-inv(16) AML (p = 0.0049, 0.0247, and 0.0005 respectively). Moreover, both univariate and multivariate analyses showed that high SLC38A1 expression was an independent unfavorable prognostic biomarker for AML (p = 0.0057 and 0.0483, respectively). In summary, our study revealed SLC38A1 as a valuable prognostic and predictive marker for AML. Further, glutamine transporter SLC38A1 might serve as a potential target for the development of novel therapeutic drugs in the treatment of AML.

20.
Emerg Microbes Infect ; 8(1): 895-908, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223062

RESUMO

The Prp8 intein is one of the most widespread eukaryotic inteins, present in important pathogenic fungi, including Cryptococcus and Aspergillus species. Because the processed Prp8 carries out essential and non-redundant cellular functions, a Prp8 intein inhibitor is a mechanistically novel antifungal agent. In this report, we demonstrated that cisplatin, an FDA-approved cancer drug, significantly arrested growth of Prp8 intein-containing fungi C. neoformans and C. gattii, but only poorly inhibited growth of intein-free Candida species. These results suggest that cisplatin arrests fungal growth through specific inhibition of the Prp8 intein. Cisplatin was also found to significantly inhibit growth of C. neoformans in a mouse model. Our results further showed that cisplatin inhibited Prp8 intein splicing in vitro in a dose-dependent manner by direct binding to the Prp8 intein. Crystal structures of the apo- and cisplatin-bound Prp8 inteins revealed that two degenerate cisplatin molecules bind at the intein active site. Mutation of the splicing-site residues led to loss of cisplatin binding, as well as impairment of intein splicing. Finally, we found that overexpression of the Prp8 intein in cryptococcal species conferred cisplatin resistance. Overall, these results indicate that the Prp8 intein is a novel antifungal target worth further investigation.


Assuntos
Antifúngicos/administração & dosagem , Cisplatino/administração & dosagem , Criptococose/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Proteínas Fúngicas/genética , Inteínas , Proteínas de Ligação a RNA/genética , Sequência de Aminoácidos , Animais , Antifúngicos/química , Cisplatino/química , Cryptococcus neoformans/genética , Cryptococcus neoformans/crescimento & desenvolvimento , Cryptococcus neoformans/metabolismo , Feminino , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Alinhamento de Sequência
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