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1.
Commun Biol ; 5(1): 50, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35027659

RESUMO

The genes in polyphyllins pathway mixed with other steroid biosynthetic genes form an extremely complex biosynthetic network in Paris polyphylla with a giant genome. The lack of genomic data and tissue specificity causes the study of the biosynthetic pathway notably difficult. Here, we report an effective method for the prediction of key genes of polyphyllin biosynthesis. Full-length transcriptome from eight different organs via hybrid sequencing of next generation sequencingand third generation sequencing platforms annotated two 2,3-oxidosqualene cyclases (OSCs), 216 cytochrome P450s (CYPs), and 199 UDP glycosyltransferases (UGTs). Combining metabolic differences, gene-weighted co-expression network analysis, and phylogenetic trees, the candidate ranges of OSC, CYP, and UGT genes were further narrowed down to 2, 15, and 24, respectively. Beside the three previously characterized CYPs, we identified the OSC involved in the synthesis of cycloartenol and the UGT (PpUGT73CR1) at the C-3 position of diosgenin and pennogenin in P. polyphylla. This study provides an idea for the investigation of gene cluster deficiency biosynthesis pathways in medicinal plants.

3.
Sci Total Environ ; 811: 152350, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34919931

RESUMO

Although many studies have investigated the toxic effects of polystyrene microplastics (PS-MPs), toxicity of natural aged of PS-MPs to soil organisms remains unclear. The photodegradation of virgin PS-MPs under UV irradiation was investigated, and reproductive toxicity of pristine and UV-photodegraded PS-MPs at environmental concentrations (0.1-100 µg/L) was examined to Caenorhabditis elegans. Using brood size and egg ejection rate as endpoints, acute exposure to aged PS-MPs resulted in more severe reproductive toxicity than pristine PS-MPs. Exposure to 100 µg/L aged PS-MPs significantly increased the number of HUS-1::GFP foci and the expression of genes required for DNA damage, such as clk-2, cep-1, and egl-1, suggesting induction of DNA damage. Additionally, the number of cell corpses and apoptosis-related gene expression (e.g., ced-3, ced-4, and ced-9) were significantly altered, indicating induction of apoptosis. Germline apoptosis induced by aged PS-MPs was altered in egl-1, hus-1, cep-1, ced-3, ced-4, and ced-9 mutants. Thus, the reproductive toxicity of aged PS-MPs may be due to DNA damage-induced cell apoptosis, and the HUS-1-CEP-1-EGL-1-CED-9-CED-4-CED-3 signalling pathway is involved in regulating cell apoptosis in nematodes.

4.
Front Cell Dev Biol ; 9: 770115, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34901016

RESUMO

Background: Altered copper levels have been observed in several cancers, but studies on the relationship between serum copper and early-stage triple-negative breast cancer (TNBC) remain scare. We sought to establish a predictive model incorporating serum copper levels for individualized survival predictions. Methods: We retrospectively analyzed clinicopathological information and baseline peripheric blood samples of patients diagnosed with early-stage TNBC between September 2005 and October 2016 at Sun Yat-sen University Cancer Center. The optimal cut-off point of serum copper level was determined using maximally selected log-rank statistics. Kaplan-Meier curves were used to estimate survival probabilities. Independent prognostic indicators associated with survival were identified using multivariate Cox regression analysis, and subsequently, prognostic nomograms were established to predict individualized disease-free survival (DFS) and overall survival (OS). The nomograms were validated in a separate cohort of 86 patients from the original randomized clinical trial SYSUCC-001 (SYSUCC-001 cohort). Results: 350 patients were eligible in this study, including 264 in the training cohort and 86 in the SYSUCC-001 cohort. An optimal cut-off value of 21.3 µmol/L of serum copper was determined to maximally divide patients into low- and high-copper groups. After a median follow-up of 87.1 months, patients with high copper levels had significantly worse DFS (p = 0.002) and OS (p < 0.001) than those with low copper levels in the training cohort. Multivariate Cox regression analysis revealed that serum copper level was an independent factor for DFS and OS. Further, prognostic models based on serum copper were established for individualized predictions. These models showed excellent discrimination [C-index for DFS: 0.689, 95% confidence interval (CI): 0.621-0.757; C-index for OS: 0.728, 95% CI: 0.654-0.802] and predictive calibration, and were validated in the SYSUCC-001 cohort. Conclusion: Serum copper level is a potential predictive biomarker for patients with early-stage TNBC. Predictive nomograms based on serum copper might be served as a practical tool for individualized prognostication.

5.
Int J Ophthalmol ; 14(12): 1834-1842, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34926196

RESUMO

AIM: To investigate the inhibitory effect of the combined use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and oridonin on choroidal melanoma cell lines, and to explore its underlying mechanism. METHODS: MUM-2B and C918 cells were treated with different concentrations of TRAIL and oridonin, and MTT assay used to evaluate the inhibition rate of the two compounds on cells. Then, the cell cycle distribution and apoptosis were detected by flow cytometry, and changes in apoptosis-related proteins such as death receptor 5 (DR5), a-caspase-3, and x-linked inhibitor of apoptosis protein (XIAP) were detected by Western blot. MUM-2B cells were transfected with si-DR5, which interfered with the expression of the DR5 gene. MTT and Western blot assay were used to detect cell activity and apoptosis-related proteins. RESULTS: When TRAIL and oridonin were simultaneously administered to the MUM-2B cells, the apoptosis rate was significantly higher than that by the two drugs individually. However, the effect of combined use of TRAIL and oridonin on C918 cells was not significantly different from that used alone. Cell cycle analysis showed that TRAIL and oridonin could induce G2/M arrest in MUM-2B cells. The Western blot results showed that the protein expression levels of the DR5, a-caspase-3, and BAX increased, while the expression levels of the anti-apoptosis-related proteins XIAP and BCL-2 were suppressed when TRAIL and oridonin simultaneously administered to MUM-2B cells. Interfering the expression of DR5 gene in MUM-2B cells could reverse the inhibitory effect of oridonin and TRAIL on the proliferation and apoptosis induction of MUM-2B cells. CONCLUSION: The inhibitory effects of oridonin and TRAIL on MUM-2B cells are significantly enhanced when they were administered as a combined treatment, which may ascribe to up-regulation of DR5.

6.
Chemosphere ; : 133360, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34929275

RESUMO

Organochlorine pesticide lindane in the environment and biota results in the potential risks on ecosystem and human health. Lindane can adversely affect the locomotion and nervous system, yet the potential neurotoxicity of lindane over generations remains uncertain. In this study, the neurotoxicity and underlying mechanisms in Caenorhabditis elegans (C. elegans) were investigated after parental (P0) exposure to lindane at environmentally relevant concentrations over generations. Exposure to lindane at concentrations of 10-100 ng/L significantly decreased body bends and head thrashes in P0 generation. Significant decrease of fluorescence labeled different neurotransmitters, and clear morphological changes by exposure to lindane at 10-100 ng/L suggested that lindane could induce the neuronal damage in C. elegans. During the transgenerational process, decreased locomotive behaviors were also observed in F1-F3 generations, and head thrashes returned to normal levels in F4 generation. Moreover, lindane exposure down-regulated the expression of dat-1, dop-1, glr-1 and mod-1genes, while up-regulated unc-30 gene in P0 generation, which recovered to normal levels in F4 generation. Interestingly, eat-4 continued to be regulated from inhibition to stimulation in P0-F4 generations, suggesting that glutamatergic transmission may more contribute to the neurotoxicity of lindane over generations.

7.
Int J Womens Health ; 13: 1053-1064, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34785957

RESUMO

Background: Aging, an inevitable process characterized by functional decline over time, is a significant risk factor for various tumors. However, little is known about aging-related genes (ARGs) in breast cancer (BC). We aimed to explore the potential prognostic role of ARGs and to develop an ARG-based prognosis signature for BC. Methods: RNA-sequencing expression profiles and corresponding clinicopathological data of female patients with BC were obtained from public databases in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). An ARG-based risk signature was constructed in the TCGA cohort based on results of least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis, and its prognostic value was further validated in the GSE20685 cohort. Results: A six ARG-based signature, including CLU, DGAT1, MXI1, NFKBI, PIK3CA and PLAU, was developed in the TCGA cohort and significantly stratified patients into low- and high-risk groups. Patients in the former group showed significantly better prognosis than those in the latter. Multivariate Cox regression analysis demonstrated that the ARG risk score was an independent prognostic factor for BC. A predictive nomogram integrating the ARG risk score and three identified factors (age, N- and M-classification) was established in the TCGA cohort and validated in the GSE20685 cohort. Calibration plots showed good consistency between predicted survival probabilities and actual observations. Conclusion: A novel ARG-based risk signature was developed for patients with BC, which can be used for individual prognosis prediction and promoting personalized treatment.

8.
Front Cell Dev Biol ; 9: 777215, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34805180

RESUMO

The dysregulation of iron homeostasis has been explored in malignancies. However, studies focusing on the association between the serum iron level and prognosis of patients with early-stage triple-negative breast cancer (TNBC) are scarce. Accordingly, in current study, 272 patients with early-stage TNBC treated at Sun Yat-sen University Cancer Center (SYSUCC) between September 2005 and October 2016 were included as a training cohort, another 86 patients from a previous randomized trial, SYSUCC-001, were analyzed as a validation cohort (SYSUCC-001 cohort). We retrospectively collected their clinicopathological data and tested the serum iron level using blood samples at the diagnosis. In the training cohort, patients were divided into low-iron and high-iron groups according to the serum iron level cut-off of 17.84 µmol/L determined by maximally selected rank statistics. After a median follow-up of 87.10 months, patients with a low iron had a significantly longer median disease-free survival (DFS) of 89.13 [interquartile range (IQR): 66.88-117.38] months and median overall survival (OS) of 92.85 (IQR: 68.83-117.38) months than those in the high-iron group (median DFS: 75.25, IQR: 39.76-105.70 months, P = 0.015; median OS: 77.17, IQR: 59.38-110.28 months, P = 0.015). Univariate and multivariate Cox analysis demonstrated the serum iron level to be an independent predictor for DFS and OS. Then, a prognostic nomogram incorporating the serum iron level, T stage and N stage was developed for individualized prognosis predictions. It had good discriminative ability with a C-index of DFS (0.729; 95% CI 0.666-0.792) and OS (0.739; 95% CI 0.666-0.812), respectively. Furtherly, we validated the predictive model in the SYSUCC-001 cohort, which also showed excellent predictive performance with a C-index of DFS (0.735; 95% CI 0.614-0.855) and OS (0.722; 95% CI 0.577-0.867), respectively. All these suggested that the serum iron level might be a potential prognostic biomarker for patients with early-stage TNBC, the predictive model based on it might be served as a practical tool for individualized survival predictions.

10.
Clin Cancer Res ; 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34810217

RESUMO

PURPOSE: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first line management of hormone receptor (HR)-positive and HER2- positive metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is non-inferior to trastuzumab plus chemotherapy. EXPERIMENTAL DESIGN: We conducted an open-label, non-inferiority, phase-3, randomized, controlled trial (NCT01950182) at nine hospitals in China. Patients with HR+HER2+ MBC were enrolled. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a non-inferiority upper margin of 1.35 for the hazard ratio. The intention-to-treat population was used in primary and safety analyses. RESULTS: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n=196) or trastuzumab plus chemotherapy (CT group, n=196). After a median follow-up of 30.2 months (IQR 15.0-44.7), the median PFS was 19.2 months (95%CI 16.7-21.7) in the ET group and 14.8 months (12.8-16.8) in the CT group (hazard ratio 0.88, 95%CI 0.71-1.09; pnon-inferiority <0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group. CONCLUSIONS: Trastuzumab plus endocrine therapy was non-inferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.

11.
Microbiol Spectr ; 9(2): e0135221, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-34643438

RESUMO

The emerging new lineages of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have marked a new phase of coronavirus disease 2019 (COVID-19). Understanding the recognition mechanisms of potent neutralizing monoclonal antibodies (NAbs) against the spike protein is pivotal for developing new vaccines and antibody drugs. Here, we isolated several monoclonal antibodies (MAbs) against the SARS-CoV-2 spike protein receptor-binding domain (S-RBD) from the B cell receptor repertoires of a SARS-CoV-2 convalescent. Among these MAbs, the antibody nCoV617 demonstrates the most potent neutralizing activity against authentic SARS-CoV-2 infection, as well as prophylactic and therapeutic efficacies against the human angiotensin-converting enzyme 2 (ACE2) transgenic mouse model in vivo. The crystal structure of S-RBD in complex with nCoV617 reveals that nCoV617 mainly binds to the back of the "ridge" of RBD and shares limited binding residues with ACE2. Under the background of the S-trimer model, it potentially binds to both "up" and "down" conformations of S-RBD. In vitro mutagenesis assays show that mutant residues found in the emerging new lineage B.1.1.7 of SARS-CoV-2 do not affect nCoV617 binding to the S-RBD. These results provide a new human-sourced neutralizing antibody against the S-RBD and assist vaccine development. IMPORTANCE COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 pandemic has posed a serious threat to global health and the economy, so it is necessary to find safe and effective antibody drugs and treatments. The receptor-binding domain (RBD) in the SARS-CoV-2 spike protein is responsible for binding to the angiotensin-converting enzyme 2 (ACE2) receptor. It contains a variety of dominant neutralizing epitopes and is an important antigen for the development of new coronavirus antibodies. The significance of our research lies in the determination of new epitopes, the discovery of antibodies against RBD, and the evaluation of the antibodies' neutralizing effect. The identified antibodies here may be drug candidates for the development of clinical interventions for SARS-CoV-2.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , COVID-19/terapia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , Sítios de Ligação/imunologia , Vacinas contra COVID-19/imunologia , Cristalografia por Raios X , Modelos Animais de Doenças , Feminino , Humanos , Imunização Passiva/métodos , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Domínios e Motivos de Interação entre Proteínas/imunologia , Carga Viral/efeitos dos fármacos
12.
Cancer Cell Int ; 21(1): 482, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34517891

RESUMO

BACKGROUND: DNA Polymerase Theta (POLQ) is a DNA polymerase involved in error-prone translesion DNA synthesis (TLS) and error-prone repair of DNA double-strand breaks (DSBs), whose function in hepatocellular carcinoma has not been investigated. METHODS: In the present study, both the data collected from the Cancer Genome Atlas (TCGA) and our group's results showed higher POLQ expression in HCC tissues than the para-cancerous tissues, which was associated with higher malignancy and poor prognosis. POLQ knockdown HCC cell model (shPOLQ) was constructed along with the corresponding negative control (shCtrl) through lentivirus infection for loss-of-function study. RESULTS: We found that, upon knockdown of POLQ, the proliferation and migration of HCC cells decreased and apoptosis percentage increased. Moreover, the percentage of cells in G2 phase significantly increased in shPOLQ group compared with shCtrl group. Xenografts in mice grafted with shPOLQ cells grew much slower than that transplanted with shCtrl cells, and expressed lower Ki67 level. Furthermore, an apoptosis-related signaling array was used to explore the involvement of downstream signaling pathways, suggesting the enhanced phosphorylation of HSP27 and JNK, and the de-activation of mTOR, PRAS40, ERK1/2 and STAT3 pathways. CONCLUSIONS: Collectively, our study revealed that POLQ may participate in the development of HCC, depletion of which may be a promising treatment strategy for HCC.

13.
Front Oncol ; 11: 583283, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336633

RESUMO

Background: A higher ratio of pretreatment C-reactive protein/albumin ratio (CAR) is associated with poor prognosis in nasopharyngeal carcinoma (NPC), and Epstein-Barr virus (EBV) DNA level is known to not only participate in the occurrence of nasopharyngeal carcinoma but also affect the development and prognosis of the disease. Herein, we proposed that a combination of both these markers could improve the predictive prognostic ability. Methods: In all, 842 NPC patients who received concurrent chemoradiotherapy (CCRT) were entered in this study. We collected all patients' blood samples and EBV DNA copy numbers within one week before any treatment. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off. We employed the Kaplan-Meier method for survival analyses and the univariate and multivariate analyses (Cox proportional hazards regression model) for statistical analysis. A nomogram was constructed based on multivariate analyses results of the validation set. The model was internally validated using 1000 bootstrap samples to avoid overfitting. Another validation of 10-fold cross-validation was also applied. Calibration curves and concordance index (C-index) were calculated to determine predictive and discriminatory capacity. Results: In the whole cohort, we observed that higher CAR, EBV DNA level, and CAR-EBV DNA (C-E) grade were associated with shorter overall survival (OS) and distant metastasis-free survival (DMFS) (all P<0.05). In univariate and multivariate analyses, C-E grade was an independent prognostic factor (all P<0.05). In the training set, we gained the similar results with the whole set. According to multivariate analyses of the training set, we constructed a nomogram. The results of bootstrap samples and 10-fold cross-validation showed favorable predictive efficacy. And calibration curves of the model provided credibility to its predictive capability. Conclusion: C-E grade was confirmed as an independent prognostic predictor in patients with NPC who received CCRT. Higher level of pretreatment C-E grade could signify a higher risk of metastasis and shorter OS. The prognostic nomogram based on C-E grade was dependable in nasopharyngeal carcinoma patients.

14.
J Am Chem Soc ; 143(35): 14242-14252, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34431669

RESUMO

The transport of hydrated ions across nanochannels is central to biological systems and membrane-based applications, yet little is known about their hydrated structure during transport due to the absence of in situ characterization techniques. Herein, we report experimentally resolved ion dehydration during transmembrane transport using modified in situ liquid ToF-SIMS in combination with MD simulations for a mechanistic reasoning. Notably, complete dehydration was not necessary for transport to occur across membranes with sub-nanometer pores. Partial shedding of water molecules from ion solvation shells, observed as a decrease in the average hydration number, allowed the alkali-metal ions studied here (lithium, sodium, and potassium) to permeate membranes with pores smaller than their solvated size. We find that ions generally cannot hold more than two water molecules during this sterically limited transport. In nanopores larger than the size of the solvation shell, we show that ionic mobility governs the ion hydration number distribution. Viscous effects, such as interactions with carboxyl groups inside the membrane, preferentially hinder the transport of the mono- and dihydrates. Our novel technique for studying ion solvation in situ represents a significant technological leap for the nanofluidics field and may enable important advances in ion separation, biosensing, and battery applications.

15.
J Clin Lab Anal ; 35(8): e23911, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34260764

RESUMO

BACKGROUND: Dyslipidemia has been observed in patients with coronavirus disease 2019 (COVID-19). This study aimed to investigate blood lipid profiles in patients with COVID-19 and to explore their predictive values for COVID-19 severity. METHODS: A total of 142 consecutive patients with COVID-19 were included in this single-center retrospective study. Blood lipid profile characteristics were investigated in patients with COVID-19 in comparison with 77 age- and gender-matched healthy subjects, their predictive values for COVID-19 severity were analyzed by using multivariable logistic regression analysis, and their prediction efficiencies were evaluated by using receiver operator characteristic (ROC) curves. RESULTS: There were 125 and 17 cases in the non-severe and severe groups, respectively. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein A1 (ApoA1) gradually decreased across the groups in the following order: healthy controls, non-severe group, and severe group. ApoA1 was identified as an independent risk factor for COVID-19 severity (adjusted odds ratio [OR]: 0.865, 95% confidence interval [CI]: 0.800-0.935, p < 0.001), along with interleukin-6 (IL-6) (adjusted OR: 1.097, 95% CI: 1.034-1.165, p = 0.002). ApoA1 exhibited the highest area under the ROC curve (AUC) among all single markers (AUC: 0.896, 95% CI: 0.834-0.941); moreover, the risk model established using ApoA1 and IL-6 enhanced prediction efficiency (AUC: 0.977, 95% CI: 0.932-0.995). CONCLUSION: Blood lipid profiles in patients with COVID-19 are quite abnormal compared with those in healthy subjects, especially in severe cases. Serum ApoA1 may represent a good indicator for predicting the severity of COVID-19.


Assuntos
Apolipoproteína A-I/sangue , COVID-19/etiologia , Adulto , Idoso , Área Sob a Curva , Biomarcadores/sangue , COVID-19/sangue , COVID-19/epidemiologia , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Comorbidade , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
16.
BMC Bioinformatics ; 22(1): 358, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215183

RESUMO

BACKGROUND: A growing proportion of research has proved that microRNAs (miRNAs) can regulate the function of target genes and have close relations with various diseases. Developing computational methods to exploit more potential miRNA-disease associations can provide clues for further functional research. RESULTS: Inspired by the work of predecessors, we discover that the noise hiding in the data can affect the prediction performance and then propose an anti-noise algorithm (ANMDA) to predict potential miRNA-disease associations. Firstly, we calculate the similarity in miRNAs and diseases to construct features and obtain positive samples according to the Human MicroRNA Disease Database version 2.0 (HMDD v2.0). Then, we apply k-means on the undetected miRNA-disease associations and sample the negative examples equally from the k-cluster. Further, we construct several data subsets through sampling with replacement to feed on the light gradient boosting machine (LightGBM) method. Finally, the voting method is applied to predict potential miRNA-disease relationships. As a result, ANMDA can achieve an area under the receiver operating characteristic curve (AUROC) of 0.9373 ± 0.0005 in five-fold cross-validation, which is superior to several published methods. In addition, we analyze the predicted miRNA-disease associations with high probability and compare them with the data in HMDD v3.0 in the case study. The results show ANMDA is a novel and practical algorithm that can be used to infer potential miRNA-disease associations. CONCLUSION: The results indicate the noise hiding in the data has an obvious impact on predicting potential miRNA-disease associations. We believe ANMDA can achieve better results from this task with more methods used in dealing with the data noise.


Assuntos
MicroRNAs , Algoritmos , Área Sob a Curva , Biologia Computacional , Predisposição Genética para Doença , Humanos , MicroRNAs/metabolismo , Curva ROC
17.
J Hazard Mater ; 419: 126482, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34186424

RESUMO

Microplastics are ubiquitous in all environments and exert toxic effects in various organisms. However, the neurotoxicity and underlying mechanisms of long-term exposure to MPs aged under UV radiation remain largely unclear. In this study, Caenorhabditis elegans was treated with 0.1-100 µg/L virgin and aged polystyrene microplastics (PS-MPs) for 10 d, with locomotion behavior, neuronal development, neurotransmitter content, and neurotransmission-related to gene expression as endpoints. Using locomotion behavior as an endpoint, chronic exposure to aged PS-MPs at low concentrations (1 µg/L) caused more severe neurotoxicity than that to virgin PS-MPs. In transgenic nematodes, exposure to 10-100 µg/L aged PS-MPs significantly influenced the fluorescence intensity and percentage of worms with neurodegeneration of dopaminergic, glutamatergic, and serotonergic neurons compared with control. Further investigations showed that the content of glutamate, serotonin, and dopamine was significantly influenced in nematodes chronically exposed to 100 µg/L of aged PS-MPs. Similarly, neurotransmission-related gene (e.g., eat-4, dat-1, and tph-1) expression was also altered in nematodes. These results indicate that aged PS-MPs exert neurotoxicity owing to their effects on dopamine, glutamate, and serotonin neurotransmission. This study provides insights into the underlying mechanisms and potential risks of PS-MPs after UV radiation.


Assuntos
Microplásticos , Poluentes Químicos da Água , Animais , Caenorhabditis elegans/genética , Dopamina , Ácido Glutâmico , Plásticos , Poliestirenos , Serotonina , Transmissão Sináptica , Raios Ultravioleta , Poluentes Químicos da Água/toxicidade
18.
Res Vet Sci ; 138: 62-68, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34111715

RESUMO

Haemophilus parasuis is the main agent of Glässer's disease, which causes substantial losses in pig production. However, the pathogenic mechanism and virulence factors of H. parasuis have not been fully determined. In this study, berberine is shown to have a good therapeutic effect in vivo against H. parasuis; the minimal inhibitory concentration (MIC) in vitro was 2 µg/mL. Berberine inhibited H. parasuis adhesion to and invasion of PK-15 pig kidney cells. Proteomics studies of H. parasuis after berberine treatment identified a total of 97 differentially-expressed proteins; 35 upregulated and 62 downregulated. Bioinformatics analysis showed that berberine may inhibit the growth of H. parasuis by affecting outer membrane proteins, transferrins, and energy metabolism. This study provides a basis for the development of new antibacterial agents.


Assuntos
Antibacterianos/farmacologia , Berberina/farmacologia , Regulação da Expressão Gênica , Haemophilus parasuis/efeitos dos fármacos , Proteoma , Animais , Linhagem Celular , Infecções por Haemophilus/tratamento farmacológico , Infecções por Haemophilus/veterinária , Testes de Sensibilidade Microbiana/veterinária , Sus scrofa , Suínos , Doenças dos Suínos/tratamento farmacológico
19.
Cell Rep ; 35(5): 109070, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33951441

RESUMO

Four potent native human monoclonal antibodies (mAbs) targeting distinct epitopes on tetanus toxin (TeNT) are isolated with neutralization potency ranging from approximately 17 mg to 6 mg each that are equivalent to 250 IU of human anti-TeNT immunoglobulin. TT0170 binds fragment B, and TT0069 and TT0155 bind fragment AB. mAb TT0067 binds fragment C and blocks the binding of TeNT to gangliosides. The co-crystal structure of TT0067 with fragment C of TeNT at a 2.0-Å resolution demonstrates that mAb TT0067 directly occupies the W pocket of one of the receptor binding sites on TeNT, resulting in blocking the binding of TeNT to ganglioside on the surface of host cells. This study reveals at the atomic level the mechanism of action by the TeNT neutralizing antibody. The key neutralization epitope on the fragment C of TeNT identified in our work provides the critical information for the development of fragment C of TeNT as a better and safer tetanus vaccine.

20.
J Exp Clin Cancer Res ; 40(1): 149, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931075

RESUMO

BACKGROUND: Radiotherapy is a conventional and effective local treatment for breast cancer. However, residual or recurrent tumors appears frequently because of radioresistance. Novel predictive marker and the potential therapeutic targets of breast cancer radioresistance needs to be investigated. METHODS: In this study, we screened all 10 asparagine-linked glycosylation (ALG) members in breast cancer patients' samples by RT-PCR. Cell viability after irradiation (IR) was determined by CCK-8 assay and flow cytometry. The radiosensitivity of cell lines with different ALG3 expression was determined with the colony formation assay by fitting the multi-target single hit model to the surviving fractions. Cancer stem-like traits were assessed by RT-PCR, Western blot, and flow cytometry. The mechanisms of ALG3 influencing radiosensitivity was detected by Western blot and immunoprecipitation. And the effect of ALG3 on tumor growth after IR was verified in an orthotopic xenograft tumor models. The association of ALG3 with prognosis of breast cancer patients was confirmed by immunohistochemistry. RESULTS: ALG3 was the most significantly overexpressing gene among ALG family in radioresistant breast cancer tissue. Overexpression of ALG3 predicted poor clinicopathological characteristics and overall survival (OS), and early local recurrence-free survival (LRFS) in breast cancer patients. Upregulating ALG3 enhanced radioresistance and cancer stemness in vitro and in vivo. Conversely, silencing ALG3 increased the radiosensitivity and repressed cancer stemness in vitro, and more importantly inhibition of ALG3 effectively increased the radiosensitivity of breast cancer cells in vivo. Mechanistically, our results further revealed ALG3 promoted radioresistance and cancer stemness by inducing glycosylation of TGF-ß receptor II (TGFBR2). Importantly, both attenuation of glycosylation using tunicamycin and inhibition of TGFBR2 using LY2109761 differentially abrogated the stimulatory effect of ALG3 overexpression on cancer stemness and radioresistance. Finally, our findings showed that radiation played an important role in preventing early recurrence in breast cancer patients with low ALG3 levels, but it had limited efficacy in ALG3-overexpressing breast cancer patients. CONCLUSION: Our results suggest that ALG3 may serve as a potential radiosensitive marker, and an effective target to decrease radioresistance by regulating glycosylation of TGFBR2 in breast cancer. For patients with low ALG3 levels, radiation remains an effective mainstay therapy to prevent early recurrence in breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Manosiltransferases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Glicosilação , Humanos , Manosiltransferases/genética , Camundongos , Tolerância a Radiação , Ensaios Antitumorais Modelo de Xenoenxerto
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