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1.
Dev Comp Immunol ; 127: 104296, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34656644

RESUMO

Stimulator of interferon gene (STING), an adaptor molecule in the immune system, is involved in mediating the response to viral and bacterial infections, anti-tumor immunity, autoimmune diseases, and lipid metabolism. There have been reports on the cloning and function of STING in humans, pigs, chickens, and cats; however, STING has not been characterized in non-human primates or monkeys to date. Therefore, in this study, the rhesus macaque (Macaca mulata) STING gene was cloned, and we performed preliminary functional tests to examine its role in the interferon (IFN) pathway. The M. mulatta STING complementary DNA was 1140 bp in length and encoded 380 amino acid residues. Phylogenetic analysis showed that Homo sapiens and M. mulatta STING are closely related and clustered on the same branch. M. mulatta STING was confirmed to increase the promoter activities of IFN-ß, nuclear factor-κB, and interferon-sensitive response element, and STING overexpression increased the mRNA levels of IFN-α, IFN-ß, and interferon regulatory factor 3. Infection of Marc-145 cells with porcine reproductive and respiratory syndrome virus activated STING, and its expression increased along with increases in viral multiplicity of infection titer and time. Moreover, STING expression was time- and dose-dependently up-regulated by poly (I:C) and poly (dA:dT) treatments in Marc-145 cells. In summary, these results highlight STING as a vital immune system signal protein in the IFN pathway. This study provides a basis for understanding the immune characteristics of M. mulatta, and may have important implications for both monkey and human diseases.

2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1504-1509, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34627431

RESUMO

OBJECTIVE: To investigate the effect of arsenic disulfide (AS2S2) combined with itraconazole on the proliferation, apoptosis and hedgehog pathway of diffuse large B-cell lymphoma (DLBCL) cells. METHODS: The human DLBCL cell OCI-LY3 was treated with different concentrations of AS2S2 and itraconazole. Cell proliferation inhibition was detected by CCK-8, cell apoptosis rate was determined by flow cytometry. The expression levels of BCL-2, BAX, SMO and GLi1 were detected by Western blot. RESULTS: The DLBCL cell viability was decreased significantly at 24, 48 or 72 h as cultured with itraconazole. Along with the increasing of itraconazole concentration, the DLBCL cell viability was significantly reduced as compared with that in control group, and the results showed statistically significant(r=-0.690,r=-0.639, r=-0.833, r=-0.808, r=-0.578). The inhibitory and apoptosis rates of the cells were significantly increased as compared with those of the single drug-treated group after treated by the combination of itraconazole and AS2S2(P<0.05). The protein levels of SMO and Glil were significantly down-regulated after treated by arsenic disulfide and itraconazole alone(P<0.01). The protein expression levels of SMO and Glil was down-regulated in the combined-treatment group(P<0.01). CONCLUSION: Itraconazole can inhibit proliferation of DLBCL cells in a concentration-and time-dependent manner. In addition, the combination of AS2S2 and itraconazole show a synergistic effects, which may be related with the down-regulated protein expression of SMO and Glil of Hedgehog signaling pathway.


Assuntos
Proteínas Hedgehog , Linfoma Difuso de Grandes Células B , Apoptose , Arsenicais , Humanos , Itraconazol/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Sulfetos
3.
Anim Biotechnol ; : 1-11, 2021 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-34658301

RESUMO

This study aimed to assess the growth performance and blood metabolites, as well as metabolic profiles in the urine of lambs fed on dietary rumen-protected choline (RPC). Thirty-six Dorper × Hu lambs weighing approximately 20 kg were equally assigned to three groups, and fed on three diets supplemented with different RPC concentrations (0, 0.25% and 0.75%) for 45 days. Supplementation of RPC significantly increased average daily gain (ADG) and decreased feed-to-gain ratio (F/G) of lambs (p < 0.05). Dietary RPC was significantly associated with elevated plasma high-density lipoprotein (HDL) and suppressed low-density lipoprotein (LDL) levels when compared to the control group (p < 0.05). Moreover, concentrations of very-low-density lipoprotein (VLDL) exhibited an increasing trend (p = 0.065), whereas ß-hydroxybutyrate (BHBA) levels decreased (p = 0.086) in plasma. Analysis of urine metabolome revealed that RPC supplementation significantly suppressed urinary concentrations of pyruvate (p < 0.05), while increased urinary concentrations of trimethylamine oxide, p-cresol, phenylacetylglycine and hippurate (p < 0.05). These findings suggest that RPC supplementation can promote weight gain, alter plasma lipid metabolism and modify urinary metabolome which is correlated with energy metabolism, lipid metabolism and intestinal microbial metabolism in lambs. In conclusion, based on our findings, we recommend 0.25% RPC as a supplement for growing lambs.

4.
J Mater Chem B ; 9(39): 8185-8201, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34528037

RESUMO

During the global outbreak of coronavirus disease 2019 (COVID-19), a hyperinflammatory state called the cytokine storm was recognized as a major contributor to multiple organ failure and mortality. However, to date, the diagnosis and treatment of the cytokine storm remain major challenges for the clinical prognosis of COVID-19. In this review, we outline various nanomaterial-based strategies for preventing the COVID-19 cytokine storm. We highlight the contribution of nanomaterials to directly inhibit cytokine release. We then discuss how nanomaterials can be used to deliver anti-inflammatory drugs to calm the cytokine storm. Nanomaterials also play crucial roles in diagnostics. Nanomaterial-based biosensors with improved sensitivity and specificity can be used to detect cytokines. In summary, emerging nanomaterials offer platforms and tools for the detection and treatment of the COVID-19 cytokine storm and future pandemic.


Assuntos
COVID-19/complicações , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Humanos
5.
Front Cell Dev Biol ; 9: 706454, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336859

RESUMO

Background: Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) play a crucial part in maintaining genomic instability. We therefore identified genome instability-related lncRNAs and constructed a prediction signature for early stage lung adenocarcinoma (LUAD) as well in order for classification of high-risk group of patients and improvement of individualized therapies. Methods: Early stage LUAD RNA-seq and clinical data from The Cancer Genome Atlas (TCGA) were randomly divided into training set (n = 177) and testing set (n = 176). A total of 146 genomic instability-associated lncRNAs were identified based on somatic mutation profiles combining lncRNA expression profiles from TCGA by the "limma R" package. We performed Cox regression analysis to develop this predictive indicator. We validated the prognostic signature by an external independent LUAD cohort with microarray platform acquired from the Gene Expression Omnibus (GEO). Results: A genome instability-related six-lncRNA-based gene signature (GILncSig) was established to divide subjects into high-risk and low-risk groups with different outcomes at statistically significant levels. According to the multivariate Cox regression and stratification analysis, the GILncSig was an independent predictive factor. Furthermore, the six-lncRNA signature achieved AUC values of 0.745, 0.659, and 0.708 in the training set, testing set, and TCGA set, respectively. When compared with other prognostic lncRNA signatures, the GILncSig also exhibited better prediction performance. Conclusion: The prognostic lncRNA signature is a potent tool for risk stratification of early stage LUAD patients. Our study also provided new insights for identifying genome instability-related cancer biomarkers.

6.
Front Genet ; 12: 668311, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34434213

RESUMO

The purpose of this study was to construct a circular RNA (circRNA)-related competing endogenous RNA (ceRNA) regulatory network and risk score model for lung adenocarcinoma (LUAD). The relationship of the risk score to immune landscape and sensitivity to chemotherapy and targeted therapy of LUAD was assessed. We downloaded mRNA and miRNA expression data, along with clinical information, from The Cancer Genome Atlas (TCGA) program, and circRNA expression data from the Gene Expression Omnibus (GEO) database and identified differently expressed circRNA (DEcircRNA), miRNA (DEmiRNA), and mRNA (DEmRNA) using R software. We then constructed the circRNA-related network using bioinformatics method. The risk score model was established by LASSO Cox regression analysis based on 10 hub genes. In addition, the risk score model was an independent predictor for overall survival (OS) in both the TCGA and CPTAC datasets. Patients in the high-risk group had shorter OS and disease-free survival (DFS) than those in the low-risk group and were more sensitive to chemotherapy and targeted therapy. The types of tumor-infiltrating immune cells were different in the high- and low-risk groups. Our data revealed that the circRNA-related risk score model is closely associated with the level of immune cell infiltration in the tumor and the effects of adjuvant treatment. This network may be useful in designing personalized treatments for LUAD patients.

7.
Front Vet Sci ; 8: 636943, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295931

RESUMO

The biochemical parameters related to nitrogenous metabolism in maternal biofluids may be linked and even reflect the fetal metabolism and growth. The present study have measured the concentrations of various parameters related to amino acid (AA) and lipid metabolism, as well as different metabolites including the free AAs in maternal plasma and amniotic and allantoic fluid corresponding to fetuses with different body weight (BW) during different gestation periods, in order to identify the possible relationships between biochemical parameters and fetal growth. A total of 24 primiparous Huanjiang mini-pigs were fed with a standard diet. Data showed that, from day 45 to day 110 of gestation, the maternal plasma levels of alanine aminotransferase (ALT), albumin (ALB), Ile, Orn, Car, α-ABA, and ß-AiBA increased (P < 0.05); while the levels of ammonia (AMM), choline esterase (CHE), high density lipoprotein-cholesterol (HDL-C), Leu, Glu, Cys, Asp, and Hypro decreased (P < 0.05). From day 45 to 110 of gestation, the amniotic fluid levels of aspartate transaminase (AST), CHE, total protein (TP), and urea nitrogen (UN) increased (P < 0.05), as well as the level of CHE and TP and concentration of Pro in allantoic fluid; while the amniotic fluid concentrations of Arg, Glu, Orn, Pro, and Tau decreased (P < 0.05), as well as allantoic fluid concentrations of Arg and Glu. At day 45 of gestation, the amniotic fluid concentrations of Arg, Orn, and Tau corresponding to the highest BW (HBW) fetuses were higher (P < 0.05), whereas the allantoic fluid concentrations of His and Pro were lower (P < 0.05) when compared with the lowest BW (LBW) fetuses. At day 110 of gestation, the amniotic fluid concentration of Tau corresponding to the HBW fetuses was higher (P < 0.05) than the LBW fetuses. These findings show that the sows display increased protein utilization and decreased lipid metabolism and deposition from day 75 to 110 of gestation. In addition, our data are indicative of a likely stronger ability of HBW fetuses to metabolize protein; and finally of a possible key role of Arg, Gln, Glu, Pro, Tau, and His for the fetal growth and development.

8.
Artigo em Chinês | MEDLINE | ID: mdl-34304459

RESUMO

In 1972, the Committee on Hearing and Equilibrium of the American Academy of Otoaryngology (AAO-CHE) produced the first diagnostic guidelines for Ménière's disease. The American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNS) modified them in 1985, 1995 and 2015. Then, AAO-HNS developed the latest updated version of the Ménière's Disease Guidelines in 2020, based on the latest evidence-based medicine foundation. In this paper, the overall framework and key content of the latest guideline in 2020 are interpreted for domestic colleagues.


Assuntos
Doença de Meniere , Otolaringologia , Medicina Baseada em Evidências , Audição , Testes Auditivos , Humanos , Doença de Meniere/diagnóstico , Doença de Meniere/terapia , Guias de Prática Clínica como Assunto , Estados Unidos
9.
Cell Tissue Res ; 386(2): 281-296, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34223978

RESUMO

Sensory hair cells (HCs) are highly susceptible to damage by noise, ototoxic drugs, and aging. Although HCs cannot be spontaneously regenerated in adult mammals, previous studies have shown that signaling pathways are involved in HC regeneration in the damaged mouse cochlea. Here, we used a Notch antagonist (DAPT), a Wnt agonist (QS11), and recombinant Sonic hedgehog (SHH) protein to investigate their concerted actions underlying HC regeneration in the mouse cochlea after neomycin-induced damage both in vivo and in vitro. With DAPT, the numbers of HCs increased, and supporting cell (SC) proliferation was seen in both the intact and damaged cochlear sensory epithelia, while these numbers were unchanged in the presence of QS11. When simultaneously treated with DAPT and QS11, the number of HCs increased dramatically, and much greater SC proliferation was seen in the cochlear epithelium. In transgenic mice with both Notch1 conditional knockout and ß-catenin over-expression, cochlear SC proliferation and HC regeneration were more obvious than in either Notch1 knockout or ß-catenin over-expressing mice separately. When cochleae were treated with DAPT, QS11, and SHH together, SC proliferation was even greater, and this proliferation was seen in both the HC region and the greater epithelial ridge. High-throughput RNA sequencing was used to identify the differentially expressed genes between all groups, and the results showed that the SHH and Wnt signaling pathways are involved in SC proliferation. Our study suggests that co-regulation of the Notch, Wnt, and SHH signaling pathways promotes extensive cell proliferation and regeneration in the mouse cochlea.

10.
Cell Rep ; 36(4): 109459, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34320357

RESUMO

Active brown adipose tissue (BAT) consumes copious amounts of glucose, yet how glucose metabolism supports thermogenesis is unclear. By combining transcriptomics, metabolomics, and stable isotope tracing in vivo, we systematically analyze BAT glucose utilization in mice during acute and chronic cold exposure. Metabolite profiling reveals extensive temperature-dependent changes in the BAT metabolome and transcriptome upon cold adaptation, discovering unexpected metabolite markers of thermogenesis, including increased N-acetyl-amino acid production. Time-course stable isotope tracing further reveals rapid incorporation of glucose carbons into glycolysis and TCA cycle, as well as several auxiliary pathways, including NADPH, nucleotide, and phospholipid synthesis pathways. Gene expression differences inconsistently predict glucose fluxes, indicating that posttranscriptional mechanisms also govern glucose utilization. Surprisingly, BAT swiftly generates fatty acids and acyl-carnitines from glucose, suggesting that lipids are rapidly synthesized and immediately oxidized. These data reveal versatility in BAT glucose utilization, highlighting the value of an integrative-omics approach to understanding organ metabolism.

11.
Medicine (Baltimore) ; 100(25): e26496, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160464

RESUMO

ABSTRACT: Esophageal cancer (EC) is relatively common; at the time of diagnosis, 50% of cases present with distant metastases, and most patients are men. This study aimed to examine and compare the clinicopathological characteristics and metastatic patterns of male EC (MEC) and female EC (FEC). In addition, risk factors associated with MEC prognosis were evaluated.The present study population was extracted from the Surveillance Epidemiology and End Results database. MEC characteristics and factors associated with prognosis were evaluated using descriptive analysis, the Kaplan-Meier method, and the Cox regression model.A total of 12,558 MEC cases were included; among them, 3454 cases had distant organ metastases. Overall, 27.5% of the entire cohort were patients with distant organ metastases. Compared with patients with non-metastatic MEC, patients with metastatic MEC were more likely to be aged ≤60 years, of Black and White race, have a primary lesion in the overlapping esophagus segments, and have a diagnosis of adenocarcinoma of poorly differentiated and undifferentiated grade that was treated with radiotherapy and chemotherapy rather than surgery; moreover, they were also more likely to be married and insured. In addition, patients with MEC were more likely to be aged ≤60 years, White race, and diagnosed with a primary lesion in the lower third of the esophagus and overlapping esophagus segments, and treated without chemotherapy, compared with those with FEC. Patients in the former group were also more likely than those in the latter group to be unmarried and have bone metastasis only and lung metastasis only. Liver, lung, and bone metastases separately, and simultaneous liver and lung metastases were associated with poor survival in MEC patients.Metastatic MEC is associated with clinicopathological characteristics and metastatic patterns different from those associated with non-metastatic MEC and metastatic FEC. Metastatic MEC and FEC patients may have similar prognoses. Distant organ metastasis may be associated with poor prognosis in patients with MEC and FEC.


Assuntos
Neoplasias Ósseas/epidemiologia , Neoplasias Encefálicas/epidemiologia , Neoplasias Esofágicas/patologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Quimiorradioterapia/estatística & dados numéricos , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/secundário , Neoplasias Esofágicas/terapia , Esofagectomia/estatística & dados numéricos , Esôfago , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Estado Civil/estatística & dados numéricos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Programa de SEER/estatística & dados numéricos , Fatores Sexuais , Adulto Jovem
12.
Mol Ther ; 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34174443

RESUMO

Myosin VI(MYO6) is an unconventional myosin that is vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments for Myo6 mutation causing hearing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate hearing loss in a Myo6WT/C442Y mouse model that recapitulated the phenotypes of human patients. The in vivo editing efficiency of the AAV-SaCas9-KKH-Myo6-g2 system on Myo6C442Y is 4.05% on average in Myo6WT/C442Y mice, which was ∼17-fold greater than editing efficiency of Myo6WT alleles. Rescue of auditory function was observed up to 5 months post AAV-SaCas9-KKH-Myo6-g2 injection in Myo6WT/C442Y mice. Meanwhile, shorter latencies of auditory brainstem response (ABR) wave I, lower distortion product otoacoustic emission (DPOAE) thresholds, increased cell survival rates, more regular hair bundle morphology, and recovery of inward calcium levels were also observed in the AAV-SaCas9-KKH-Myo6-g2-treated ears compared to untreated ears. These findings provide further reference for in vivo genome editing as a therapeutic treatment for various semi-dominant forms of hearing loss and other semi-dominant diseases.

13.
Hear Res ; 407: 108275, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34089989

RESUMO

Loss of hair cells (HCs) accounts for most sensorineural hearing loss, and regeneration of cochlear HCs is considered as the ultimate strategy for restoring hearing. Several lines of evidence have shown that Lgr5+ progenitor cells can spontaneously regenerate new HCs after HC loss at the neonatal stage, and most of which are immature. IHCs are resistant to ototoxic drugs and noise and cannot be ablated efficiently in order to precisely investigate IHC regeneration in existing hearing injury models, and thus we generated a new transgenic mouse model by inserting diphtheria toxin receptor (DTR) under the control of the Vglut3 promoter. In this model, IHCs were selectively ablated in a dose-dependent manner after the injection of diphtheria toxin (DT) at the neonatal stage, while OHCs remained intact with normal hair bundle structures until adulthood. With this IHC-specific injury model, we observed HC regeneration from Lgr5+ progenitors after IHC ablation at the neonatal stage. Some of the newly generated HCs replaced the lost IHCs in-situ and re-build the structure of the organ of Corti through the asymmetrical mitosis of progenitor cells. While, the majority of the regenerated HCs did not survive until adulthood, and the loss of spiral ganglion neurons was observed after the IHC ablation, which led to profound hearing loss after DT injection in Vglut3DTR+ mice at the neonatal stage. The model presented here shows promise for investigating the mechanisms behind IHC loss and subsequent regeneration.

14.
Mol Ther Oncolytics ; 21: 134-143, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-33981829

RESUMO

We developed a predictive model associated with ferroptosis to provide a more comprehensive view of esophageal squamous cell carcinoma (ESCC) immunotherapy. Gene expression data and corresponding clinical outcomes were obtained from the GEO and The Cancer Genome Atlas (TCGA) databases, and a ferroptosis-related gene set was obtained from the FerrDb database. We identified 45 ferroptosis-related genes that were differentially expressed, including enrichment in genes involved in the immune system process. We established a ferroptosis-related gene-based prognostic model based on the results of univariate Cox regression and multivariate Cox regression analyses, with an area under the curve (AUC) of 0.76 (3 years). We found that the patients with low-risk scores showed a higher proportion of CD8+ T cells, CD4+ memory activated T cells, etc. Finally, a predictive ferroptosis-related prognostic nomogram, which included the predictive values of age, gender, grade, TNM stage, and risk score, was established to predict overall survival. In sum, we developed a ferroptosis-related gene-based prognostic model that provides novel insights into the prediction of ESCC prognosis and identifies the relevance of the immune microenvironment for patient outcomes.

15.
Front Oncol ; 11: 644860, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34041021

RESUMO

Background: The hepatic metastasis pattern of esophageal cancer (EC) has not been fully explored. The primary objective of this study was to explore the predictors of esophageal cancer with hepatic metastasis (ECHM) at the time of diagnosis. In addition, we also analyzed the factors affecting ECHM prognosis. Methods: We used the Surveillance, Epidemiology and End Result (SEER) database to identify ECHM patients at the time of initial diagnosis. The ECHM predictors were identified using multivariate logistic regression. Multivariate Cox regression and competing survival risk analyses were performed to identify factors associated with all-cause mortality and EC-specific mortality of ECHM, respectively. Results: A total of 10,965 eligible EC patients were identified in the SEER database between 2010 and 2016, of which 1,197 were ECHM patients, accounting for 10.9% of the entire cohort. In the whole cohort, eight ECHM predictors (age, primary site, grade, histology type, T staging, N staging, insurance status, and number of extrahepatic metastatic sites) were determined using multivariate logistic regression analysis. Multivariate Cox regression and multivariate competing survival risks models confirmed that the male sex, advanced age, squamous cancer, and multiple extrahepatic metastasis increased the risk of both all-cause and EC-specific mortality, whereas chemotherapy and chemotherapy plus radiotherapy significantly reduced the risk of both. Conclusions: This study explored population-level predictors of hepatic metastasis at the time of EC diagnosis and analyzed the clinical characteristics affecting the prognosis in ECHM patients. These findings may provide clinicians with a reference for the screening and treatment of hepatic metastasis in EC.

16.
Cell Rep ; 35(3): 109016, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33882317

RESUMO

The mammalian cochlea cannot regenerate functional hair cells (HCs) spontaneously. Atoh1 overexpression as well as other strategies are unable to generate functional HCs. Here, we simultaneously upregulated the expression of Gfi1, Pou4f3, and Atoh1 in postnatal cochlear supporting cells (SCs) in vivo, which efficiently converted SCs into HCs. The newly regenerated HCs expressed HC markers Myo7a, Calbindin, Parvalbumin, and Ctbp2 and were innervated by neurites. Importantly, many new HCs expressed the mature and terminal marker Prestin or vesicular glutamate transporter 3 (vGlut3), depending on the subtypes of the source SCs. Finally, our patch-clamp analysis showed that the new HCs in the medial region acquired a large K+ current, fired spikes transiently, and exhibited signature refinement of ribbon synapse functions, in close resemblance to native wild-type inner HCs. We demonstrated that co-upregulating Gfi1, Pou4f3, and Atoh1 enhances the efficiency of HC generation and promotes the functional maturation of new HCs.

17.
Aging (Albany NY) ; 13(5): 7430-7453, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33686019

RESUMO

Glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is a key enzyme associated with glucose metabolism and uridine diphosphate-N-acetylglucosamine biosynthesis. Abnormal GNPNAT1 expression might be associated with carcinogenesis. We analyzed multiple lung adenocarcinoma (LUAD) gene expression databases and verified GNPNAT1 higher expression in LUAD tumor tissues than in normal tissues. Moreover, we analyzed the survival relationship between LUAD patients' clinical status and GNPNAT1 expression, and found higher GNPNAT1 expression in LUAD patients with unfavorable prognosis. We built GNPNAT1 gene co-expression networks and further annotated the co-expressed genes' Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and various associated regulatory factors. These co-expression genes' functional networks mainly participate in chromosome segregation, RNA metabolic process, and RNA transport. We analyzed GNPNAT1 genetic alterations and co-occurrence networks, and the functional networks of these genes showed that GNPNAT1 participates in multiple steps of cell cycle transition and in the development of some cancers. We assessed the correlation between GNPNAT1 expression and cancer immune infiltrates and showed that GNPNAT1 expression is correlated with several immune cells, chemokines, and immunomodulators in LUAD. We found that GNPNAT1 correlates with LUAD development and prognosis, laying a foundation for further research, especially in immunotherapy.


Assuntos
Adenocarcinoma de Pulmão/enzimologia , Glucosamina 6-Fosfato N-Acetiltransferase/metabolismo , Neoplasias Pulmonares/enzimologia , Adenocarcinoma de Pulmão/etiologia , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Variação Genética/genética , Glucosamina 6-Fosfato N-Acetiltransferase/genética , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Linfócitos do Interstício Tumoral , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Transcriptoma , Adulto Jovem
18.
Genome Biol ; 22(1): 86, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33752742

RESUMO

BACKGROUND: Aging, noise, infection, and ototoxic drugs are the major causes of human acquired sensorineural hearing loss, but treatment options are limited. CRISPR/Cas9 technology has tremendous potential to become a new therapeutic modality for acquired non-inherited sensorineural hearing loss. Here, we develop CRISPR/Cas9 strategies to prevent aminoglycoside-induced deafness, a common type of acquired non-inherited sensorineural hearing loss, via disrupting the Htra2 gene in the inner ear which is involved in apoptosis but has not been investigated in cochlear hair cell protection. RESULTS: The results indicate that adeno-associated virus (AAV)-mediated delivery of CRISPR/SpCas9 system ameliorates neomycin-induced apoptosis, promotes hair cell survival, and significantly improves hearing function in neomycin-treated mice. The protective effect of the AAV-CRISPR/Cas9 system in vivo is sustained up to 8 weeks after neomycin exposure. For more efficient delivery of the whole CRISPR/Cas9 system, we also explore the AAV-CRISPR/SaCas9 system to prevent neomycin-induced deafness. The in vivo editing efficiency of the SaCas9 system is 1.73% on average. We observed significant improvement in auditory brainstem response thresholds in the injected ears compared with the non-injected ears. At 4 weeks after neomycin exposure, the protective effect of the AAV-CRISPR/SaCas9 system is still obvious, with the improvement in auditory brainstem response threshold up to 50 dB at 8 kHz. CONCLUSIONS: These findings demonstrate the safe and effective prevention of aminoglycoside-induced deafness via Htra2 gene editing and support further development of the CRISPR/Cas9 technology in the treatment of non-inherited hearing loss as well as other non-inherited diseases.

19.
Plants (Basel) ; 10(2)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670570

RESUMO

It is reported that the production of floral sexual phenotype in hexaploid monoecious persimmon (Diospyros kaki) is closely related to a pseudogene called OGI, and a short interspersed nuclear element (SINE)-like insertion (named Kali) in the OGI promoter leads to the gene silence. As a result, DNA methylation level of MeGI promoter determines the development of male or female flowers. However, the molecular mechanism in androecious D. kaki, which only bear male flowers, remains elusive. Here, real-time quantitative polymerase chain reaction (RT-qPCR), molecular cloning, and bisulfite PCR sequencing technique were carried out using 87 materials, including 56 androecious resources, 15 monoecious, and 16 gynoecious cultivars, to investigate the performance of OGI and MeGI on the specific androecious type of D. kaki in China. In conclusion, the Kali insertion was exactly located in the OGI promoter region, and the OGI gene and the Kali sequence were existing and conserved in androecious D. kaki. Meanwhile, we also demonstrated that the MeGI gene was widespread in our investigated samples. Ultimately, our result convincingly provided evidence that the low expression of OGI is probably ascribed to the presence of Kali displaying strong methylation in the OGI promoter, and low expression of MeGI, as well as high DNA methylation level, in the promoter was closely connected with the production of male flowers; this result was consistent with the monoecious persimmon model. Our findings provide predominant genetic aspects for investigation into androecious D. kaki, and future perfecting the sex-determining mechanisms in persimmon.

20.
Front Oncol ; 11: 603953, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33718154

RESUMO

Background: Esophageal cancer is one of the most common cancer types, with its most common distant metastatic site being the lung. Currently, population-based data regarding the proportion and prognosis of patients with esophageal cancer with lung metastases (ECLM) at the time of diagnosis is insufficient. Therefore, we aimed to determine the proportion of patients with ECLM at diagnosis, as well as to investigate the prognostic parameters of ECLM. Methods: This population-based observational study obtained data from the Surveillance, Epidemiology, and End Results (SEER) database registered between 2010 and 2016. Multivariable logistic regression was performed to identify predictors of the presence of ECLM at diagnosis. Multivariable Cox regression and competing risk analysis were used to assess prognostic factors in patients with ECLM. Median survival was estimated using Kaplan-Meier curves. Results: Of 10,965 patients diagnosed with esophageal cancer between 2010 and 2016, 713 (6.50%) presented with initial lung metastasis at diagnosis. Lung metastasis represented 27.15% of all cases with metastatic disease to any distant site. Considering all patients with esophageal cancer, multivariable logistic regression indicated that pathology grade, pathology type, T staging, N staging, race, and number of extrapulmonary metastatic sites were predictive factors for the occurrence of lung metastases at diagnosis. The median survival time of patients with ECLM was 4.0 months. Patients receiving chemotherapy or chemoradiotherapy had the longest median overall survival, 7.0 months. Multivariable Cox regression indicated that age, histology type, T2 staging, number of extrapulmonary metastatic sites, and treatment (chemotherapy, radiotherapy, or chemoradiotherapy) were independent predictors for overall survival (OS). Multivariable competing risk analysis determined that age, number of extrapulmonary metastatic sites, and treatment were independent predictors for esophageal cancer-specific survival (CSS). Conclusion: The findings of this study may provide important information for the early diagnosis of ECLM, as well as aid physicians in choosing appropriate treatment regimens for these patients.

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