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1.
J Nanosci Nanotechnol ; 20(4): 2308-2315, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492241

RESUMO

While most of the fluorescent nanoparticles used in stimulated emission depletion (STED) microscopy have a long excitation wavelength, many applications need shorter wavelength fluorophores, which are yet to be developed for STED microscopy applications. Here, three kinds of fluorescent nanoparticles, namely silica nanoparticles (NFv465), fluoro-max blue aqueous fluorescent nanoparticles (FBs) and light yellow nanoparticles (LYs) with short excitation wavelength in violet band have been studied to assess whether they are applicable in STED microscopy. The experimental configuration utilizes a 405 nm continuous wave (CW) laser as excitation beam and a 532 nm CW laser as depletion beam. We compare the photostability, photobleaching and depletion efficiency of three kinds of fluorescent nanoparticles in a series of experiments. Light yellow nanoparticles are proved to be a good candidate as fluorophore in STED microscopy.

2.
Opt Lett ; 44(19): 4769-4772, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31568438

RESUMO

X-ray luminescence computed tomography (XLCT) based on x-ray-excitable nanophosphors has been proposed as a new modality for molecular imaging. The technique has two main advantages compared to other modalities. First, autofluorescence, which is problematic for fluorescence imaging, can be substantially reduced. Second, deep-tissue in vivo imaging with high optical contrast and spatial resolution becomes achievable. Here, we extend the novel XLCT modality from the visible or infrared region to a shortwave infrared wavelength by developing an x-ray-induced shortwave infrared luminescence computed tomography (SWIR-XLCT). For this application, rare-earth nanophosphors (RENPs) were synthesized as core/shell structures consisting of a Ho-doped NaYbF4 core surrounded by a NaYF4 shell that emit light efficiently in the shortwave infrared spectral region under x-ray excitation. Through numerical simulations and phantom experiments, we showed the feasibility of SWIR-XLCT and demonstrated its potential for x-ray luminescence imaging with high spatial resolution and deep depth.

3.
J Craniofac Surg ; 30(7): 2102-2105, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31574784

RESUMO

OBJECTIVE: To explore the efficacy of nerve injury unit mode and conventional management mode for the treatment of patients with moderate or severe traumatic brain injury (TBI). METHODS: Eighty patients with TBI in our hospital from July 2016 to December 2017 were included as observation groups (Treated with injury unit mode). Eighty-three patients with TBI from January 2015 to June 2016 were included as control group (Treated with conventional management mode). The incidence of complications, satisfaction rate, Glasgow Coma Scale (GCS) scores, Barthel index (BI), National Institutes of Health Stroke Scale (NIHSS) scores and average length of hospital stay of 2 groups were compared. RESULTS: Observation group achieved lower incidence of complications, higher satisfaction rate, higher GCS scores, higher GOS prognosis scores, higher BI, lower NIHSS scores, and shorter average length of hospital stay compared with control group (P < 0.05). There were no significant differences in the average hospitalization cost between 2 groups (P > 0.05). CONCLUSION: For patients with TBI, the nerve injury unit mode can reduce the incidence of complications, improve patient satisfaction rate, shorten the hospitalization time, enhance the daily living ability, improve the patient's neurological function, improve the ability to return to society and have a significant role in promoting the rehabilitation of patients.

4.
Small ; : e1903060, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31599125

RESUMO

Engineering of smart photoactivated nanomaterials for targeted drug delivery systems (DDS) has recently attracted considerable research interest as light enables precise and accurate controlled release of drug molecules in specific diseased cells and/or tissues in a highly spatial and temporal manner. In general, the development of appropriate light-triggered DDS relies on processes of photolysis, photoisomerization, photo-cross-linking/un-cross-linking, and photoreduction, which are normally sensitive to ultraviolet (UV) or visible (Vis) light irradiation. Considering the issues of poor tissue penetration and high phototoxicity of these high-energy photons of UV/Vis light, recently nanocarriers have been developed based on light-response to low-energy photon irradiation, in particular for the light wavelengths located in the near infrared (NIR) range. NIR light-triggered drug release systems are normally achieved by using two-photon absorption and photon upconversion processes. Herein, recent advances of light-responsive nanoplatforms for controlled drug release are reviewed, covering the mechanism of light responsive small molecules and polymers, UV and Vis light responsive nanocarriers, and NIR light responsive nanocarriers. NIR-light triggered drug delivery by two-photon excitation and upconversion luminescence strategies is also included. In addition, the challenges and future perspectives for the development of light triggered DDS are highlighted.

5.
J Mol Cell Biol ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31565729

RESUMO

Bromodomain-containing proteins are known readers of histone acetylation that regulate chromatin structure and transcription. Although the functions of bromodomain-containing proteins in development, homeostasis, and disease states have been well studied, their role in self-renewal of hematopoietic stem and progenitor cells (HSPCs) remains poorly understood. Here, we performed a chemical screen using 9 bromodomain inhibitors, and found that the bromodomain and PHD finger containing protein 1 (Brpf1) inhibitor OF-1 enhanced the expansion of Lin-Sca-1+c-Kit+ HSPCs (LSKs) ex vivo without skewing their lineage differentiation potential. Importantly, our results also revealed distinct functions of Brpf1 isoforms in HSPCs. Brpf1b promoted the expansion of HSPCs. By contrast, Brpf1a is the most abundant isoform in adult HSPCs, but enhanced HSPC quiescence and decreased the HSPC expansion. Furthermore, inhibition of Brpf1a by OF-1 promoted histone acetylation and chromatin accessibility leading to increased expression of self-renewal related genes (e.g. Mn1). The phenotypes produced by OF-1 treatment can be rescued by suppression of Mn1 in HSPCs. Our findings underscore this novel bromodomain inhibitor OF-1 can promote the clinical application of HSPCs.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31580926

RESUMO

STUDY OBJECTIVE: To evaluate in vitro fertility (IVF) outcomes of proximal fallopian tube embolization by interventional radiology compared with laparoscopic salpingectomy before embryo transfer (ET) in patients with hydrosalpinx. DESIGN: A single-center, off-label, nonrandomized prospective study. SETTING: Academic university hospital. PATIENTS: One hundred and fifty-five patients with hydrosalpinx were identified on ultrasound or hysterosalpingography desiring IVF between April 2016 and December 2017. INTERVENTIONS: Radiologically guided tubal occlusion with embolization microcoils (RTO-EM) and laparoscopic salpingectomy. MEASUREMENTS AND MAIN RESULTS: Of 155 analyzed patients, 42 were treated with RTO-EM and 113 with laparoscopic salpingectomy. The subsequent IVF outcomes including implantation, clinical pregnancy, miscarriage, ectopic pregnancy, and ongoing pregnancy (fetal heartbeat on ultrasound beyond 10 weeks) were compared between the two groups. Implantation and clinical pregnancy per ET cycle in the RTO-EM group were similar to that of the salpingectomy group (26.7% vs. 30.2%, p = .511, and 39.0% vs. 45.3%, p = .400, respectively), with a similar miscarriage rate. There was no statistically significant difference in ectopic pregnancies between the two groups. Moreover, no difference was detected in ongoing pregnancy per cycle between the two groups (33.9% vs. 41.2%, p = .324). The ongoing-pregnancy rate per patient following RTO-EM was 47.6% (20 of 42) compared with 61.9% (70 of 113) following salpingectomy (p = .108; odds ratio: 0.56; 95% confidence interval, 0.27-1.14). CONCLUSION: Pregnancy in the RTO-EM group was comparable to the salpingectomy group in patients with hydrosalpinx prior to ET treatment. Radiologically guided tubal occlusion with embolization microcoils may be an alternative to salpingectomy for patients with hydrosalpinx planning IVF-ET.

7.
Pathol Res Pract ; : 152667, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31585814

RESUMO

MicroRNAs (miRNAs) have been found to be aberrantly expressed and exert essential roles in the tumorigenesis and progression of gastric cancer (GC). miR-301b-3p has been recognized as a cancer-related miRNA in lung cancer, bladder cancer and hepatocellular carcinoma. However, the function of miR-301b-3p in GC progression and its underlying mechanism have not been studied yet. In this study, we found that miR-301b-3p expression was up-regulated in GC tissues compared to adjacent noncancerous tissues. Furthermore, the elevated levels of miR-301b-3p were detected in GC cell lines (SGC-7901, AGS, MKN-45 and MGC-803) as compared with GES-1 cells. Interestingly, GC tissues from patients with tumor size ≥ 5 cm and advanced tumor stages showed obvious higher levels of miR-301b-3p compared to matched controls. Functionally, miR-301b-3p knockdown prominently inhibited cell proliferation, and induced cell cycle arrest at G1 phase and apoptosis in MGC-803 cells. Meanwhile, ectopic expression of miR-301b-3p conversely regulated these biological behaviors of MKN-45 cells. Next, we found that miR-301b-3p knockdown increased, whereas miR-301b-3p overexpression reduced the expression of zinc finger and BTB domain containing 4 (ZBTB4) in GC cells. Accordingly, luciferase reporter assay identified ZBTB4 as a direct target of miR-301b-3p. ZBTB4 overexpression markedly restrained the growth of MGC-803 cells. More importantly, ZBTB4 silencing partially reversed miR-301b-3p knockdown-induced tumor suppressive effects on MGC-803 cells. In conclusion, we firstly revealed that miR-301-3p was highly expressed in GC and contributed to tumor progression via attenuating ZBTB4, which might provide a novel molecular-targeted strategy for GC treatment.

8.
Gastroenterology ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31589872

RESUMO

BACKGROUND & AIMS: The long-term risks of colorectal cancer (CRC) and CRC-related death following adenoma removal are uncertain. Data are needed to inform evidence-based surveillance guidelines, which vary in follow-up recommendations for some polyp types. Using data from a large, community-based integrated health care setting, we examined the risks of CRC and related death by baseline colonoscopy adenoma findings. METHODS: Participants at 21 medical centers underwent baseline colonoscopies from 2004 through 2010; findings were categorized as no adenoma, low-risk adenoma, or high-risk adenoma. Participants were followed until the earliest of CRC diagnosis, death, health plan disenrollment, or December 31, 2017. Risks of CRC and related deaths among the high- and low-risk adenoma groups were compared with the no adenoma group using Cox regression adjusting for confounders. RESULTS: Among 186,046 patients, 64,422 met eligibility criteria (54.3% female; mean age, 61.6±7.1 y; median follow-up time, 8.1 y from the baseline colonoscopy). Compared with the no-adenoma group (45,881 patients), the high-risk adenoma group (7563 patients) had a higher risk of CRC (hazard ratio [HR], 2.61; 95% CI, 1.87-3.63) and related death (HR, 3.94; 95% CI, 1.90-6.56), whereas the low-risk adenoma group (10,978 patients) did not have a significant increase in risk of CRC (HR, 1.29; 95% confidence interval, 0.89-1.88) or related death (HR, 0.65; 95% CI, 0.19-2.18). CONCLUSIONS: With up to 14-years of follow-up, high-risk adenomas were associated with an increased risk of CRC and related death, supporting early colonoscopy surveillance. Low-risk adenomas were not associated with a significantly increased risk of CRC or related deaths. These results can inform current surveillance guidelines for high- and low-risk adenomas.

9.
Acta Trop ; : 105211, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31600522

RESUMO

Enterocytozoon bieneusi is a potentially important zoonotic pathogen. However, there is no information on E. bieneusi infection of captive long-tailed macaques (Macaca fascicularis) in Hainan Province, China. Here 193 fecal specimens of M. fascicularis were collected from a breeding base in Hainan Province, China, housing non-human primates for experimental use. E. bieneusi was identified and genotyped by nested PCR analysis of the internal transcribed spacer (ITS) region of the rRNA gene. A total of 59 (30.6%) specimens were PCR-positive for E. bieneusi and 16 ITS genotypes were identified including nine known genotypes: Type IV (n = 19), D (n = 11), CM1 (n = 8), PigEBITS7 (n = 4), Pongo2 (n = 4), Peru8 (n = 3), Peru11 (n = 1), WL21 (n = 1) and CM2 (n = 1) and seven novel genotypes HNM-I to HNM-VII (one each). Importantly, genotypes D, Type IV, Peru8, PigEBITS7, and Peru11, which were the predominant (38/59, 64.4%) genotypes identified among captive M. fascicularis in this study, are also well-known human-pathogenic genotypes. All the genotypes of E. bieneusi identified here, including the seven novel ones, belonged to zoonotic Group 1. This is the first report of the identification of E. bieneusi in M. fascicularis in Hainan Province, China. The finding that the numerous known human-pathogenic types and seven novel genotypes of E. bieneusi all belong to zoonotic Group 1 indicates the possibility of transmission of this important pathogenic parasite between M. fascicularis and humans.

10.
Chin Med J (Engl) ; 132(19): 2292-2299, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31567375

RESUMO

BACKGROUND: The dose and time point for switching from clopidogrel to ticagrelor remain controversial, especially for Chinese acute coronary syndrome (ACS) patients with complicated coronary artery disease (CAD). Hence, the purpose of this study was to further explore the optimal dose and time point for the switching strategy to balance the increase in platelet inhibition and the decrease in adverse events in Chinese ACS patients with complicated CAD managed by percutaneous coronary intervention (PCI). METHODS: From July 2017 to December 2017, the prospective, randomized, open-label study (the SwitcHIng from clopidogrel to ticagrelor study) assigned the eligible Chinese ACS patients with complicated CAD managed by PCI (n = 102) for 90 mg of ticagrelor at 12 h (T-90 mg-12 h), 90 mg of ticagrelor at 24 h (T-90 mg-24h) or 180 mg ticagrelor at 24 h (T-180 mg-24 h) after the last dose of clopidogrel. The primary endpoint was the comparison of maximal platelet aggregation (MPA) values at 2 h after switching strategies among the three groups. In addition, the MPA values at baseline, 8 h and before discharge and the rates of high on-treatment platelet reactivity were evaluated, the incidences of bleeding episodes and dyspnea during hospitalization and at 30-day follow-up in our study were also recorded. The MPA was measured by light transmittance aggregometry in our study. A repeated-measures analysis of variance (ANOVA) model and one-way ANOVA were used to compare data for the primary endpoint. RESULTS: The MPA values were significantly decreased in the T-180 mg-24 h group compared with the T-90 mg-12 h group (P = 0.017) and decreased numerically compared with the T-90 mg-24 h group (P = 0.072) at 2 h. In particular, the MPA values were markedly reduced in the T-90 mg-24 h group compared with the T-90 mg-12 h group at 8 h after switching treatment (P = 0.002). There was no significant difference among the three groups in all bleedings and dyspnea events. CONCLUSIONS: The optimal treatment strategy recommended in this study for Chinese ACS patients with complicated CAD managed by PCI is 180 or 90 mg of ticagrelor at 24 h after the last dose of clopidogrel. In addition, a negative interaction was detected in this study between the overlap for clopidogrel and ticagrelor at 12 h after the last dose of clopidogrel. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03577652; http://clinicaltrials.gov/ct2/show/NCT03577652.

11.
Cell Death Differ ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570856

RESUMO

Emerging evidences have suggested the vital roles of circular RNA (circRNA) in the human cancers. However, the underlying biological functions and biogenesis of circRNA in the oral squamous cell carcinoma (OSCC) is still ambiguous. Here, we investigate the oncogenic roles and biogenesis of the novel identified circRNA, circUHRF1 (hsa_circ_0002185), in the OSCC tumorigenesis. Results showed that circUHRF1 was markedly upregulated in the OSCC cells and tissue, besides, the overexpression was closely correlated with the poor prognosis of OSCC patients. Functionally, circUHRF1 promoted the proliferation, migration, invasion, and epithelial mesenchymal transformation (EMT) in vitro and the tumor growth in vivo. Mechanically, circUHRF1 acted as the sponge of miR-526b-5p, thereby positively regulating c-Myc. Transcription factor c-Myc could accelerate the transcription of TGF-ß1 and ESRP1. Moreover, splicing factor ESRP1 promoted the circularization and biogenesis of circUHRF1 by targeting the flanking introns, forming the circUHRF1/miR-526b-5p/c-Myc/TGF-ß1/ESRP1 feedback loop. In conclusion, our research identified the oncogenic roles of circUHRF1 in the OSCC tumorigenesis and EMT via circUHRF1/miR-526b-5p/c-Myc/TGF-ß1/ESRP1 feedback loop, shedding light on the pathogenic mechanism of circUHRF1 for OSCC and providing the potential therapeutic target.

12.
Cell Syst ; 9(3): 271-285.e7, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31542414

RESUMO

Many signaling systems execute adaptation under circumstances that require noise attenuation. Here, we identify an intrinsic trade-off existing between sensitivity and noise attenuation in the three-node networks. We demonstrate that although fine-tuning timescales in three-node adaptive networks can partially mediate this trade-off in this context, it prolongs adaptation time and imposes unrealistic parameter constraints. By contrast, four-node networks can effectively decouple adaptation and noise attenuation to achieve dual function without a trade-off, provided that these functions are executed sequentially. We illustrate ideas in seven biological examples, including Dictyostelium discoideum chemotaxis and the p53 signaling network and find that adaptive networks are often associated with a noise attenuation module. Our approach may be applicable to finding network design principles for other dual and multiple functions.

13.
Cancer ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31490550

RESUMO

BACKGROUND: Diabetes is positively associated with various cancers, but its relationship with tumors of the esophagus/esophagogastric junction remains unclear. METHODS: Data were harmonized across 13 studies in the International Barrett's and Esophageal Adenocarcinoma Consortium, comprising 2309 esophageal adenocarcinoma (EA) cases, 1938 esophagogastric junction adenocarcinoma (EGJA) cases, 1728 Barrett's esophagus (BE) cases, and 16,354 controls. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% CIs for self-reported diabetes in association with EA, EGJA, and BE. Adjusted ORs were then combined using random-effects meta-analysis. RESULTS: Diabetes was associated with a 34% increased risk of EA (OR, 1.34; 95% CI, 1.00-1.80; I2  = 48.8% [where 0% indicates no heterogeneity, and larger values indicate increasing heterogeneity between studies]), 27% for EGJA (OR, 1.27; 95% CI, 1.05-1.55; I2  = 0.0%), and 30% for EA/EGJA combined (OR, 1.30; 95% CI, 1.06-1.58; I2  = 34.9%). Regurgitation symptoms modified the diabetes-EA/EGJA association (P for interaction = .04) with a 63% increased risk among participants with regurgitation (OR, 1.63; 95% CI, 1.19-2.22), but not among those without regurgitation (OR, 1.03; 95% CI, 0.74-1.43). No consistent association was found between diabetes and BE. CONCLUSIONS: Diabetes was associated with increased EA and EGJA risk, which was confined to individuals with regurgitation symptoms. Lack of an association between diabetes and BE suggests that diabetes may influence progression of BE to cancer.

14.
Biologicals ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31542343

RESUMO

The residual DNA derived from host cells in antibody drugs have potential safety risks. In this paper, the antibody in the test sample was removed by magnetic bead separation method, and the residual DNA were quantitatively determined by Q-PCR method. The residual DNA in the sample was analyzed according to the standard curve. We validated the species specificity, accuracy, precision, quantitative restrictions, reproducibility of this method. The results showed the linearrange was of 1 × 10-1~1 × 102 pg/µL and the curve linear was good, this method can specifically detect CHO cell DNA. Compared with the method of extracting residual DNA by magnetic beads, the method has the advantages of simplicity, rapidity and low cost, and can be used for quantitative determination of the residual host cell DNA in antibody drugs producted by CHO cells.

15.
J Epidemiol ; 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31474675

RESUMO

Backgroud Establishment of an unbiased association between gestational weight gain (GWG) and perinatal health is urgently needed in China, which has the largest population in the world. Our study aimed to create weight-gain-for-gestational-age charts using early pregnancy body mass index (BMI) to present selected percentiles of GWG in China.Methods A population-based follow-up study was conducted based on the Maternal and Newborn Health Monitoring System, which recruited 132,835 pregnant women between October 2013 and September 2016 in 12 districts/counties of 6 provinces in China. Multilevel analyses and restricted cubic splines were performed to model the longitudinal repeated maternal weight gain measurements and obtain smoothed curves for GWG. The internal and external validation of each model was also assessed.Results To develop models of GWG, 34,288 women were included. Smoothed percentiles of GWG in the 3rd, 10th, 50th, 90th, and 97th percentiles were estimated for each week of gestation. The median figures for GWG were 15.0 kg, 14.4 kg, 13.5 kg, and 12.1 kg in underweight, normal weight, overweight, and obese women, respectively, at 40 weeks. Of all the weight measurements, more than 70% and 95% fell within the expected 1 to 2 standard deviations, respectively. To accomplish external validation of the models, 20,458 women were included. The specificities of measurements in the 5th, 10th, 15th, 25th, 75th, 85th, 90th, and 95th percentiles in four BMI categories were between 90% and 100%.Conclusions The population-based gestational weight gain z-score charts performed well in providing guidance regarding expected gestational weight gain in Chinese women.

16.
Arch Biochem Biophys ; : 108112, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31550443

RESUMO

Wilms' tumor is one of the most common malignancies in children, and early diagnosis is critical for its subsequent treatment and prognosis. Our previous study employed proteomics to investigate protein markers in the serum of Wilms' tumor children. The present study aimed to identify specific protein markers in Wilms' tumor. Proteomic comparison of Wilms' tumor with normal kidney tissues and the sera of systemic inflammatory response syndrome (SIRS) controls was performed. Surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF-MS) identified a protein with m/z 8350 as specific to Wilms' tumor. The target protein was purified using sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and identified as profilin-1 by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF). Its expression was validated using real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Our data identify profilin-1 as a potential protein marker for Wilms' tumor and demonstrate the feasibility of the above procedures for screening and identification of tumor-specific protein markers.

17.
Mol Pain ; : 1744806919880643, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31530215

RESUMO

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus with obscure underlying mechanisms. The adaptor protein APPL1 is critical in mediating the insulin sensitizing and insulin signaling. In neurons, APPL1 reportedly affects synaptic plasticity, while its role in the pathogenesis of PDN is masked. Our western blotting revealed significantly decreased APPL1 expression in the dorsal horn in streptozocin (STZ)-induced rats versus the control rats, coupled with concomitant mechanical and thermal hyperalgesia. Afterwards, the determination of exact localization of APPL1 in spinal cord by immunofluorescent staining assay revealed highly expressed APPL1 in the lamina of spinal dorsal horn in control rats, with the overexpression in neurons, microglia and underexpression in astrocytes. The APPL1 expression in laminae I and II was significantly downregulated in PDN rats. Additionally, APPL1 deficiency or overexpression contributed to the increase or decrease of Map and Bassoon, respectively. The localization and immunoactivity of APPL1 and mammalian target of rapamycin (mTOR) were determined in spinal dorsal horn in PDN rats and control rats by immunohistochemistry, suggesting pronounced decrease in APPL1 expression in the superficial layer of the spinal cord in PDN rats, with p-mTOR expression markedly augmented. APPL1 knockdown by infection with lentiviral vector facilitated the activation of mTOR and abrogated mechanical withdrawal threshold (MWT) values in PDN rats. Genetically overexpressed APPL1 significantly eliminated the activation of mTOR and resulted in the augmented MWT values and thermal withdrawal latency (TWL) values. Further, the APPL1 levels affect phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), and Akt, the phosphorylation of AMPK and Akt as well as the small GTPase, Rab5 expression in PDN rats. Our results uncovered a novel mechanism by which APPL1 deficiency facilitates the mTOR activation, and thus exacerbates the hyperalgesia in STZ-induced diabetic rats, presumably via the regulation of Rab5/Akt and AMPK signaling pathway.

18.
Cancer Res ; 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530567

RESUMO

The N6-methyladenosine (m6A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined. Here, we showed that the m6A methyltransferase METTL3 sustained its oncogenic role by modulating NMD of splicing factors and alternative splicing isoform switches in glioblastoma (GBM). MeRIP-seq analyses showed that m6A modification peaks were enriched at metabolic pathway-related transcripts in glioma stem cells (GSCs) compared with neural progenitor cells (NPCs). In addition, the clinical aggressiveness of malignant gliomas was associated with elevated expression of METTL3. Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs. Integrated transcriptome and MeRIP-seq analyses revealed that downregulating the expression of METTL3 decreased m6A modification levels of serine- and arginine-rich splicing factors (SRSFs), which led to YTHDC1-dependent NMD of SRSFs transcripts and decreased SRSFs protein expression. Reduced expression of SRSFs led to larger changes in alternative splicing isoform switches. Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms. Overall, these results establish a novel function of m6A in modulating NMD and uncover the mechanism by which METTL3 promotes GBM tumor growth and progression.

19.
Anal Chem ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31556999

RESUMO

Currently, one of important research directions of photoelectrochemical (PEC) bioanalysis is to exploit innovative photoactive species and their elegant implementations for selective detection and signal transduction. Different from existing candidates for photoelectrode development, this study, exemplified by the cationic dipeptide nanoparticles (CDNPs), reports the first demonstration of self-assembled peptide nanostructures (SAPNs) for the PEC bioanalysis. Specifically, the CDNPs were prepared as representative materials and then immobilized onto the indium tin oxide (ITO) electrode for the PEC differentiation of several commonly involved biomolecules such as ascorbic acid (AA) and l-cysteine. Significantly, the experimental results disclosed that the CDNPs possessed unique photocathodic responses and good analytical performance toward AA detection in terms of rapid response, high stability, and excellent selectivity. This work demonstrates the great potential of the large SAPN family for the future PEC bioanalysis development and has not been reported to our knowledge.

20.
Biochem Biophys Res Commun ; 519(1): 134-140, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31477271

RESUMO

Tumor microenvironment is composed of biological, chemical and physical factors. Mechanical factors are more and more focused these years. Therefore, mimicking mechanical factors' contribution to cancer cell malignancy will greatly improve the advance in this field. Although the induced malignant behaviors are present under many stimuli such as growth or inflammatory factors, the cell key physical migration mechanisms are still missing. In this study, we identify that low shear stress significantly promotes the formation of needle-shaped membrane protrusions, which is called filopodia and important for the sense and interact of a cell with extracellular matrix in the tumor microenvironment. Under low shear stress, the migration is promoted while it is inhibited in the presence of ROCK inhibitor Y27632, which could abolish the F-actin network. Using cell imaging, we further unravel that key to these protrusions is Cell division cycle 42 (Cdc42) dependent. After Cdc42 activation, the filopodia is more and longer, acting as massagers to pass the information from a cell to the microenvironment for its malignant phenotype. In the Cdc42 inhibition, the filopodia is greatly reduced. Moreover, small GTPases Cdc42 rather than Rac1 and Rho directly controls the filopodia formation. Our work highlights that low shear stress and Cdc42 activation are sufficient to promote filopodia formation, it not only points out the novel structure for cancer progression but also provides the experimental physical basis for the efficient drug anti-cancer strategies.

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