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1.
Protein Pept Lett ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34791998

RESUMO

The organism responds to a decrease in temperature by producing a series of cold shock proteins (CSPs). These proteins play a critical role in growing and functioning characteristic at low temperatures. CSPs have been discovered in a wide range of organisms and show enormous diversity; their mechanisms of action are also complicated. Transcription and translation in microorganisms typically occur via a single linear chain, but upon exposure to low temperatures, RNA forms a complex secondary structure that prevents ribosomes from binding to it, slowing down translation. CSPs bind to mRNA as RNA molecular chaperones to keep the mRNA secondary structure in a single-stranded linear conformation, allowing successful translation at low temperatures.

2.
Transl Vis Sci Technol ; 10(13): 10, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34751744

RESUMO

Purpose: The purpose of this study was to engineer deep learning (DL) models that can identify myopic maculopathy in patients with high myopia based on optical coherence tomography (OCT) images. Methods: An artificial intelligence (AI) system was developed using 2342 qualified OCT macular images from 1041 patients with pathologic myopia admitted to the Affiliated Eye Hospital of Wenzhou Medical University (WMU). We adopted an ResNeSt101 architecture to train five independent models to identify the following five myopic maculopathies: macular choroidal thinning, macular Bruch membrane (BM) defects, subretinal hyper-reflective material (SHRM), myopic traction maculopathy (MTM), and dome-shaped macula (DSM). We tested the models with an independent test dataset that included 450 images obtained from 297 patients with high myopia. Focal loss was used to address class imbalance, and optimal operating thresholds were determined according to the Youden Index. The performance was quantified using the area under the receiver operating characteristic (AUC), sensitivity, specificity, and confusion matrix. Results: For the identification of myopic maculopathy, the AUCs of receiver operating characteristic (ROC) curves were 0.927 to 0.974 for 5 myopic maculopathies. Our AI system achieved sensitivities equal to or even better than those of junior retinal specialists (56.16-99.73%). The diagnosis of it is also interpretable that we provide visual explanations clearly via heatmaps. Conclusions: We developed a convolutional neural network (CNN)-based DL AI system for detection and classification of myopic maculopathy in patients with high myopia using OCT macular images. Our AI system achieved sensitivities equal to or even better than those of junior retinal specialists. Translational Relevance: This AI system can be widely applied in sophisticated situations in large-scale high myopia screening.

4.
Diabetes ; 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34810178

RESUMO

GRP75, defined as a major component of both mitochondrial quality control system and mitochondria-associated membrane, plays a key role in mitochondrial homeostasis. In this study, we assessed the roles of GRP75, other than as a component, in insulin action in both in vitro and in vivo models with insulin resistance. We found that GRP75 was downregulated in HFD-fed mice, and induction of Grp75 in mice could prevent HFD induced obesity and insulin resistance. Mechanistically, GRP75 influenced insulin sensitivity by regulating mitochondrial function through its modulation of mitochondrial-supercomplex turnover rather than MAM communication: GRP75 was negatively associated with respiratory-chain complex activity and was essential for mitochondrial-supercomplex assembly and stabilization. Moreover, mitochondrial dysfunction in Grp75-knockdown cells might further increase mitochondrial fragmentation, thus trigger cytosolic mitochondrial DNA release and activate the cGAS/STING-dependent pro-inflammatory response. Therefore, GRP75 can serve as a potential therapeutic target of insulin resistant-related diabetes or other metabolic diseases.

5.
Ophthalmol Ther ; 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34778916

RESUMO

INTRODUCTION: To evaluate and compare the efficacy and safety of YAG laser vitreolysis in treating symptomatic vitreous floaters of complete posterior vitreous detachment (PVD) and non-PVD. METHODS: In this prospective cohort study, 51 eyes with symptomatic floaters were treated with YAG laser vitreolysis. Participants were divided into complete PVD and non-PVD groups. Objective visual quality measures including the Strehl ratio (SR), internal spherical aberration (SA), internal comatic aberration (CA), internal high-order aberration (HOA), area ratio of modulation transfer function (MTFa) and Vitreous Floaters Symptom Questionnaire (VFSQ-13) scores were used to compare the efficacy of YAG laser vitreolysis treatment between two groups. RESULTS: The mean age of all patients was 56.80 ± 10.82 years old. In total, 36 of 51 (70.59%; 95% CI 58.10-83.10) patients reported their symptoms as significant or complete improvement after YAG laser vitreolysis treatment. Post-treatment MTFa, internal SA and internal HOA were significantly better compared to baseline (26.19 ± 14.73 vs. 29.19 ± 17.98, p = 0.013; 0.05 ± 0.05 vs. 0.04 ± 0.04, p = 0.031 and 0.23 ± 0.22 vs. 0.16 ± 0.07, p = 0.044; respectively) in all eyes. Twenty-nine of 51 (56.86%) eyes had floaters of non-PVD type. Significant or complete subjective improvements in the PVD group and non-PVD group were 72.73% and 68.97% (p = 0.344), respectively. CONCLUSIONS: Improved subjective and objective visual quality in participants with symptomatic floaters following YAG laser vitreolysis was found in both groups. The efficacy of YAG laser vitreolysis was comparable in floaters of complete PVD and non-PVD types.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34648167

RESUMO

There are a large number of active cold-adapted microorganisms in the perennial cold environment. Due to their high-efficiency and energy-saving catalytic properties, cold-adapted microorganisms have become valuable natural resources with potential in various biological fields. In this study, a series of cold response strategies for microorganisms were summarized. This mainly involves the regulation of cell membrane fluidity, synthesis of cold adaptation proteins, regulators and metabolic changes, energy supply, and reactive oxygen species. Also, the potential of biocatalysts produced by cold-adapted microorganisms including cold-active enzymes, ice-binding proteins, polyhydroxyalkanoates, and surfactants was introduced, which provided a guidance for expanding its application values. Overall, new insights were obtained on response strategies of microorganisms to cold environments in this review. This will deepen the understanding of the cold tolerance mechanism of cold-adapted microorganisms, thus promoting the establishment and application of low-temperature biotechnology.

7.
BMC Ophthalmol ; 21(1): 369, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663240

RESUMO

BACKGROUND: The pathogenesis of myopia has been found to be associated with the blood supply of the choroid. This study aimed to determine the relationship between the distribution pattern of choroidal remodeling and the degree of myopia in young patients. METHODS: Young patients (age < 18 years) with the spherical equivalent of less than - 12 diopters (D) were included. Spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging (EDI) modality was used to measure the choroidal thickness (CT) and choroidal vascularity index (CVI) in the macular regions. CVI was calculated as the proportion of luminal area to choroidal area and was measured within 1 mm and 3 mm nasal (N1 and N3), temporal (T1 and T3), superior (S1 and S3), and inferior (I1 and I3) to the foveal center. CVI was compared across different ages (i.e., 5 ~ 9 years, 10 ~ 13 years, and 14 ~ 18 years), axial lengths (ALs) (i.e., 21.00 ~ 25.00 mm and 25.01 ~ 29.00 mm), and spherical equivalents (SEs) (i.e., SE > -0.5D, - 0.5 ~ - 3.0D, - 3.01 ~ - 6.0D, and < - 6.0D). Linear regression analysis was applied to assess the association between independent (i.e., age, AL, SE, and intraocular pressure) and dependent variables (i.e., CVI of different regions). RESULTS: One hundred sixty-four eyes from 85 volunteers were included. The mean CT in the central foveal was 269.87 ± 63.32 µm (93.00 µm to 443.00 µm). The mean subfoveal-CVI was 67.66 ± 2.40% (57.84 to 79.60%). Multiple linear regression results revealed significant correlations between SE and T1-CVI (p < 0.05, r2 = 0.082, ß = 0.194), N1-CVI (p < 0.05, r2 = 0.039, ß = 0.212). Simple linear regression results revealed that T1-CVI (p < 0.05, r2 = 0.09) and T3-CVI (p < 0.05, r2 = 0.05) were negatively correlated with SE; N1-CVI (p < 0.05, r2 = 0.05) and N3-CVI (p < 0.05, r2 = 0.04) were negatively correlated with SE. CONCLUSIONS: CVI in the horizontal meridian underwent the largest change as myopia worsened. Temporal and nasal CVIs within the r = 1 mm, and r = 3 mm subfoveal range were positively associated with the degree of myopia in young patients. The CVI value may be used to assess the vascular status of the choroid and be a potential marker of myopic progression.


Assuntos
Corioide , Miopia , Adolescente , China/epidemiologia , Humanos , Estudos Retrospectivos , Tomografia de Coerência Óptica
9.
Am J Clin Pathol ; 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34698344

RESUMO

OBJECTIVES: Determining mitochondrial DNA (mtDNA) A-to-G substitution at nucleotide 3243 (m.3243A>G) heteroplasmy is essential for both precision diagnosis of m.3243A>G-associated mitochondrial disease and genetic counseling. Precise determination of m.3243A>G heteroplasmy is challenging, however, without appropriate strategies to accommodate heteroplasmic levels ranging from 1% to 100% in samples carrying thousands to millions of mtDNA copies. METHODS: We used a combined strategy of amplification-refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR) and droplet digital PCR (ddPCR) to determine m.3243A>G heteroplasmy. Primers were specifically designed and screened for both ARMS-qPCR and ddPCR to determine m.3243A>G heteroplasmy. An optimized ARMS-qPCR-ddPCR-based strategy was established using artificial standards, with different mixtures of m.3243A-containing and m.3243G-containing plasmids and further tested using clinical samples containing the m.3243A>G mutation. RESULTS: One of 20 primer pairs designed in the study was omitted for ARMS-qPCR-ddPCR strategy application according to criteria of 85% to 110%, R2  > 0.98 amplification efficiency, melt curve with a single clear peak, and specificity for m.3243A and m.3243G artificial standards (|CtWt-CtMut|max). Using plasmid standards with various m.3243A>G heteroplasmy (1%-100%) at low, mid, and high copy numbers (3,000, 104, and 105-107, respectively) and DNA from the blood of 20 patients carrying m.3243A>G with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, we found that ARMS-qPCR was reliable for determining m.3243A>G at 3% to 100% for low copy number and 1% to 100% for mid to high copy number samples. Meanwhile, ddPCR was reliable for determining m.3243A>G at 1% to 100% at low to mid copy number samples. CONCLUSIONS: An ARMS-qPCR-ddPCR-based strategy was successfully established for precise determination of m.3243A>G heteroplasmy in complex clinical samples.

10.
Cell Metab ; 33(10): 2059-2075.e10, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34536344

RESUMO

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.

11.
Int J Ophthalmol ; 14(8): 1205-1212, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34414085

RESUMO

AIM: To analyse macular microvascular alterations in myopic choroidal neovascularization (mCNV) and the efficiency of anti-vascular endothelial growth factor (anti-VEGF) therapy for mCNV by optical coherence tomography angiography (OCTA). METHODS: A total of 123 patients were included in this retrospective study, divided into mCNV group, high myopia (HM) group, and normal group at the Affiliated Eye Hospital of Wenzhou Medical University from January 2017 to January 2019. Superficial vessel density, deep capillary density, foveal avascular zone (FAZ) area, A-circularity index (AI) and vessel density around the 300 µm width of the FAZ region density (FD) and the area of choroidal neovascularization (CNV) lesion (only for mCNV group) were measured on 3×3 mm2 OCTA images. FAZ area was corrected for axial length. Central macular thickness (CMT) was measured on OCT in mCNV group. Compared the parameters on OCTA of 3 groups and pre-anti-VEGF and post-anti-VEGF at 1, 2, 3, and 6mo follow-up in mCNV group. RESULTS: There were significant differences among 3 groups in superficial vessel density, deep capillary density and FD (P<0.05). FAZ area in HM group was smaller than normal group (P<0.05), but there was no significant difference between mCNV group and the other two group. AI increased in mCNV group (P<0.05). The mean CMT, area and flow area of CNV lesion decreased after treatment (P<0.05), while vessel density and FAZ didn't change. The mean CMT, area and flow area of CNV lesion statistically decreased after anti-VEGF treatment in mCNV group (P<0.05), while superficial vessel density, deep capillary density and FAZ area, AI and FD didn't change. The mean reduction ratio of lesions was 50.32% (7.07% to 100%). Lesion regression 100% was observed in 2 cases (4.88%). There was a negative correlation between the CNV lesion area and reduction ratio (r=-0.380, P=0.042) and the flow lesion area and reduction ratio (r=-0.402, P=0.030). CONCLUSION: Macular vessel density decreases, FAZ turns smaller and more irregular in mCNV eyes. Anti-VEGF therapy is efficient for mCNV without affecting vessel density and FAZ, but it is unable to completely eliminate CNV lesions in most cases. The bigger mCNV lesions have lower reduction ratio.

12.
Acta Ophthalmol ; 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34403203

RESUMO

PURPOSE: In eyes with diabetic macular oedema (DME), aqueous humour (AH) cytokine levels before and after anti-vascular endothelial growth factor (VEGF) treatment were compared and correlated with optical coherence tomography structural parameters. METHODS: This prospective study included 56 control patients with cataracts and 83 patients with DME manifesting as diffuse retinal thickening (DRT), cystoid macular oedema and serous retinal detachment (SRD). AH samples were obtained before intravitreal injection of anti-VEGF or cataract surgery. VEGF, interleukin (IL)-6, IL-8, IL-10, interferon-inducible protein 10 (IP-10) and monocyte chemotactic protein 1 (MCP-1) levels were measured by multiplex bead assay. AH cytokine levels, central macular thickness (CMT), number of hyper-reflective foci (HF), continuity of external limiting membrane and ellipsoid zone (EZ) and best-corrected visual acuity were evaluated. RESULTS: In SRD, IL-6 and MCP-1 levels and HF were increased (all p < 0.05) compared to DRT. At baseline, the number of HF was correlated with VEGF, IL-6, IL-8, IP-10 and MCP-1 (all p < 0.05). Eyes sensitive to anti-VEGF treatment had high baseline levels of VEGF, MCP-1, HF and many EZ disruptions (all p < 0.05). DME patients with normal VEGF levels but with high levels of IL-8, IP-10 and MCP-1 (all p < 0.05) had little change in CMT after anti-VEGF treatment (p = 0.678). CONCLUSIONS: AH concentrations of some inflammatory cytokines in DME were differentially expressed among the three DME morphologies. HF was associated with VEGF and other inflammatory cytokine levels. Multiple HF at baseline predicted a significant decrease in CMT, and eyes with normal VEGF but increased inflammatory cytokines may be insensitive to anti-VEGF treatment.

14.
PLoS Med ; 18(8): e1003741, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34464382

RESUMO

BACKGROUND: For locally advanced rectal cancer (LARC) patients who receive neoadjuvant chemoradiotherapy (nCRT), there are no reliable indicators to accurately predict pathological complete response (pCR) before surgery. For patients with clinical complete response (cCR), a "Watch and Wait" (W&W) approach can be adopted to improve quality of life. However, W&W approach may increase the recurrence risk in patients who are judged to be cCR but have minimal residual disease (MRD). Magnetic resonance imaging (MRI) is a major tool to evaluate response to nCRT; however, its ability to predict pCR needs to be improved. In this prospective cohort study, we explored the value of circulating tumor DNA (ctDNA) in combination with MRI in the prediction of pCR before surgery and investigated the utility of ctDNA in risk stratification and prognostic prediction for patients undergoing nCRT and total mesorectal excision (TME). METHODS AND FINDINGS: We recruited 119 Chinese LARC patients (cT3-4/N0-2/M0; median age of 57; 85 males) who were treated with nCRT plus TME at Fudan University Shanghai Cancer Center (China) from February 7, 2016 to October 31, 2017. Plasma samples at baseline, during nCRT, and after surgery were collected. A total of 531 plasma samples were collected and subjected to deep targeted panel sequencing of 422 cancer-related genes. The association among ctDNA status, treatment response, and prognosis was analyzed. The performance of ctDNA alone, MRI alone, and combining ctDNA with MRI was evaluated for their ability to predict pCR/non-pCR. Ranging from complete tumor regression (pathological tumor regression grade 0; pTRG0) to poor regression (pTRG3), the ctDNA clearance rate during nCRT showed a significant decreasing trend (95.7%, 77.8%, 71.1%, and 66.7% in pTRG 0, 1, 2, and 3 groups, respectively, P = 0.008), while the detection rate of acquired mutations in ctDNA showed an increasing trend (3.8%, 8.3%, 19.2%, and 23.1% in pTRG 0, 1, 2, and 3 groups, respectively, P = 0.02). Univariable logistic regression showed that ctDNA clearance was associated with a low probability of non-pCR (odds ratio = 0.11, 95% confidence interval [95% CI] = 0.01 to 0.6, P = 0.04). A risk score predictive model, which incorporated both ctDNA (i.e., features of baseline ctDNA, ctDNA clearance, and acquired mutation status) and MRI tumor regression grade (mrTRG), was developed and demonstrated improved performance in predicting pCR/non-pCR (area under the curve [AUC] = 0.886, 95% CI = 0.810 to 0.962) compared with models derived from only ctDNA (AUC = 0.818, 95% CI = 0.725 to 0.912) or only mrTRG (AUC = 0.729, 95% CI = 0.641 to 0.816). The detection of potential colorectal cancer (CRC) driver genes in ctDNA after nCRT indicated a significantly worse recurrence-free survival (RFS) (hazard ratio [HR] = 9.29, 95% CI = 3.74 to 23.10, P < 0.001). Patients with detectable driver mutations and positive high-risk feature (HR_feature) after surgery had the highest recurrence risk (HR = 90.29, 95% CI = 17.01 to 479.26, P < 0.001). Limitations include relatively small sample size, lack of independent external validation, no serial ctDNA testing after surgery, and a relatively short follow-up period. CONCLUSIONS: The model combining ctDNA and MRI improved the predictive performance compared with the models derived from individual information, and combining ctDNA with HR_feature can stratify patients with a high risk of recurrence. Therefore, ctDNA can supplement MRI to better predict nCRT response, and it could potentially help patient selection for nonoperative management and guide the treatment strategy for those with different recurrence risks.


Assuntos
DNA Tumoral Circulante/uso terapêutico , Terapia Neoadjuvante/estatística & dados numéricos , Neoplasias Retais/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Neoplasias Retais/diagnóstico , Resultado do Tratamento
15.
Am J Transl Res ; 13(6): 5985-6000, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34306339

RESUMO

In vitro cell experiments showed that knocking out the placenta-specific protein 8 (PLAC8) gene significantly increased the sensitivity of tumor cells to radiation. This study used two nude mouse models of nasopharyngeal carcinoma (NPC) to investigate the radio-sensitization and molecular mechanism of PLAC8 knockout in vivo. The expression of PLAC8 in 120 NPC tissues and 30 nasopharyngitis (NPG) tissues was detected by immunohistochemistry (IHC) to analyze the relationship between PLAC8 and neck lymph node metastasis and prognosis in NPC patients. The mRNA expression level of PLAC8 in several NPC cell lines was detected by semi-quantitative RT-PCR. The PLAC8 gene was knocked out in CNE-2 cells using CRISPR/Cas9. The effect of PLAC8 gene knockout on the radiotherapy sensitivity of NPC cells was analyzed by establishing model 1 and model 2 tumor-bearing nude mouse models with two different irradiation methods. The expression of γH2AX, Bax, Bcl-2, Caspase-3 and cleaved Caspase-3 was detected by immunofluorescence (IF), IHC and western blot analysis. PLAC8 expression was significantly increased in NPC tissue samples and NPC cell lines compared with NPG tissue samples and normal cell lines (P<0.01). PLAC8 upregulation was associated with lymph node metastasis and a poor prognosis in patients with NPC (P<0.01). Both animal models showed that radiotherapy after PLAC8 knockout significantly slowed tumor growth and reduced tumor volume, with tumor inhibition rates of 100% and 66.04%, respectively. In model 2, PLAC8 knockout with radiotherapy increased the expressions of γH2AX, Bax, Caspase-3 and cleaved Caspase-3 but decreased the expression of Bcl-2 (P<0.01). In model 1, there was no tumor formation at the site where the cancer cells were injected. The expression levels of γH2AX, Bax, Caspase-3 and cleaved Caspase-3 in skin tissues taken at the injection site were lower than those in NPC tissues treated with radiotherapy, while the expression level of Bcl-2 was higher (P<0.01). PLAC8 expression is closely related to neck metastasis and the prognosis of NPC. PLAC8 gene knockout significantly increases the radio-sensitivity of NPC cells in vivo by promoting apoptosis, which is an effective strategy for the radiotherapy sensitization of NPC.

16.
Am J Transl Res ; 13(6): 6191-6199, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34306358

RESUMO

The aim of this study was to evaluate factors affecting the recurrence of positive RT-PCR results. By performing a retrospective analysis, we evaluated the clinical data of recurrent positive coronavirus disease 2019 (COVID-19) patients in multiple medical institutions in Wuhan. We recruited COVID-19 patients who were hospitalized from January 1 to March 10, 2020, in three tertiary hospitals in Wuhan, met the discharge criteria and received at least one additional nucleic acid test before leaving the hospital. According to the RT-PCR results, patients were split into a recurrent positive group (RPos group) and a nonrecurrent positive group (non-RPos group). Clinical characteristics, therapeutic schedules and antibody titers were compared between the two groups. AI-assisted chest high-resolution computed tomography (HRCT) technology was applied to investigate pulmonary inflammatory exudation and compare the extent of lung areas with different densities. This study involved 122 COVID-19 patients. There were no significant differences in age, sex, preexisting diseases, clinical symptoms, clinical classification, course of disease, therapeutic schedules or serum-specific antibodies between the two groups. A higher proportion of patients who showed pulmonary inflammatory exudation on HRCT scans were recurrent positive at the time of discharge than other patients (81.6% vs 13.7%, P < 0.01). In addition, the degree of pulmonary fibrosis was higher in the RPos group than in the non-RPos group (P < 0.05). Subpleural exudation at the peripheral edge of the lung and extensive pulmonary fibrosis at the time of discharge represent risk factors for the recurrence of COVID-19.

17.
Front Oncol ; 11: 715193, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249768

RESUMO

The MDM2 binding protein (MTBP) has been considered an important regulator of human malignancies. In this study, we demonstrate that the high level of MTBP's endogenous expression is correlated with poor prognosis of advanced hepatocellular carcinoma (HCC) patients who received sorafenib. MTBP interacted with the Pregnane X receptor (PXR) and enhanced the transcription factor activity of PXR. Moreover, MTBP enhanced the accumulation of PXR in HCC cells' nuclear and the recruitment of PXR to its downstream gene's (cyp3a4's) promoter region. Mechanically, the knockdown of MTBP in MHCC97-H cells with high levels of MTBP decelerated the clearance or metabolism of sorafenib in HCC cells and led to the resistance of HCC cells to sorafenib. Whereas overexpression of MTBP in in MHCC97-L cells with low levels of MTBP showed the opposite trend. By establishing the interaction between MTBP and PXR, our results indicate that MTBP could function as a co-activator of PXR and could be a promising therapeutic target to enhance the sensitivity of HCC cells to molecular targeting agents.

18.
Bioengineered ; 12(1): 3398-3409, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34224316

RESUMO

Our previous study found that in nasopharyngeal carcinoma (NPC) cells, overexpression of Notch2 can inhibit epithelial-mesenchymal transition (EMT), which plays a vital role in mediating radiosensitivity. The purpose of this study was to explore the radiosensitizing efficacy of the Notch2 gene in NPC cells and its potential mechanism. We used the recombinant plasmid transfection technique to establish Notch2-overexpressing 5-8 F and CNE-2 NPC cells. Cell proliferation, radiosensitivity, apoptosis and cell cycle distribution were assessed by cell counting kit-8 (CCK-8) experiments, colony formation experiments and flow cytometry. The levels of proteins related to cell cycle, apoptosis, and the AKT/mTOR signaling pathway were evaluated by using Western blotting. The results suggested that Notch2 overexpression increased the radiosensitivity of NPC cells, with sensitizing enhancement ratios (SERs) of 1.24 (5-8 F cells) and 1.34 (CNE-2 cells). Flow cytometry indicated that the level of apoptosis and percentage of cells in G2/M-phase were highest in NPC cells overexpressing Notch2 and treated with radiotherapy compared to cells overexpressing Notch2 alone or administered radiotherapy alone. Western blotting showed that compared to that of cells treated with Notch2 overexpression or radiotherapy alone, the levels of γH2AX, Bax, Bcl-2, Cyclin D1 and AKT/mTOR signaling pathway-related proteins were modified in NPC cells overexpressing Notch2 and treated with radiotherapy. These findings showed that overexpression of Notch2 can increase the radiosensitivity of NPC cells by inhibiting the AKT/mTOR pathway.AbbreviationsNPC: Nasopharyngeal carcinoma; EMT: Epithelial-mesenchymal transition; CCK8: Cell counting kit-8; EBV: Epstein-Barr virus; FBS: Fetal bovine serum; PE: Plating efficiency; SF: Survival fraction; SER: Sensitizing enhancement ratio; DSBs: DNA double-strand breaks[Figure: see text].

19.
Reprod Toxicol ; 104: 1-7, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34166781

RESUMO

Mesenchymal cell proliferation is critical for the growth of the palate shelf. All-trans retinoic acid (atRA), as well as pathways associated with TGF-ß/Smad signaling, play crucial roles in the proliferation of mouse embryonic palate mesenchymal (MEPM) cells. We have found that MEPM-cell proliferation was regulated by atRA and exogenous TGF-ß3 could significantly antagonize the atRA-mediated suppression of MEPM cell proliferation, which is closely associated with the regulation of TGF-ß/Smad signaling pathway. The long non-coding RNA (lncRNA) MEG3 has been reported to activate TGF-ß/Smad signaling, thereby regulating cellular proliferation, differentiation, and related processes. Here, we found that Meg3 expression increased significantly in atRA-treated MEPM cells while TGF-ß3 treatment markedly inhibited Meg3 expression and antagonized the effect of atRA on Meg3. Moreover, Smad2 was found to interact directly with Meg3, and atRA treatment significantly enriched Meg3 in Smad2-immunoprecipitated samples. After Meg3 deletion, the effects of atRA on the proliferation of MEPM cells and TGF-ß3-dependent protein expression were lost. Hence, we speculate that Meg3 has a role in the RA-induced suppression of MEPM cell proliferation by targeting Smad2 and thereby mediating TGF-ß/Smad signaling inhibition.

20.
Int J Ophthalmol ; 14(6): 875-880, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34150543

RESUMO

AIM: To observe whether silicone oil (SO) tamponade could decrease macular perfusion after retinal detachment repair. METHODS: A prospective observational case-control study. Patients diagnosed with primary macular off rhegmatogenous retinal detachment undergoing successful retinal repair surgery with vitrectomy were strictly selected. Optical coherence tomography angiography findings were compared between SO and air tamponade groups. Two postoperative visiting points were set (1 and 3mo). RESULTS: Totally 29 patients (29 eyes) were enrolled. Twenty cases had SO tamponade while 9 cases were with air tamponade. At the first visiting point, superficial parafoveal vessel density (PFSVD) significantly decreased in the SO group (P=0.0403), especially in the superior quadrant or superior-hemi area (P=0.0089, 0.0426, respectively). Parafoveal deep vessel density (PFDVD) had no difference between the two groups. At the second visiting point, all quadrants of PFSVD reduced significantly in the SO group (P=0.0256, 0.0001, 0.0031, <0.0001 in temporal, superior, nasal, and inferior area, respectively), but PFDVD remained no different. In the air group, all areas of PFSVD showed significantly improving from the first visit to the second one (P=0.0324, 0.0001, 0.0371, 0.0026, in temporal, superior, nasal, and inferior area, respectively); however, almost all quadrants of PFDVD showed no changes during this period. In the SO group, both PFSVD and PFDVD showed no obvious changes between the two visiting points. Besides, parafoveal full retinal thickness in the SO group reduced significantly at both visiting points over the air tamponade, while the foveal avascular zone area showed no difference in the two groups. CONCLUSION: After retinal detachment surgery with vitrectomy and SO tamponade, superficial macular perfusion and full retinal thickness could decrease obviously when compared to air tamponade. This reduction process could persist throughout the tamponade period.

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