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1.
PLoS One ; 14(10): e0223430, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31584978

RESUMO

Influenza virus causes a heterogeneous respiratory infectious disease ranging from self-limiting symptoms to non-resolving pathology in the lungs. Worldwide, seasonal influenza infections claim ~500,000 lives annually. Recent reports describe pathologic pulmonary sequelae that result in remodeling the architecture of lung parenchyma following respiratory infections. These dysfunctional recovery processes that disproportionately impact the elderly have been understudied. Macrophages are involved in tissue remodeling and are critical for survival of severe influenza infection. Here, we found intrinsic deficiency of the nuclear receptor PPAR-γ in myeloid cells delayed the resolution of pulmonary inflammation following influenza infection. Mice with myeloid cell-specific PPAR-γ deficiency subsequently presented with increased influenza-induced deposition of pulmonary collagen compared to control mice. This dysfunctional lung remodeling was progressive and sustained for at least 3 months following infection of mice with myeloid PPAR-γ deficiency. These progressive changes were accompanied by a pro-fibrotic gene signature from lung macrophages and preceded by deficiencies in activation of genes involved with damage repair. Importantly similar aberrant gene expression patterns were also found in a secondary analysis of a study where macrophages were isolated from patients with fibrotic interstitial lung disease. Quite unexpectedly, mice with PPAR-γ deficient macrophages were more resistant to bleomycin-induced weight loss whereas extracellular matrix deposition was unaffected compared to controls. Therefore PPAR-γ expression in macrophages may be a pathogen-specific limiter of organ recovery rather than a ubiquitous effector pathway in response to generic damage.

2.
Chemistry ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31585022

RESUMO

Chiral α,α-difluoromethyl carbinols are recurring structural motifs in many therapeutic agents. Despite the indubitable interest in the catalytic asymmetric synthesis of such compounds, this research field still remains largely underexplored. Herein, an efficient approach to a range of chiral homopropargylic α,α-difluoromethyl carbinols has been developed, via a Cu-catalyzed enantioselective propargylation of α,α-difluoroketones with (pinacolato)allenylboron. In the presence of an cuprous complex, generated in-situ from CuCl and a spiroketal-based diphosphine (SKP) ligand, a variety of aryl-, heteroaryl-, alkyl-, alkynyl, alkenyl or benzyloxycarbonyl-substituted α,α-difluoromethyl carbinols were obtained in 75-99% yields with 84-98% ee values. The catalytic system was further investigated using a combined dynamic NMR spectroscopic, X-ray crystallographic, and non-linear effect studies. The origin of the enantioselection was rationalized based on DFT calculations. Finally, several efficient transformations were showcased to highlight the utilities of the protocol in synthesis of complex compounds bearing a α,α-difluoromethyl carbinol moiety.

3.
Parasit Vectors ; 12(1): 464, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31585545

RESUMO

BACKGROUND: Bluetongue disease of ruminants is a typical insect-borne disease caused by bluetongue virus (BTV) of the genus Orbivirus (family Reoviridae) and transmitted by some species of Culicoides (Diptera: Ceratopogonidae). Recently, the detection of BTV in yaks in high altitude meadows of the Shangri-La district of Yunnan Province, China, prompted an investigation of the Culicoides fauna as potential vectors of BTV. METHODS: A total of 806 Culicoides midges were collected by light trapping at three sites at altitudes ranging from 1800 to 3300 m. The species were identified based on morphology and the DNA sequences of cytochrome c oxidase subunit 1 (cox1). PCR and quantitative PCR following reverse transcription were used to test for the presence of BTV RNA in Culicoides spp. A phylogenetic analysis was used to analyze the cox1 sequences of some specimens. RESULTS: Four species dominated these collections and cox1 barcoding revealed that at least two of these appear to belong to species new to science. Culicoides tainanus and a cryptic species morphologically similar to C. tainanus dominated low altitude valley collections while C. nielamensis was the most abundant species in the high-altitude meadow. A species related to C. obsoletus occurred at all altitudes but did not dominate any of the collections. BTV RT-qPCR analysis detected BTV RNA in two specimens of C. tainanus, in one specimen closely related to C. tainanus and in one specimen closely related to C. obsoletus by barcode sequencing. CONCLUSIONS: This study suggests that BTV in high altitude areas of Yunnan is being transmitted by three species of Culicoides, two of which appear to be new to science. This research may be useful in improving understanding of the effects of global warming on arboviral disease epidemiology and further study is important in research into disease control and prevention.

4.
J Cell Physiol ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566711

RESUMO

Several studies have shown that low expression of epoxide hydrolase 1 (EPHX1) is closely associated with varying human cancers, including hepatocellular carcinoma (HCC). This study aims to explore the potential mechanism of EPHX1 silencing and revealed a novel regulatory pathway in the pathogenesis of HCC. In this study, micro ribonucleic acid (miR)-184 was predicted and validated to be a regulator of EPHX1 through experiments, and its expression was negatively correlated with the messenger RNA (mRNA) levels of EPHX1 in primary tumors. Elevation of EPHX1 suppressed cell proliferation and migration as well as cell cycle progression, and induced apoptosis, while downregulation of miR-184 exhibited the opposite effect on cellular processes. Moreover, LINC00205 interacted with miR-184 and was markedly downregulated in tumors. The effects of the miR-184 inhibitor on cell proliferation, apoptosis, and migration were reversed in part by the transfection with LINC00205 small interfering RNAs. In addition, LINC00205 acted as a molecular sponge to positively regulate the mRNA and protein levels of EPHX1 via regulating miR-184. The tumorigenicity of HCC cells was enhanced by LINC00205 shRNA but diminished by overexpression of EPHX1 in vivo. Clinically, the EPHX1 expression in patients with HCC was markedly downregulated. Taken together, the results of this study suggest that as a competing endogenous RNA, LINC00205 may regulate EPHX1 by inhibiting miR-184 in the progression of HCC and that targeting the LINC00205/miR-184/EPHX1 axis may provide a treatment protocol for patients.

5.
Theranostics ; 9(22): 6424-6442, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588227

RESUMO

Atherosclerosis is the main pathological basis of ischemic cardiovascular and cerebrovascular diseases and has attracted more attention in recent years. Multiple studies have demonstrated that the signal transducer and activator of transcription 3 (STAT3) plays essential roles in the process of atherosclerosis. Moreover, aberrant STAT3 activation has been shown to contribute to the occurrence and development of atherosclerosis. Therefore, the study of STAT3 inhibitors has gradually become a focal research topic. In this review, we describe the crucial roles of STAT3 in endothelial cell dysfunction, macrophage polarization, inflammation, and immunity during atherosclerosis. STAT3 in mitochondria is mentioned as well. Then, we present a summary and classification of STAT3 inhibitors, which could offer potential treatment strategies for atherosclerosis. Furthermore, we enumerate some of the problems that have interfered with the development of mature therapies utilizing STAT3 inhibitors to treat atherosclerosis. Finally, we propose ideas that may help to solve these problems to some extent. Collectively, this review may be useful for developing future STAT3 inhibitor therapies for atherosclerosis.

6.
Nat Neurosci ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591560

RESUMO

Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.

7.
Nano Lett ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31594301

RESUMO

Nanoscale photodynamic therapy (PDT) is an appealing antitumor modality for which apoptosis is the major mechanism of toxicity induction. It was postulated that the highly reactive singlet oxygen in PDT could deplete glutathione (GSH) and activate ferroptosis, the extent to which could be further manipulated by a redox-responsive nanocarrier. To validate this, a disulfide-bearing imidazole ligand coordinated with zinc to form an all-active metal organic framework (MOF) nanocarrier where a photosensitizer (chlorin e6/Ce6) was encapsulated. Regardless of light irradiation, the Ce6-loaded nanocarrier caused the depletion of intracellular GSH via the disulfide-thiol exchange reaction in a murine mammary carcinoma cell line (4T1). The GSH depletion further caused the inactivation of glutathione peroxide 4 (GPX4) and the enhancement of cytotoxicity that was alleviated by ferroptosis inhibitors. The superior in vivo antitumor efficacy of the all-active nanocarrier was corroborated in a 4T1 tumor-bearing mice model regarding tumor growth suppression and animal survival rate. The coadministration of an iron chelator weakened the antitumor potency of the nanocarrier due to ferroptosis inhibition, which was supported by the fact of tumor growth upsurge and the recovered GPX4 activity. The current work highlights the contribution of ferroptotic machinery to antitumor PDT via an activatable, adaptable, all-active MOF nanocarrier.

8.
Rev Cardiovasc Med ; 20(3): 187-197, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601093

RESUMO

Myocardial ischemia-reperfusion (I/R) injury is leading cause of death worldwide. miR-34a-5p was up-regulated in myocardial ischemia-reperfusion injury rats. We aim to explore how miR-34a-5p inhibition protected myocardium against I/R injury in both cell and animal models. In vivo rat and in vitro cell model were firstly constructed. quantitative real-time polymerase chain reaction was employed to investigate expression of miR-34a-5p and its target genes. Functional assays were conducted to detect the impact of miR-34a-5p on myocardial I/R injury. Enzyme-linked immunosorbent assay was performed to validate the expression levels of marker proteins of ischemia-reperfusion I/R-induced myocardial injury. MTT was performed to assess the cell viability and flow cytometry was utilized to detect cell apoptosis and reactive oxygen species accumulation. The interaction between miR-34a-5p and Notch Receptor 1 were also examined through luciferase reporter assay. miR-34a-5p was up-regulated post-reperfusion at rat myocardium. miR-34a-5p inhibitor attenuated myocardial ischemia-reperfusion injury, as shown by decreasing apoptosis rate, reducing infarct size and reactive oxygen species accumulation. In in vitro cell model, miR-34a-5p inhibitor also promoted cell proliferation, inhibited cell apoptosis and reactive oxygen species accumulation through targeting Notch Receptor 1 signaling. Our results revealed that miR-34a-5p knocking down attenuated myocardial I/R injury by promoting Notch Receptor 1 signaling-mediated inhibition of reactive oxygen species accumulation and cell apoptosis. Hence, miR-34a-5p might be a potential target for treatment of myocardial ischemia-reperfusion injury.

9.
Wei Sheng Yan Jiu ; 48(4): 646-650, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31601350

RESUMO

OBJECTIVE: To establish a method for determination of ochratoxin A and ochratoxin alpha in wine by ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS) based on isotopic internal standard method. METHODS: The wine sample was adjusted to pH 9. 0 by 5% ammonia and concentrated by a MAX solid phase extraction cartridge. The UPLC separation was performed on a ACQUITY BEH C_(18) column(100 mm×2. 1 mm, 1. 7 µm)with a isocratic elution program of acetonitrile and 5 mmol/L ammonium acetate as the mobile phase. Electrospray ionization was applied and operated in the positive ion mode. The concentration of wine was quantified by isotope internal standard. RESULTS: The calibration curves were linear in the concentration range of 1. 0-50. 0 µg/L, the coefficients of correlation were 0. 9996 and 0. 9993, respectively. The limits of detection(LODs) of both were 0. 10 µg/kg, and the limits of quantitative were 0. 35 µg/kg. The average recoveries at the spiked levels of 0. 35, 2. 00 and 10. 00 mg/kg were 88. 6%-108. 0%, and the relative standard deviations(RSDs) were 2. 1%-9. 2%, respectively. CONCLUSION: This method is simple, sensitive, accurate and reliable, which is suitable for the determination of ochratoxin A and ochratoxin alpha in wine.

10.
Artif Cells Nanomed Biotechnol ; 47(1): 3929-3937, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31571510

RESUMO

Immune hepatic injury is a liver disease closely related to an immune imbalance of T cells and macrophages. Our previous series of studies have demonstrated that taraxasterol isolated from Taraxacum possesses great anti-inflammatory and immunomodulatory effects in vivo and in vitro. In this study, we explored the preventive effects of taraxasterol and its underlying mechanisms on concanavalin A (Con A)-induced acute hepatic injury in mice. It was found that treatment with taraxasterol significantly decreased the Con A-induced increase of liver index, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and hepatic malondialdehyde (MDA) levels, and increased the Con A-induced decrease of hepatic glutathione (GSH) and superoxide dismutase (SOD) production. Taraxasterol also significantly inhibited the release of pro-inflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, interferon-γ (IFN-γ) and IL-4. In addition, treatment with taraxasterol alleviated the hepatic histopathological injury and apoptosis induced by Con A. Furthermore, taraxasterol dramatically down-regulated the expressions of T toll-like receptor (TLR2), TLR4 and nuclear factor-κappaB (NF-κB) p65, and decreased the expression ratio of Bax/Bc1-2 in hepatic tissues. These findings suggest that taraxasterol prevents Con A-induced acute hepatic injury in mice by inhibiting TLRs/NF-κB inflammatory signalling pathway and promoting Bax/Bc1-2 anti-apoptotic signalling pathway.

11.
Drug Des Devel Ther ; 13: 3269-3280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571829

RESUMO

Purpose: To prepare a novel wound dressing to facilitate cutaneous wound healing. Methods: Curcumin (Cur) was added to the ring-shaped ß-cyclodextrin (CD) to form a ß-CD-Cur inclusion complex (CD-Cur). CD-Cur was then integrated into a composite chitosan-alginate (CA) mix. Finally, CA-CD-Cur was generated with a freeze-drying technique. Water-uptake capacity, degradation rate, and drug-release kinetics of the newly formed dressing were investigated in vitro. In animal studies, cutaneous wounds in rats were created, treated with CA-CD-Cur, then compared to CA-Cur, CA, and gauze. Results: CA-CD-Cur-treated wounds showed accelerated closure rates, improved histopathological results, and lower SOD, lipid peroxidation, pI3K, and pAktkt levels than other groups. On the contrary, catalase, IκBα, and TGFß1 levels were higher than others. Conclusion: CA-CD-Cur may facilitate cutaneous wound dressing that facilitate wound healing.

12.
Clin Cancer Res ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481507

RESUMO

PURPOSE: We aimed to develop a diagnostic platform to capture the transcriptomic resemblance of individual adult diffuse gliomas of WHO grades II-IV to neural development and the genomic signature associated with glioma progression. EXPERIMENTAL DESIGN: Based on the EM/PM classification scheme, we designed a RT-PCR-based TaqMan Low-density array (TLDA) containing 44 classifier and 4 reference genes. Samples of a training data set (GSE48865), characterized by RNA-sequencing, were utilized to optimize the TLDA design and to develop a support vector machine (SVM)-based prediction model. Complemented with Sanger sequencing for IDH1/2, and low coverage whole genome sequencing (WGS), the TLDA and SVM prediction model were tested in a validation (31 gliomas) and a test (121 gliomas) dataset. RESULTS: Independent of morphologically defined subtypes and grades, gliomas can be individually assigned into the EM and PM glioma subtypes with the respective areas under ROC curves at 0.86 and 0.85 in the validation dataset. The EM gliomas showed a medium overall survival (OS) of 15.6 months, whereas the medium OS for PM gliomas was not reached (hazard ratio = 3.55, 95% confidence interval: 1.96 to 6.45). The EM and PM gliomas showed distinct patterns of genomic alterations, with IDH mutation and 1p19q co-deletion in the PM gliomas and gain of chromosome 7/loss of chromosome 10 in the EM gliomas. Extensive chromosomal abnormalities marked the progression of PM gliomas. CONCLUSIONS: The integration of EM/PM subtyping, IDH sequencing and low coverage WGS may improve the risk stratification and selection of treatment regimens for glioma patients.

13.
J Cell Physiol ; 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541468

RESUMO

Triple-negative breast cancer (TNBC) is highly metastatic and frequently has a poor prognosis. The lack of comprehension of TNBC and gene therapy targets has led to limitedly effective treatment for TNBC. This study was conducted to better understand the molecular mechanism behind TNBC progression, and to find out promising gene therapy targets for TNBC. Herein the influence of miR-122-5p's binding charged multivesicular body protein 3 (CHMP3) 3'-untranslated region (3'-UTR) on in TNBC cells was investigated. in vitro experiments quantitative real-time polymerase chain reaction, immunoblot analysis, dual-luciferase reporter gene assay, cell counting assay, transwell invasion assay, and flow cytometry-determined cell apoptosis assay were employed. We also used TargetScan Human 7.2 database to find out the target relationship between miR-122-5p and CHMP3 3'-UTR. TImer algorithm was used to provide an overview of the expression of CHMP3 gene across human pan-cancer, to predict the survival outcome of breast cancer patients, and to predict the correlation between CHMP3 gene expression and epithelial-mesenchymal transition (EMT) and mitogen-activated protein kinase (MAPK)-related gene expression. CHMP3 gene was significantly downregulated across a wide range of human cancers including breast cancer (BRCA). A higher level of CHMP3 gene predicted a better 3- and 5-year survival outcome of patients with BRCA. In our experiments, miR-122-5p was significantly upregulated and CHMP3 gene was significantly downregulated in TNBC cells compared with normal cell line. miR-122-5p mimics enhanced TNBC cell viability, proliferation, and invasion whereas the upregulation of CHMP3 gene led to an opposite outcome. Forced expression of miR-122-5p suppressed cell apoptosis, compelled EMT and MAPK signaling whereas forced expression of CHMP3 did the opposite. We then conclude that miR-122-5p promotes aggression and EMT in TNBC by suppressing CHMP3 through MAPK signaling.

14.
Cancer Sci ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31487418

RESUMO

NOP2/Sun domain family, member 2 (NSUN2) is a nuclear RNA methyl-transferase catalyzing 5-methylcytosine formation. Evidence shows that NSUN2 is correlated with cell unlimited proliferation. However, its functional role in gallbladder carcinoma (GBC), which is the most common biliary tract malignancy and has a poor prognosis, remains to be determined. Here we found that NSUN2 was highly expressed in GBC tissues as well as cell lines. NSUN2 silencing repressed GBC cell proliferation and tumorigenesis both in vitro and in vivo. Conversely, upregulation of NSUN2 enhanced GBC cell growth and colony formation. We further discovered that RPL6 was a closely interacting partner with NSUN2. Silencing RPL6 resulted in insufficient NSUN2 translational level and accumulative NSUN2 transcriptional level. Exogenous expression of NSUN2 partially rescued the effect of RPL6 in gallbladder cancer progression. Taken together, our data provided novel mechanic insights into the function of NSUN2 in GBC, thus pointing to NSUN2 as a potential and effective therapeutic approach to GBC treatment.

15.
J Cardiothorac Surg ; 14(1): 172, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547844

RESUMO

OBJECTIVE: This study aims to discuss the efficacy and safety of the application of thrombus aspiration catheters during emergency PCI operations for acute ST-elevation myocardial infarction (STEMI) patients with high thrombus load. METHODS: A total of 204 patients diagnosed with acute STEMI and high thrombus load in the Sixth Affiliated Hospital of Guangxi Medical University from July 1, 2016 to June 30, 2017 were selected for the present study. These patients were randomly divided into two groups: thrombus catheter aspiration group (group A, n = 101), and balloon dilatation group (group B, n = 103). The blood flow of the culprit coronary artery in the thrombolysis in myocardial infarction (TIMI) immediately after the emergency PCI operation in these two groups of patients was recorded. Then, an echocardiogram was performed to determine the left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) after the operation, and data on major adverse cardiovascular events (MACE) during the 30 days of postoperative follow-up were collected. RESULTS: The comparative difference between these two groups of patients in terms of hypertension, smoking, diabetes, usage rate of GPIIb/IIIa receptor antagonist, time from hospitalization to balloon dilatation (D2B) and other basic clinical data was not statistically significant (P > 0.05). The postoperative TIMI flow grade of these two groups of patients improved, and the comparative difference between the data obtained from these two groups was statistically significant (P < 0.05). The comparative difference between these two groups in terms of LVEDD and LVEF at 7 days after the operation was not statistically significant (P > 0.05). There was a difference in the occurrence rate of MACE in these two groups of patients during the 30 days of postoperative follow-up, but the comparative difference between these two groups was not statistically significant (P = 0.335). CONCLUSION: The application of thrombus aspiration catheter during the emergency PCI operation of STEMI patients with high thrombus load can better improve the myocardial reperfusion. There is no basis for increasing the stroke occurrence risk. However, it obviously fails to improve the recent prognosis and more studies need to explore its effect on myocardial remodeling and major adverse cardiovascular events.

16.
Gut ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562239

RESUMO

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose at resectable stage. Recent studies have suggested that extracellular vesicles (EVs) contain long RNAs. The aim of this study was to develop a diagnostic (d-)signature for the detection of PDAC based on EV long RNA (exLR) profiling. DESIGN: We conducted a case-control study with 501 participants, including 284 patients with PDAC, 100 patients with chronic pancreatitis (CP) and 117 healthy subjects. The exLR profile of plasma samples was analysed by exLR sequencing. The d-signature was identified using a support vector machine algorithm and a training cohort (n=188) and was validated using an internal validation cohort (n=135) and an external validation cohort (n=178). RESULTS: We developed a d-signature that comprised eight exLRs, including FGA, KRT19, HIST1H2BK, ITIH2, MARCH2, CLDN1, MAL2 and TIMP1, for PDAC detection. The d-signature showed high accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.960, 0.950 and 0.936 in the training, internal validation and external validation cohort, respectively. The d-signature was able to identify resectable stage I/II cancer with an AUC of 0.949 in the combined three cohorts. In addition, the d-signature showed superior performance to carbohydrate antigen 19-9 in distinguishing PDAC from CP (AUC 0.931 vs 0.873, p=0.028). CONCLUSION: This study is the first to characterise the plasma exLR profile in PDAC and to report an exLR signature for the detection of pancreatic cancer. This signature may improve the prognosis of patients who would have otherwise missed the curative treatment window.

17.
Immunity ; 51(3): 491-507.e7, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533057

RESUMO

Tissue-resident memory CD8+ T (Trm) cells share core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic, and epigenetic regulation of Trm cell and TIL development and function is largely undefined. Here, we found that the transcription factor Bhlhe40 was specifically required for Trm cell and TIL development and polyfunctionality. Local PD-1 signaling inhibited TIL Bhlhe40 expression, and Bhlhe40 was critical for TIL reinvigoration following anti-PD-L1 blockade. Mechanistically, Bhlhe40 sustained Trm cell and TIL mitochondrial fitness and a functional epigenetic state. Building on these findings, we identified an epigenetic and metabolic regimen that promoted Trm cell and TIL gene signatures associated with tissue residency and polyfunctionality. This regimen empowered the anti-tumor activity of CD8+ T cells and possessed therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights into the local regulation of Trm cell and TIL function.

18.
Acta Pharmacol Sin ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534201

RESUMO

Inefficient diabetic ulcer healing and scar formation remain a challenge worldwide, owing to a series of disordered and dynamic biological events that occur during the process of healing. A functional wound dressing that is capable of promoting ordered diabetic wound recovery is eagerly anticipated. In this study, we designed a silicone elastomer with embedded 20(S)-protopanaxadiol-loaded nanostructured lipid carriers (PPD-NS) to achieve ordered recovery in scarless diabetic ulcer healing. The nanostructured lipid carriers were prepared through an emulsion evaporation-solidification method and then incorporated into a network of silicone elastomer to form a unique nanostructured lipid carrier-enriched gel formulation. Interestingly, the PPD-NS showed excellent in vitro anti-inflammatory and proangiogenic activity. Moreover, in diabetic mice with full-thickness skin excision wound, treatment with PPD-NS significantly promoted in vivo scarless wound healing through suppressing inflammatory infiltration in the inflammatory phase, promoting angiogenesis during the proliferation phase, and regulating collagen deposition in the remodeling phase. Hence, this study demonstrates that the developed PPD-NS could facilitate ordered diabetic wound recovery via multifunctional improvement during different wound-healing phases. This novel approach could be promising for scarless diabetic wound healing.

19.
BMC Genomics ; 20(1): 688, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477016

RESUMO

BACKGROUND: Pekin duck is an important animal model for its ability for fat synthesis and deposition. However, transcriptional dynamic regulation of adipose differentiation driven by complex signal cascades remains largely unexplored in this model. This study aimed to explore adipogenic transcriptional dynamics before (proliferation) and after (differentiation) initial preadipocyte differentiation in ducks. RESULTS: Exogenous oleic acid alone successfully induced duck subcutaneous preadipocyte differentiation. We explored 36 mRNA-seq libraries in order to study transcriptome dynamics during proliferation and differentiation processes at 6 time points. Using robust statistical analysis, we identified 845, 652, 359, 2401 and 1933 genes differentially expressed between -48 h and 0 h, 0 h and 12 h, 12 h and 24 h, 24 h and 48 h, 48 h and 72 h, respectively (FDR < 0.05, FC > 1.5). At the proliferation stage, proliferation related pathways and basic cellular and metabolic processes were inhibited, while regulatory factors that initiate differentiation enter the ready-to-activate state, which provides a precondition for initiating adipose differentiation. According to weighted gene co-expression network analysis, pathways positively related to adipogenic differentiation are significantly activated at the differentiation stage, while WNT, FOXO and other pathways that inhibit preadipocyte differentiation are negatively regulated. Moreover, we identified and classified more than 100 transcription factors that showed significant changes during differentiation, and found novel transcription factors that were not reported to be related to preadipoctye differentiation. Finally, we manually assembled a proposed regulation network model of subcutaneous preadipocyte differentiation base on the expression data, and suggested that E2F1 may serve as an important link between the processes of duck subcutaneous preadipocyte proliferation and differentiation. CONCLUSIONS: For the first time we comprehensively analyzed the transcriptome dynamics of duck subcutaneous preadipocyte proliferation and differentiation. The current study provides a solid basis for understanding the synthesis and deposition of subcutaneous fat in ducks. Furthermore, the information generated will allow future investigations of specific genes involved in particular stages of duck adipogenesis.

20.
J Exp Clin Cancer Res ; 38(1): 385, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481102

RESUMO

In the original publication of this article [1], there are mistakes in Fig. 3A and Fig. 3D.

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