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1.
Eur J Med Chem ; 227: 113953, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34731760

RESUMO

As epigenetic readers, bromodomain and extra-terminal domain (BET) family proteins bind to acetylated-lysine residues in histones and recruit protein complexes to promote transcription initiation and elongation. Inhibition of BET bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for cancer. Herein, we describe our efforts toward the discovery of a novel series of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as BET inhibitors. Intensive structural modifications led to the identification of compound 35f as the most active inhibitor of BET BRD4 with selectivity against BET family proteins. Further biological studies revealed that compound 35f can arrest the cell cycle in G0/G1 phase and induce apoptosis via decreasing the expression of c-Myc and other proteins related to cell cycle and apoptosis. More importantly, compound 35f showed favorable pharmacokinetic properties and antitumor efficacy in MV4-11 mouse xenograft model with acceptable tolerability. These results indicated that BET inhibitors could be potentially used to treat hematologic malignancies and some solid tumors.

2.
J Colloid Interface Sci ; 611: 545-553, 2021 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-34971965

RESUMO

Aberrant reactive oxygen species (ROS) generation is one of the crucial mediators in the pathogenesis of inflammation. So, the development of nanocatalytic medicine to catalyze the ROS-scavenging reactions in pathological regions are promising for anti-inflammatory therapy. Herein, a type of biocompatible metal free carbon dots is prepared via a hydrothermal method which can exhibit peroxidase (POD)-like, catalase (CAT)-like and superoxide dismutase (SOD)-like activities. It has been found that the carbon dots have the capability to efficiently deplete the excessive ROS such as peroxide (H2O2), superoxide anion (O2-) and hydroxyl radical (OH) for their abundant functional groups. After the tail injection in mice with liver inflammation induced by lipopolysaccharide, the carbon dots efficiently reduced the excessive production of ROS and proinflammatory cytokines in vitro. Both in vitro and in vivo results endowed the biocompatible carbon dots with great potential in nanocatalytic medicine for the treatment of disease.

3.
Drug Metab Dispos ; 2021 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-34965924

RESUMO

Fibroblast growth factor 15/19 (FGF15/19) are endocrine growth factors that play an important role in bile acid homeostasis. FGF15/19 based therapies are currently being tested in clinical trials for the treatment of non-alcoholic steatohepatitis and cholestatic liver diseases. To determine the physiological impact of long-term elevations of FGF15/19, we developed a transgenic mouse model to overexpress Fgf15 (Fgf15 Tg). In the current study, RNA-seq analysis revealed elevations of the expression of several genes encoding phase I drug metabolizing enzymes, including Cyp2b10 and Cyp3a11, in Fgf15 Tg mice. We found that the induction of several Cyp2b isoforms resulted in increased function of CYP2B in microsomal metabolism and pharmacokinetics studies. Because CYP2B family is known to be induced by constitutive androstane receptor (CAR), to determine the role of CAR in the observed inductions, we crossed Fgf15 Tg mice with CAR knockout mice and found that CAR played a minor role in the observed alterations in drug metabolizing enzyme expression. Interestingly, we found that the overexpression of Fgf15 resulted in a phenotypical switch from a male hepatic expression pattern of drug metabolizing enzymes in wild type mice to a female expression pattern in Fgf15 Tg mice. Growth hormone differences between males and females is known to drive sexually dimorphic expression patterns in the livers of rodents in a STAT5b dependent manner. We found that male Fgf15 Tg mice presented with many features similar to wild type female mice, including lowered body length and weight, Igf-1 and Igfals expression, and STAT5 signaling. Significance Statement The overexpression of Fgf15 in mice causes an alteration in DMEs at the mRNA, protein, and functional levels, which is not entirely due to CAR activation but associated with lower GH signaling.

4.
Bioorg Chem ; : 105505, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34838332

RESUMO

Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.

5.
Opt Express ; 29(17): 27041-27047, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34615126

RESUMO

With current trends to progressively miniaturize optical systems, it is now essential to look for alternative methods to control light at extremely small dimensions. Metalenses are composed of subwavelength nanostructures and have an excellent ability to manipulate the polarization, phase, and amplitude of incident light. Although great progress of metalenses has been made, the compact metalens-integrated devices have not been researched adequately. In the study, we present compact imaging devices for near-infrared microscopy, in which a metalens is exploited. The indicators including resolution, magnification, and image quality are investigated via imaging several specimens of intestinal cells to verify the overall performance of the imaging system. The further compact devices, where the metalens is integrated directly on the CMOS imaging sensor, are also researched to detect biomedical issues. This study provides an approach to constructing compact imaging devices based on metalenses for near-infrared microscopy, micro-telecopy, etc., which can promote the miniaturization tending of futural optical systems.

6.
Phys Chem Chem Phys ; 23(35): 19841-19853, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34525148

RESUMO

In this work, the n-type and p-type conductivity mechanisms of bulk BiOCl are systematically investigated using first-principles calculations. Under the O-rich growth conditions, BiOCl presents the intrinsic p-type conductivity, which primarily originates from the contributions of the antisite defects OCl. This is in excellent agreement with the observed p-type conductivity in BiOCl under high oxygen partial pressure or in oxygen-saturated solutions in experiments. While BiOCl displays the intrinsic n-type conductivity under the Bi-rich growth conditions, the vacancy defects VCl are responsible for the character. Nevertheless, the extrinsic means or effects could lead to the production and ionization of the O vacancies, which could contribute to the n-type conductivity in BiOCl. Therefore, the intrinsic n-type conductivity behavior reported in BiOCl in recent experiments is well explained. Under the Cl-rich growth conditions, the major donor defects VCl and the major acceptor defects VBi in BiOCl compensate each other, leading to an intrinsic insulator. However, it is shown that the usual unintentional H impurities HBi could form the p-type conductivity in BiOCl under Cl-rich growth conditions and enhance the p-type conductivity under O-rich growth conditions. This helps to understand the p-type conductivity behavior reported or mentioned in BiOCl in many experiments. At the same time, we found that Group II elements Ca and Sr are superior p-type doping elements for BiOCl under the Cl-rich and O-rich growth conditions. The defect physics in the bulk BiOCl photocatalyst is well understood. This work may inspire more magnificent studies on developing BiOCl-based photocatalysts.

7.
Eur J Cancer Prev ; 30(6): 423-430, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34545020

RESUMO

BACKGROUND AND AIMS: The overall evidence on the association between gallbladder conditions (GBC: gallstones and cholecystectomy) and pancreatic cancer (PC) is inconsistent. To our knowledge, no previous investigations considered the role of tumour characteristics on this association. Thus, we aimed to assess the association between self-reported GBC and PC risk, by focussing on timing to PC diagnosis and tumour features (stage, location, and resection). METHODS: Data derived from a European case-control study conducted between 2009 and 2014 including 1431 PC cases and 1090 controls. We used unconditional logistic regression models to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for recognized confounders. RESULTS: Overall, 298 (20.8%) cases and 127 (11.6%) controls reported to have had GBC, corresponding to an OR of 1.70 (95% CI 1.33-2.16). The ORs were 4.84 (95% CI 2.96-7.89) for GBC diagnosed <3 years before PC and 1.06 (95% CI 0.79-1.41) for ≥3 years. The risk was slightly higher for stage I/II (OR = 1.71, 95% CI 1.15-2.55) vs. stage III/IV tumours (OR = 1.23, 95% CI 0.87-1.76); for tumours sited in the head of the pancreas (OR = 1.59, 95% CI 1.13-2.24) vs. tumours located at the body/tail (OR = 1.02, 95% CI 0.62-1.68); and for tumours surgically resected (OR = 1.69, 95% CI 1.14-2.51) vs. non-resected tumours (OR = 1.25, 95% CI 0.88-1.78). The corresponding ORs for GBC diagnosed ≥3 years prior PC were close to unity. CONCLUSION: Our study supports the association between GBC and PC. Given the time-risk pattern observed, however, this relationship may be non-causal and, partly or largely, due to diagnostic attention and/or reverse causation.

8.
Front Genet ; 12: 653657, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421982

RESUMO

Objective: This study aimed to investigate the expression and biological functions of TNK2 and miR-125a-3p in colon cancer. Materials and methods: The expression of TNK2 and miR-125a-3p in colon cancer tissues was analyzed using data deposited on public databases including UALCAN and ONCOMINE. We verified their expression in colon cancer cell lines by RT-qPCR and western blotting. By regulating the expression of TNK2 and miR-125a-3p in colon cancer cells, their functions and potential mechanisms were explored. Results: TNK2 was overexpressed in colon cancer cell lines, and it was found to directly bind to miR-125a-3p, which was downregulated in these cell lines. Their expression affected the proliferation and invasion of colon cancer cells. Additionally, colon cancer patients with lower TNK2 expression had better prognoses than those with higher TNK2 expression. Conclusion: Our results indicated that TNK2 and miR-125a-3p play critical roles in colon cancer, and could also serve as biomarkers for the diagnosis and prognosis of this malignant disease.

9.
Gastroenterology ; 161(5): 1601-1614.e23, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34303658

RESUMO

BACKGROUND & AIMS: Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex. RESULTS: We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types. CONCLUSIONS: Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.

10.
Signal Transduct Target Ther ; 6(1): 249, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34219130

RESUMO

Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.

11.
Inorg Chem ; 60(12): 8451-8455, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34061510

RESUMO

An open-frame aluminophosphate, K[(Zn0.5Al0.5)2P2O8] (KZAPO), was rationally designed by a substitution design strategy and synthesized by a high-temperature molten salt method. Compared with the parent crystal of K[ZnBP2O8], KZAPO was characterized by similar 4 × 8 × 8 networks, a comparable short-wave ultraviolet transparency and a more regular tetrahedral frame with the mixing of (ZnO4)6- and (AlO4)5- anionic groups, highlighting the multifunctional roles that anionic group mixing played in structural and property modulations. In particular, KZAPO was characterized by a high thermal stability (over 850 °C) and a congruent-melting behavior, being conducive to practical applications.

12.
Acta Pharmacol Sin ; 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117368

RESUMO

Hepatocellular carcinoma (HCC), the most prevalent liver cancer, is considered one of the most lethal malignancies with a dismal outcome mainly due to frequent intrahepatic and distant metastasis. In the present study, we demonstrated that oroxylin A, a natural product extracted from Scutellaria radix, significantly inhibits transforming growth factor-beta1 (TGF-ß1)-induced epithelial-mesenchymal transition (EMT) and metastasis in HCC. Oroxylin A blocked the TGF-ß1/Smad signaling via upregulating the non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) expression. Oroxylin A promoted NAG-1 transcription by regulating the acetylation of CCAAT/enhancer binding protein ß (C/EBPß), a transcription factor that binds to the NAG-1 promoter. In terms of the underlying mechanism, oroxylin A may interact with histone deacetylase 1 (HDAC1) by forming hydrogen bonds with GLY149 residue and induce proteasome-mediated degradation of HDAC1 subsequently impairing HDAC1-mediated deacetylation of C/EBPß and promoting the expression of NAG-1. Taken together, our findings revealed a previously unknown tumor-suppressive mechanism of oroxylin A. Oroxylin A should be further investigated as a potential clinical candidate for inhibiting HCC metastasis.

13.
BMC Cardiovasc Disord ; 21(1): 285, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107870

RESUMO

BACKGROUND: Lipoprotein(a) is genetically determined and increasingly recognized as a major risk factor for arteriosclerotic cardiovascular disease. We examined whether plasma lipoprotein(a) concentrations were associated with intraplaque neovascularization (IPN) grade in patients with carotid stenosis and in terms of increasing plaque susceptibility to haemorrhage and rupture. METHODS: We included 85 patients diagnosed with carotid stenosis as confirmed using carotid ultrasound who were treated at Guangdong General Hospital. Baseline data, including demographics, comorbid conditions and carotid ultrasonography, were recorded. The IPN grade was determined using contrast-enhanced ultrasound through the movement of the microbubbles. Univariate and multivariate binary logistic regression analyses were used to evaluate the association between lipoprotein(a) and IPN grade, with stepwise adjustment for covariates including age, sex, comorbid conditions and statin therapy (model 1), total cholesterol, triglyceride, low-density lipoprotein cholesterol calculated by Friedwald's formula, high-density lipoprotein cholesterol, apolipoprotein A and apolipoprotein B (model 2), maximum plaque thickness and total carotid maximum plaque thickness, degree of carotid stenosis and internal carotid artery (ICA) occlusion (model 3). RESULTS: Lipoprotein(a) was a significant predictor of higher IPN grade in binary logistic regression before adjusting for other risk factors (odds ratio [OR] 1.238, 95% confidence interval [CI] (1.020, 1.503), P = 0.031). After adjusting for other risk factors, lipoprotein(a) still remained statistically significant in predicting IPN grade in all model. (Model 1: OR 1.333, 95% CI 1.074, 1.655, P = 0.009; Model 2: OR 1.321, 95% CI 1.059, 1.648, P = 0.014; Model 3: OR 1.305, 95% CI 1.045, 1.628, P = 0.019). Lp(a) ≥ 300 mg/L is also significantly related to IPN compare to < 300 mg/L (OR 2.828, 95% CI 1.055, 7.580, P = 0.039) as well as in model 1, while in model 2 and model 3 there are not significant difference. CONCLUSIONS: Plasma lipoprotein(a) concentrations were found to be independently associated with higher IPN grade in patients with carotid stenosis. Lowering plasma lipoprotein(a) levels may result in plaque stabilization by avoiding IPN formation.

14.
Bioprocess Biosyst Eng ; 44(10): 2167-2179, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34043089

RESUMO

A new aerotolerant strain of Clostridium beijerinckii LY-5 was isolated from the pit mud of the Chinese Baijiu-making process for butanol production. Plackett-Burman design and artificial neural network were used to optimize the fermentation medium and a total of 13.54 ± 0.22 g/L butanol and 19.91 ± 0.52 g/L ABE were attained under aerotolerant condition. Moreover, distillers' grain waste (DGW), the main by-product in the Baijiu production process, was utilized as potential substrate for butanol production. DGW was hydrolyzed by α-amylase and glucoamylase and then fermented after a detoxifying process of overliming. Butanol and ABE concentrations were 9.02 ± 0.18 and 9.57 ± 0.19 g/L with the yield of 0.21 and 0.23 g/g sugar, respectively. The higher ratio of butanol to ABE might be caused by the inhibitors in DGW medium affecting the metabolic pathways of C. beijerinckii LY-5 and approximately 1.48 ± 0.04 g/L isopropanol was found at the end of fermentation. This work highlights the feasibility of using DGW as a promising feedstock for butanol production by a new aerotolerant strain of C. beijerinckii LY-5, with benefit to the environment.

15.
PLoS One ; 16(4): e0250455, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33886664

RESUMO

Stethoscopes have been suggested to be a possible vector of contact transmission. However, only a few studies have focused on the prevalence of contamination by multidrug-resistant (MDR) bacteria and effectiveness of disinfection training to reduce. This study is to investigate the burden of stethoscope contamination with nosocomial pathogens and multidrug-resistant (MDR) bacteria and to analyze habit changes in disinfection of stethoscopes among healthcare workers (HCWs) before and after education and training. We performed a prospective pre and post quasi-experimental study. A total of 100 HCWs (55 doctors and 45 nurses) were recruited. HCWs were surveyed on their disinfection behavior and stethoscopes were cultured by pressing the diaphragm directly onto a blood agar plate before and after education on disinfection. Pulsed-field gel electrophoresis was performed to determine the relatedness of carbapenem-resistant Enterobacteriaceae. Most of the stethoscopes were contaminated with microorganisms before and after the intervention (97.9% and 91.5%, respectively). The contamination rate of stethoscopes with nosocomial pathogens before and after education was 20.8% and 19.2%, respectively. Stethoscope disinfection habits improved (55.1% vs 31.0%; p<0.001), and the overall bacterial loads of contamination were reduced (median colony-forming units, 15 vs 10; p = 0.019) after the intervention. However, the contamination rate by nosocomial pathogens and MDR bacteria did not decrease significantly. A carbapenemase-producing Klebsiella pneumoniae isolates from a stethoscope was closely related to isolates from the patients admitted at the same ward where the stethoscope was used. Stethoscopes were contaminated with various nosocomial pathogens including MDR bacteria and might act as a vehicle of MDR bacteria. Continuous, consistent education and training should be provided to HCWs using multifaceted approach to reduce the nosocomial transmission via stethoscopes.


Assuntos
Infecção Hospitalar/microbiologia , Enterobacteriaceae/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Estetoscópios/microbiologia , Adulto , Carbapenêmicos/farmacologia , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/prevenção & controle , Desinfecção/normas , Contaminação de Medicamentos , Farmacorresistência Bacteriana Múltipla/genética , Enterobacteriaceae/patogenicidade , Contaminação de Equipamentos/prevenção & controle , Feminino , Pessoal de Saúde , Humanos , Klebsiella pneumoniae/patogenicidade , Masculino , Pessoa de Meia-Idade , Médicos , Estudos Prospectivos
16.
Genome Med ; 13(1): 15, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33517887

RESUMO

BACKGROUND: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. METHODS: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. RESULTS: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. CONCLUSIONS: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

17.
Clin Epigenetics ; 13(1): 18, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33499904

RESUMO

BACKGROUND: Hypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored. METHODS: A hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism. RESULTS: We quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT. CONCLUSIONS: This study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.

18.
Sci Rep ; 11(1): 2495, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510309

RESUMO

Dielectric materials with good thermal transport performance and desirable dielectric properties have significant potential to address the critical challenges of heat dissipation for microelectronic devices and power equipment under high electric field. This work reported the role of synergistic effect and interface on through-plane thermal conductivity and dielectric properties by intercalating the hybrid fillers of the alumina and boron nitride nanosheets (BNNs) into epoxy resin. For instance, epoxy composite with hybrid fillers at a relatively low loading shows an increase of around 3 times in through-plane thermal conductivity and maintains a close dielectric breakdown strength compared to pure epoxy. Meanwhile, the epoxy composite shows extremely low dielectric loss of 0.0024 at room temperature and 0.022 at 100 ℃ and 10-1 Hz. And covalent bonding and hydrogen-bond interaction models were presented for analyzing the thermal conductivity and dielectric properties.

19.
Gastroenterology ; 160(5): 1755-1770.e17, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33388318

RESUMO

BACKGROUND & AIMS: Oncogenic KrasG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM), an actin-based morphogenetic process, and drives pancreatic ductal adenocarcinoma (PDAC). mTOR (mechanistic target of rapamycin kinase) complex 1 (mTORC1) and 2 (mTORC2) contain Rptor and Rictor, respectively, and are activated downstream of KrasG12D, thereby contributing to PDAC. Yet, whether and how mTORC1 and mTORC2 impact on ADM and the identity of the actin nucleator(s) mediating such actin rearrangements remain unknown. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven early pancreatic carcinogenesis was used. Rptor, Rictor, and Arpc4 (actin-related protein 2/3 complex subunit 4) were conditionally ablated in acinar cells to deactivate the function of mTORC1, mTORC2 and the actin-related protein (Arp) 2/3 complex, respectively. RESULTS: We found that mTORC1 and mTORC2 are markedly activated in human and mouse ADM lesions, and cooperate to promote KrasG12D-driven ADM in mice and in vitro. They use the Arp2/3 complex as a common downstream effector to induce the remodeling the actin cytoskeleton leading to ADM. In particular, mTORC1 regulates the translation of Rac1 (Rac family small GTPase 1) and the Arp2/3-complex subunit Arp3, whereas mTORC2 activates the Arp2/3 complex by promoting Akt/Rac1 signaling. Consistently, genetic ablation of the Arp2/3 complex prevents KrasG12D-driven ADM in vivo. In acinar cells, the Arp2/3 complex and its actin-nucleation activity mediated the formation of a basolateral actin cortex, which is indispensable for ADM and pre-neoplastic transformation. CONCLUSIONS: Here, we show that mTORC1 and mTORC2 attain a dual, yet nonredundant regulatory role in ADM and early pancreatic carcinogenesis by promoting Arp2/3 complex function. The role of Arp2/3 complex as a common effector of mTORC1 and mTORC2 fills the gap between oncogenic signals and actin dynamics underlying PDAC initiation.


Assuntos
Células Acinares/enzimologia , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Carcinoma Ductal Pancreático/enzimologia , Transformação Celular Neoplásica/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Mutação , Ductos Pancreáticos/enzimologia , Neoplasias Pancreáticas/enzimologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Células Acinares/patologia , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Metaplasia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Proteína Regulatória Associada a mTOR/genética , Proteína Regulatória Associada a mTOR/metabolismo , Transdução de Sinais
20.
Gut ; 70(2): 319-329, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32409590

RESUMO

OBJECTIVES: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI). DESIGN: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis. RESULTS: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55). CONCLUSION: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Obesidade/complicações , Neoplasias Pancreáticas/etiologia , Idoso , Índice de Massa Corporal , Peptídeo C/sangue , Estudos de Casos e Controles , Causalidade , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Escolaridade , Feminino , Hemoglobina A Glicada/análise , Humanos , Masculino , Análise de Mediação , Pessoa de Meia-Idade , Obesidade/genética , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fatores Sexuais , Fumar/efeitos adversos
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