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1.
J Agric Food Chem ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33464893

RESUMO

As potential endogenous biomarkers, reactive carbonyl species (RCS) have gained abundant attention for monitoring oxidative and carbonyl stress. However, there is no accurate method to evaluate multiple RCS in biological samples. In this study, a 2,4-dinitrophenylhydrazine (DNPH) derivatization-based LC-MS method was developed and validated to quantitate eight RCS: malondialdehyde (MDA), acrolein (ACR), 4-hydroxy-2-nonenal (4-HNE), 4-oxo-2-nonenal (4-ONE), methylglyoxal (MGO), glyoxal (GO), 3-deoxyglucosone (3-DG), and 2-keto-d-glucose (2-Keto). Subsequently, the method was applied to assess the RCS in low fat (LF), high fat (HF), and HF plus rosemary extract (RE) diet-fed mouse samples. The quantitative results on RCS levels indicated that the HF diet significantly increased the total RCS levels in mouse urine, plasma, and kidney with an average rate of 280.69%, 153.87%, and 61.30%, respectively. The RE administration significantly inhibited the elevated RCS levels induced by the HF diet, especially for MDA, 4-ONE, 4-HNE, and 2-Keto in mouse plasma, and ACR and 2-Keto in mouse kidney. This is the first study to simultaneously measure eight RCS in biological samples and demonstrate that RE was able to eliminate the accumulation of the HF diet-induced RCS.

2.
Neurol Sci ; 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33483886

RESUMO

OBJECTIVE: We aimed to study the clinical characteristics and biological indicators of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis with different severity levels to explore factors predicting disease severity at admission. METHODS: Using the modified Rankin scale (mRS), patients were divided into mild-to-moderate group (mRS ≤ 3) and severe group (mRS > 3) on admission based on severity of illness. General information, previous history, premonitory symptoms, clinical manifestations before admission, imaging findings and biochemical tests were compared to explore the clinical manifestations and biological indicators related to the severity of illness at admission. RESULTS: In the severe group, the incidences of fever, anti-infective therapy, generalized seizures, consciousness disorder, blood white blood cell, neutrophils, and neutrophil-lymphocyte ratio (NLR) were higher than those in mild-to-moderate group (P < 0.001, P = 0.001, P = 0.020, P < 0.001, P = 0.002, P < 0.001, P < 0.001, respectively); blood lymphocyte counts was lower than those in mild-to-moderate group (P < 0.001). There was the strongest significant positive correlation between the NLR and disease severity at admission (rs = 0.684, P < 0.001). In multivariate logistic regression, fever, generalized seizures, consciousness disorder, and elevated NLR were independent risk factors for disease severity; the area under the receiver operating characteristic curve was 0.896 (95%CI: 0.840-0.952, P < 0.001). CONCLUSION: Fever, generalized seizures, consciousness disorder, and elevated NLR were independent risk factors for disease severity. NLR is a good predictor of the severity of illness at admission.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33435667

RESUMO

Optical micro/nanofibers (MNFs) can be applied for ultrasensitive tactile sensing with fast response and compact size, which are attractive for restoring tactile information in minimally invasive robotic surgery and tissue palpation. Herein, we present a compact tactile sensor (CTS) with a diameter of 1.5 mm enabled by an optical MNF. The CTS provides continuous readouts for high-fidelity transduction of touch and pressure stimuli into interpretable optical signals, which permit instantaneous sensing of contact and pressure with pressure-sensing sensitivity as high as 0.108 mN-1 and a resolution of 0.031 mN. Working in pressing mode, the CTS can discriminate the difference in the hardness of two poly(dimethylsiloxane) (PDMS) slats (with shore A of 36 and 40) directly, a hardness resolving ability even beyond the human hands. Benefitting from the fast response feature, the CTS can also be operated in either scanning or tapping mode, making it feasible for hardness identification by analyzing the shape of the response curve. As a proof of concept, the hardness discrimination of a pork liver and an adductor muscle was experimentally demonstrated. Such MNF-enabled compact tactile sensors may pave the way for hardness sensing in tissue palpation, surgical robotics, and object identification.

4.
Asia Pac J Clin Nutr ; 29(4): 696-705, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33377363

RESUMO

BACKGROUND AND OBJECTIVES: The role of ursodeoxycholic acid (UDCA) in Nonalcoholic fatty liver disease (NAFLD) is not well-defined. In this meta-analysis, we analyzed the efficacy of UDCA for the treatment of NAFLD. METHODS AND STUDY DESIGN: We searched the Web of Science, Pubmed, Embase and Cochrane library databases for relevant studies published before September 1, 2019. The randomized controlled trials (RCTs) that investigated the effectiveness of UDCA in NAFLD were selected and examined by Stata (version 12.0). RESULTS: The forest plot displayed that UDCA treatment can significantly decrease the ALT (alanine aminotransferase) levels (p=0.007). Further, its' significant role in subgroup analyses (p=0.003 in people from Europe, p=0.001 in people older than 50 years and p=0.008 in longer duration). CONCLUSIONS: Although UDCA treatment was found beneficial in ALT-lowering, future meta-analysis will be required to fully confirm and validate the efficacy of UDCA in NAFL.

5.
Placenta ; 103: 232-241, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33202359

RESUMO

INTRODUCTION: Circular RNAs (circRNAs) are non-coding RNAs that are implicated in preeclampsia (PE) pathogenesis; however, their expression and functions in PE remain unclear. In this study, we aimed to investigate the expression of circRNAs in PE and construct a competing endogenous RNA (ceRNA) network, and analyze the associated pathways in PE pathogenesis. METHODS: We performed circRNA sequencing to identify the differential expression profile of circRNAs in PE as compared to normal pregnancy. The circRNA candidates were validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Subsequently, we used datasets from the GEO database to generate the interaction network between circRNAs, microRNAs (miRNAs), and mRNAs. GO and KEGG enrichment analyses were performed to understand the functional significance of the differentially expressed circRNAs in PE. RESULTS: We identified 361 differentially expressed circRNAs (252 upregulated and 109 downregulated) in preeclamptic placentas. Within the selected 31 circRNAs, 6 of them were verified by qRT-PCR. GO and KEGG analyses revealed the potential pathways affected by these circRNAs, e.g., T cell receptor signaling and MAP kinase pathways. A total of 134 miRNAs and 199 mRNAs were revealed to be differentially expressed in PE by analyzing datasets from the GEO database. The circRNA-miRNA-mRNA network comprised 206 circRNAs, 50 miRNAs, and 38 mRNAs. KEGG analysis of the 38 mRNAs included pathways involved in AMPK and PI3K-Akt signaling. DISCUSSION: Our results reported the differential expression profile of circRNAs and the circRNA-miRNA-mRNA network in PE, which provides potential therapeutic targets for this disease.

6.
Sci Rep ; 10(1): 20455, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33235257

RESUMO

No current in vitro tumor model replicates a tumor's in vivo microenvironment. A culturing technique that better preserves a tumor's pathophysiological conditions is needed for some important clinical applications, including personalized drug-sensitivity/resistance assays. In this study, we utilized autologous serum or body fluid to build a 3D scaffold and grow a patient's tumor. We named this technique "3D-ACM" (autologous culture method). Forty-five clinical samples from biopsies, surgically removed tumor tissues and malignant body fluids were cultured with 3D-ACM. Traditional 3D-FBS (fetal bovine serum) cultures were performed side-by-side for comparison. The results were that cells cultured in 3D-ACM rebuilt tissue-like structures, and retained their immuno-phenotypes and cytokine productions. In contrast, the 3D-FBS method promoted mesenchymal cell proliferation. In preliminary chemo drug-sensitivity assays, significantly higher mortality was always associated with FBS-cultured cells. Accordingly, 3D-ACM appears to more reliably preserve a tumor's biological characteristics, which might improve the accuracy of drug-testing for personalized cancer treatment.

7.
Onco Targets Ther ; 13: 10567-10580, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116635

RESUMO

Background: Murine bone marrow-derived myofibroblasts (BMFs) have previously been shown to promote gastric cancer growth. However, whether BMFs promote gastric cancer cell metastasis remains largely unknown. Methods: Wound healing assay, Transwell invasion and migration assay and 3D organotypic co-culture systems were conducted to study the effects of BMFs on invasion and migration of gastric cancer cells and the invasion and migration ability of gastric cancer stem cell-like cells (CSC-LCs) induced by BMFs. We employed two animal model to study the role of BMFs on the in vivo metastasis of gastric cancer cells and the metastatic ability of gastric BMF-induced CSC-LCs. A human gastric cancer tissue microarray and TCGA gastric cancer database were analysed to study the relationship between the expression of IL-6 and TGF-ß1 and clinicopathological characteristics and survival in gastric cancer. Results: We found that BMFs promoted the in vitro migration and invasion of gastric cancer cells. BMFs promoted liver, lung, subcutaneous, and splenic metastases of MKN28 cells in the spleen injection liver metastasis model and co-injection of caudal vein (IOCV) mouse model. BMFs reprogrammed non-gastric cancer stem cell (CSC) to CSC-LCs and enhanced CSC-LC migration and metastasis. BMF-derived IL-6 and gastric cancer cell-secreted TGF-ß1 mediated the interaction between BMFs and gastric cancer cells, promoting tumour metastasis. BMFs enhanced the expressions of STAT3 and p-STAT3 in co-cultured gastric cancer cells. A combination of Napabucasin and Galunisertib exhibited the strongest inhibition of cell migration compared to when administered alone. Gastric cancer tissue array and TCGA database indicated that the overexpression of IL-6 and TGF-ß1 was associated with gastric cancer metastasis. Conclusion: Our results demonstrated that BMFs promote gastric cancer metastasis through the activation of the TGF-ß1 and IL-6/STAT3 signalling pathways. Targeting the inhibition of these interactions may be a potent therapeutic strategy for addressing gastric cancer metastasis.

8.
Nat Biotechnol ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077961

RESUMO

Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach.

9.
Mol Nutr Food Res ; 64(22): e2000615, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32997396

RESUMO

SCOPE: In this work, an integrated strategy is developed for rapid discovery, precise identification, and automated quantification for the biomarkers of food intake (BFIs) for specific food exposure using an ultra-high-pressure liquid chromatography-high-resolution mass spectrometry (MS) based targeted metabolomics approach. METHODS AND RESULTS: Using whole grain (WG) wheat intake as an example, the combination of paired mass distance networking and parallel reaction monitoring analysis is applied to selectively extract and identify WG metabolites in human urine samples. As a result, a total of 76 wheat phytochemical-derived metabolites, including 17 alkylresorcinol metabolites, 20 benzoxazinoid derivatives, and 39 phenolic acid metabolites are identified. Subsequently, a MS spectral database consisting of the identified metabolites is created by mzVault. The characteristics of identified metabolites from the database are incorporated into the TraceFinder software to establish a quantification platform. Using a standardized urine sample, the authors are able to simultaneously quantify both free and conjugated (sulfate and glucuronide) WG wheat metabolites in real samples without further enzymatic hydrolysis, which is validated by using authentic standards to quantify these metabolites. CONCLUSION: This novel strategy opens the window to study the biomarkers of specific food intake and make it feasible to validate the BFIs in large-scale human studies.

10.
Int J Oncol ; 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32901832

RESUMO

EphA2 (EPH receptor A2) (erythropoietin­producing hepatocellular receptor tyrosine kinase subtype A2) plays a crucial role in human cancers, and is a promising target for the development of new anticancer drugs. In this study, we showed that the interaction of Annexin A1 (ANXA1) and EphA2 increased EphA2 stability by inhibiting its proteasome degradation in gastric cancer (GC) and colon cancer (CC) cells, and the amino acid residues 20­30 and 28­30 of ANXA1 N terminal were responsible for binding and stabilizing EphA2. Based on the amino acid residues of ANXA1 responsible for binding EphA2, we developed ANXA1­derived 3 amino acid­long (SKG) and 11 amino acid­long peptides (EYVQTVKSSKG) in fusion to cell­penetrating peptide, named as A1(28­30) and A1(20­30) respectively, and found that A1(28­30) and A1(20­30) blocked the binding of ANXA1 with EphA2, targeted EphA2 degradation, and suppressed the growth of GC and CC cells in vitro and in mice. Our data demonstrated that ANXA1 was able to bind and stabilize EphA2 in GC and CC cells, and disruption of ANXA1­EphA2 interaction by the two ANXA1­derived peptides inhibited the growth of GC and CC cells by targeting EphA2 degradation, presenting a potential strategy for treating GC and CC with these peptides.

11.
Cell Mol Neurobiol ; 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968928

RESUMO

Parkinson's disease (PD) seriously threatens human's health. Researches have shown a close correlation between long non-coding RNAs (lncRNAs) and PD. However, the biological function of lncRNA homeobox transcript antisense RNA (HOTAIR) in PD remains largely unknown. In this study, we established PD models in vivo and in vitro by using 1-methyl-4-phenyl-2, 3, 6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) to assess the role of HOTAIR in pyroptotic cell death and neuronal damage. RNA immunoprecipitation (RIP) and dual luciferase reporter assay were used to verify the interaction between miR-326 and HOTAIR or ELAV like RNA binding protein 1 (ELAVL1). LncRNA HOTAIR was upregulated in PD mice and MPP+ induced SH-SY5Y cells. Additionally, knockdown of HOTAIR notably attenuated the symptom of PD in vivo. Downregulation of HOTAIR could obviously promoted cell viability and suppressed NLR family pyrin domain containing 3 (NLRP3) mediated pyroptotic cell death of SH-SY5Y cells in the presence of MPP+. Further, lncRNA HOTAIR positively regulated ELAVL1 expression by targeting miR-326, and downregulation of HOTAIR or ELAVL1 notably suppressed promotive effects of miR-326 inhibitor on MPP+ induced pyroptosis via activation of NLRP3 inflammasome. Collectively, HOTAIR silencing significantly inhibits neuronal damage through repressing NLRP3 mediated pyroptosis activation via regulation of miR-326/ELAVL1 axis in PD, which may contribute to a better understanding of PD pathogenesis and provide new treatment strategies for this disease.

12.
Anal Methods ; 12(36): 4479-4486, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32869794

RESUMO

Bisphenol A (BPA) is used as a stabilizing agent in many food packaging plastics and is a known endocrine-disrupting chemical that can alter the development of mammary glands, affect egg cells, and cause chromosomal defects. However, the pretreatment of traditional assays for detecting BPA is difficult. In this work, a novel aptamer functionalized magnetic adsorbent was developed and combined with magnetic solid-phase extraction (MSPE) for the selective enrichment of BPA. First, magnetic silica-coated Fe3O4 microspheres (Fe3O4@SiO2) were synthesized by the sol-gel method, and functional magnetic nanoparticles (Fe3O4@SiO2@Apt) were formed by modifying with nucleic acids. In the presence of BPA in a MSPE system, the nucleic acid aptamer can specifically capture the target BPA. After magnetic separation, the Apt/BPA composite was eluted, and we observed enhanced fluorescence with the Apt/BPA composite that was formed. Our results showed that this method allowed a limit of detection of 0.05 ng mL-1.

13.
Biochem Biophys Res Commun ; 530(1): 314-321, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32828305

RESUMO

Myocardial ischemia/reperfusion (I/R) injury is a clinically fatal disease, caused by restoring myocardial blood supply after a period of ischemia or hypoxia. However, the underlying mechanism remains unclear. Recently, increasing evidence reveal that microRNAs (miRs) participate in myocardial I/R injury. This study aimed to investigate whether miR-128-1-5p contributed to cardiomyocyte apoptosis induced by myocardial I/R injury. Here, we showed that the expression of miR-128-1-5p was decreased in mice following myocardial I/R injury. Down-regulation of miR-128-1-5p was also showed in H9c2 cardiomyocytes after hypoxia/reoxygenation (H/R), and in neonatal rat cardiomyocytes (NRCMs) with H2O2 treatment. Importantly, we found that overexpression of miR-128-1-5p ameliorates cardiomyocyte apoptosis both in H9c2 cardiomyocytes and NRCMs. Moreover, we also found that growth arrest DNA damage-inducible gene 45 gamma (Gadd45g) is identified as a direct target of miR-128-1-5p, which negatively regulated Gadd45g expression. Additionally, silencing of Gadd45g inhibits cardiomyocyte apoptosis in H9c2 cardiomyocytes and NRCMs. These results reveal a novel mechanism by which miR-128-1-5p regulates Gadd45g-mediated cardiomyocyte apoptosis in myocardial I/R injury.

14.
Theranostics ; 10(19): 8691-8704, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754272

RESUMO

Rationale: Nanoscale vehicles responsive to abnormal variation in tumor environment are promising for use in targeted delivery of therapeutic drugs specifically to tumor sites. Herein, we report the design and fabrication of self-accelerating H2O2-responsive plasmonic gold nanovesicles (GVs) encapsulated with tirapazamine (TPZ) and glucose oxidase (GOx) for synergistic chemo/starving therapy of cancers. Methods: Gold nanoparticles were modified with H2O2-responsive amphiphilic block copolymer PEG45-b-PABE330 by ligand exchange. The TPZ and GOx loaded GVs (TG-GVs) were prepared through the self-assembly of PEG45-b-PABE330 -grafted nanoparticles together with TPZ and GOx by solvent displacement method. Results: In response to H2O2 in tumor, the TG-GVs dissociate to release the payloads that are, otherwise, retained inside the vesicles for days without noticeable leakage. The released GOx enzymes catalyze the oxidation of glucose by oxygen in the tumor tissue to enhance the degree of hypoxia that subsequently triggers the reduction of hypoxia-activated pro-drug TPZ into highly toxic free radicals. The H2O2 generated in the GOx-catalyzed reaction also accelerate the dissociation of vesicles and hence the release rate of the cargoes in tumors. The drug-loaded GVs exhibit superior tumor inhibition efficacy in 4T1 tumor-bearing mice owing to the synergistic effect of chemo/starvation therapy, in addition to their use as contrast agents for computed tomography imaging of tumors. Conclusion: This nanoplatform may find application in managing tumors deeply trapped in viscera or other important tissues that are not compatible with external stimulus (e.g. light).

15.
Cell Death Dis ; 11(8): 709, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32848131

RESUMO

EphA2 is an important oncogenic protein and emerging drug target, but the oncogenic role and mechanism of ligand-independent phosphorylation of EphA2 at tyrosine 772 (pY772-EphA2) is unclear. In this study, we established nasopharyngeal carcinoma (NPC) cell lines with stable expression of exogenous EphA2 and EphA2-Y772A (phosphorylation inactivation) using endogenous EphA2-knockdown cells, and observed that pY772A EphA2 was responsible for EphA2-promoting NPC cell proliferation and anchorage-independent and in vivo growth in mice. Mechanistically, EphA2-Y772A mediated EphA2-activating Shp2/Erk-1/2 signaling pathway in the NPC cells, and Gab1 (Grb2-associated binder 1) and Grb2 (growth factor receptor-bound protein 2) were involved in pY772-EphA2 activating this signaling pathway. Our results further showed that Shp2/Erk-1/2 signaling mediated pY772-EphA2-promoting NPC cell proliferation and anchorage-independent growth. Moreover, we observed that EphA2 tyrosine kinase inhibitor ALW-II-41-27 inhibited pY772-EphA2 and EphA2-Y772A decreased the inhibitory effect of ALW-II-41-27 on NPC cell proliferation. Collectively, our results demonstrate that pY772-EphA2 is responsible for EphA2-dependent NPC cell growth in vitro and in vivo by activating Shp2/Erk-1/2 signaling pathway, and is a pharmacologic target of ALW-II-41-27, suggesting that pY772-EphA2 can serve as a therapeutic target in NPC and perhaps in other cancers.

16.
Water Environ Res ; 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32762110

RESUMO

By summarizing 187 relevant research articles published in 2019, the review is focused on the research progress of physicochemical processes for wastewater treatment. This review divides into two sections, physical processes and chemical processes. The physical processes section includes three sub-sections, that is, adsorption, granular filtration, and dissolved air flotation, whereas the chemical processes section has five sub-sections, that is, coagulation/flocculation, advanced oxidation processes, electrochemical, capacitive deionization, and ion exchange. PRACTITIONER POINTS: Totally 187 research articles on wastewater treatment have been reviewed and discussed. The review has two major sections with eight sub-topics.

17.
Opt Express ; 28(15): 21359-21367, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32752415

RESUMO

Inspired by superficial neuromasts in the lateral line of fish for the sensing of flow rate, we report a bionic optical microfiber flow rate sensor by embedding a U-shaped microfiber into a thin PDMS film. When immersed into liquid, the PDMS film is deflected by the flowing liquid, resulting in a bending-dependent transmittance change of the embedded microfiber which is directly related to the flow rate of the liquid. The flow rate sensor exhibits a low detection limit (< 0.05 L/min), a high resolution (0.005 L/min), and a fast response time (12 ms). In addition, the sensitivity and working range of the sensor are tunable in a wide range via adjusting the thickness of PDMS film, the microfiber diameter, and/or the working wavelength.

18.
Chin Med J (Engl) ; 133(18): 2153-2160, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32826608

RESUMO

BACKGROUND: The relationship between macrocirculation and microcirculation remains controversial. The loss of coherence between microcirculation and macrocirculation has already been found in late-stage sepsis shock. The objective of this study was to determine the earliest possible time of detecting the loss of coherence between microcirculation and macrocirculation in early-stage endotoxemic shock. METHODS: We randomized 24 female New Zealand white rabbits into two groups: endotoxemic shock group (n = 14) and control group (n = 10). Rabbits in the endotoxemic shock group were equipped with arterial and venous catheters and received an intravenous infusion of Escherichia coli lipopolysaccharide (LPS, 2 mg/kg over 10 min). Rabbits in the control group received the same dose of saline infusion. Microcirculatory perfusion parameters were assessed in the sublingual mucosa using sidestream dark-field video microscopy. Systemic hemodynamics and blood lactate levels were measured at baseline and over a 120-min period. RESULTS: Ninety minutes after completing LPS infusion, all animals in the endotoxemic shock group developed a hypodynamic septic condition, characterized by low cardiac output and increased systemic vascular resistance; 120 min after completing LPS infusion, the mean arterial pressure decreased by 25% (P = 0.01), confirming ongoing endotoxemic shock. However, significant decreases in sublingual microcirculatory parameters of small vessels (microvascular flow index, perfused vessel density, and proportion of small perfused vessels) were observed 30 min after completing LPS infusion (P = 0.01, for all), and threshold decreases of 30% were found 60 min after completing LPS infusion (P = 0.001, for all) in the endotoxemic shock group. Lactate levels significantly increased to more than 2 mm/L at 90 min and more than 4 mm/L at 120 min in the endotoxemic shock group (P = 0.02 and P = 0.01, respectively). CONCLUSIONS: Changes in microcirculatory perfusion precede changes in macrocirculation and lactate levels in a rabbit model of endotoxemia shock. Microcirculation, macrocirculation, and oxygen metabolism are distinct in early-stage endotoxic shock.

19.
Cancer Res ; 80(20): 4386-4398, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32737118

RESUMO

Overexpression of ANXA1 and EphA2 has been linked to various cancers and both proteins have attracted considerable attention for the development of new anticancer drugs. Here we report that ANXA1 competes with Cbl for binding EphA2 and increases its stability by inhibiting Cbl-mediated EphA2 ubiquitination and degradation in nasopharyngeal carcinoma (NPC). Binding of ANXA1 to EphA2 promoted NPC cell growth and metastasis in vitro and in vivo by elevating EphA2 levels and increasing activity of EphA2 oncogenic signaling (pS897-EphA2). Expression of ANXA1 and EphA2 was positively correlated and both were significantly higher in NPC tissues than in the normal nasopharyngeal epithelial tissues. Patients with high expression of both proteins presented poorer disease-free survival and overall survival relative to patients with high expression of one protein alone. Furthermore, amino acid residues 20-30aa and 28-30aa of the ANXA1 N-terminus bound EphA2. An 11 amino acid-long ANXA1-derived peptide (EYVQTVKSSKG) was developed on the basis of this N-terminal region, which disrupted the connection of ANXA1 with EphA2, successfully downregulating EphA2 expression and dramatically suppressing NPC cell oncogenicity in vitro and in mice. These findings suggest that ANXA1 promotes NPC growth and metastasis via binding and stabilization of EphA2 and present a strategy for targeting EphA2 degradation and treating NPC with a peptide. This therapeutic strategy may also be extended to other cancers with high expression of both proteins. SIGNIFICANCE: These findings show that EphA2 is a potential target for NPC therapeutics and an ANXA1-derived peptide suppresses NPC growth and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4386/F1.large.jpg.

20.
Cancer Cell Int ; 20: 332, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32699531

RESUMO

Background: Fatty acid synthase (FASN) is highly expressed in various types of cancer and has an important role in carcinogenesis and metastasis. To clarify the mechanisms of FASN in liver cancer invasion and metastasis, the FASN protein interaction network in liver cancer was identified by targeted proteomic analysis. Methods: Wound healing and Transwell assays was performed to observe the effect of FASN during migration and invasion in liver cancer. Isobaric tags for relative and absolute quantitation (iTRAQ)-based mass spectrometry were used to identify proteins interacting with FASN in HepG2 cells. Differential expressed proteins were validated by co-immunoprecipitation, western blot analyses and confocal microscopy. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to demonstrate the mechanism of FASN regulating metastasis. Results: FASN knockdown inhibited migration and invasion of HepG2 and SMMC7721 cells. A total of, 79 proteins interacting with FASN were identified. Additionally, gene ontology term enrichment analysis indicated that the majority of biological regulation and cellular processes that the FASN-interacting proteins were associated with. Co-precipitation and co-localization of FASN with fascin actin-bundling protein 1 (FSCN1), signal-induced proliferation-associated 1 (SIPA1), spectrin ß, non-erythrocytic 1 (SPTBN1) and CD59 were evaluated. Knockdown of FASN in liver cancer reduced the expression of FSCN1, SIPA1, SPTBN1 and CD59. Furthermore, inhibition of FASN, FSCN1 or SPTBN1 expression in liver cancer resulted in alterations of epithelial-mesenchymal transition (EMT)-associated markers E-cadherin, N-cadherin, vimentin and transcription factors, Snail and Twist, at the mRNA level, and changes in matrix metallopeptidase (MMP)-2 and MMP-9 protein expression. Conclusion: The results suggested that the FASN-interacting protein network produced by iTRAQ-based proteomic analyses may be involved in regulating invasion and metastasis in liver cancer by influencing EMT and the function of MMPs.

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