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2.
Sci Rep ; 10(1): 8867, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483262

RESUMO

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with steadily increasing incidence and poor prognosis. Despite recent success with immunotherapy, 50% of patients still succumb to their diseases. To date, there is no Food and Drug Administration-approved targeted therapy for advanced MCC. Aberrant activation of phosphatidylinositide-3-kinase (PI3K)/AKT/mTOR pathway is frequently detected in MCC, making it an attractive therapeutic target. We previously found PI3K pathway activation in human MCC cell lines and tumors and demonstrated complete clinical response in a Stage IV MCC patient treated with PI3K inhibitor idelalisib. Here, we found that both PI3K-α and -δ isoforms are abundantly expressed in our MCC cell lines and clinical samples; we therefore examined antitumor efficacy across a panel of five PI3K inhibitors with distinctive isoform-specificities, including idelalisib (PI3K-δ), copanlisib (PI3K-α/δ), duvelisib (PI3K-γ/δ), alpelisib (PI3K-α), and AZD8186 (PI3K-ß/δ). Of these, copanlisib exerts the most potent antitumor effects, markedly inhibiting cell proliferation, survival, and tumor growth by suppressing PI3K/mTOR/Akt activities in mouse models generated from MCC cell xenografts and patient-derived tumor xenografts. These results provide compelling preclinical evidence for application of copanlisib in advanced MCC with aberrant PI3K activation for which immunotherapy is insufficient, or patients who are unsuitable for immunotherapy.

3.
Life Sci ; 256: 117971, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32553925

RESUMO

AIMS: Multiple myeloma (MM) was recently reported to rely on increased oxidative phosphorylation (OXPHOS) for survival, providing a potential opportunity for MM therapy. Herein, we aimed to propose a novel targeted drug for MM treatment, followed by the exploration of reason for OXPHOS enhancement in MM cells. MATERIALS AND METHODS: The expression of OXPHOS genes and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was analyzed using bioinformatics analyses, followed by verification in MM cell lines. The effects of SR18292 on OXPHOS were measured by qRT-PCR, Western blot, transmission electron microscopy, oxygen consumption rate and so on. The proliferation and apoptosis were evaluated by CCK-8, flow cytometry and Western blot. The efficiency and safety of SR18292 were assessed in a mouse model of MM. KEY FINDINGS: The OXPHOS genes were generally overexpressed in MM cells, which was associated with poorer prognosis of MM patients. PGC-1α, a transcriptional coactivator, was upregulated in MM cells, and MM patients with higher PGC-1α expression exhibited increased enrichment of the OXPHOS gene set. Treatment with SR18292 (an inhibitor of PGC-1α) significantly impaired the proliferation and survival of MM cells due to OXPHOS metabolism dysfunction, which leads to energy exhaustion and oxidative damage. Besides, SR18292 potently inhibited tumor growth at a well-tolerated dose in MM model mice. SIGNIFICANCE: The overexpression of OXPHOS gene set mediated by upregulated PGC-1α provides a structural basis for enhanced OXPHOS in MM cells, and SR18292 (a PGC-1α inhibitor) exerts potent antimyeloma effects, offering a potential tangible avenue for MM therapy.

4.
Food Funct ; 11(4): 2898-2909, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32242560

RESUMO

Vinegar extract is rich in phenolic compounds, which can prevent free radical-induced diseases. The aim of the present study was to explore the effects of vinegar extract on gut microbiota in alcohol-treated mice and their correlation with alcohol-induced liver damage. These results showed that vinegar extract regulated the gut microbiota composition and improved intestinal homeostasis through increasing the expression levels of ZO-1, occludin, claudin-1, Reg3b, and Reg3g in alcohol-treated mice. In addition, vinegar extract inhibited the alcohol-induced production of ROS and inflammatory factors. Moreover, Bacteroidetes, Verrucomicrobia, Akkermansia, and Lactobacillus showed a significant positive correlation with Reg3b, Reg3g, ZO-1, occludin, and claudin-1 and a negative correlation with hepatic inflammation and oxidative stress parameters. However, Firmicutes, Proteobacteria, Butyricimonas, Parabacteroides, and Bilophila exhibited the opposite effect. These findings suggest that vinegar extract modulates gut microbiota and improves intestinal homeostasis, and can be used as a novel gut microbiota manipulator against alcohol-induced liver damage.

5.
Biomed Res Int ; 2020: 9578730, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185226

RESUMO

Mounting evidences have indicated that terminal differentiation-induced lncRNA (TINCR) contributes to various cellular processes, such as proliferation, apoptosis, autophagy, migration, invasion, and metastasis. However, the function of TINCR in regulating migration of MSCs is largely unknown. In this study, the effects of TINCR on the migration of rat MSCs from the bone marrow were studied by Transwell assays and wound healing assays. Our results suggested that TINCR positively regulated migration of rMSCs. miR-761 mimics suppressed rMSC migration, whereas miR-761 inhibitor promoted migration. Target prediction analysis tools and dual-luciferase reporter gene assay identified Wnt2 as a direct target of miR-761. miR-761 could inhibit the expression of Wnt2. Further, the investigation about the function of TINCR in miR-761-induced migration of rMSCs was completed. These results demonstrated that TINCR took part in the regulation of miR-761-induced migration in rMSCs through the regulation of Wnt2 and its Wnt2 signaling pathway. Taken together, our results demonstrate that lncRNA-TINCR functions as a competitive endogenous RNA (ceRNA) to regulate the migration of rMSCs by sponging miR-761 which modulates the role of Wnt2. These findings provide evidence that lncRNA-TINCR has a chance to serve as a potential target for enhancing MSC homing through the miR-761/Wnt2 signaling pathway.

6.
Curr Med Sci ; 40(1): 63-68, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32166666

RESUMO

The contamination status of H5 avian influenza viruses and distribution of subtypes of H5N1 and H5N6 in poultry-related environment of Hubei areas were investigated. Urban and rural live poultry markets, poultry farms, intensive livestock farms and other monitoring types of 103 counties in 17 cities were selected in Hubei. Wiping samples from cage surface, wiping samples from chopping board, fecal specimens and other environmental samples were collected and tested by real-time RT-PCR using primers and probes of influenza A, avian influenza of H5, N1 and N6 from December 2017 to March 2018. The avian influenza virus positive rate was compared among different monitoring sites, samples, time and regions. Totally, 7132 environmental samples were collected in 1634 monitoring points with a positive rate of 2.24%. The positive rate of H5 avian influenza virus was the highest in urban and rural live poultry markets (3.44%, χ2=61.329, P<0.05) in 6 monitoring sites and wiping samples from chopping board (5.46%, χ2=67.072, P<0.05) in 6 sample types. H5N6 avian influenza viruses were detected more in eastern than western Hubei, and H5N6 avian influenza viruses were detected only in Xiangyang city of western Hubei. There were important high-risk places of human infection with H5 avian influenza virus in urban and rural live poultry markets and the poultry slaughtering plants. H5N6 has been the predominant subtype of H5 avian influenza viruses in the eastern and western Hubei and H5N6 avian influenza viruses were still present in a few areas of Hubei. Outbreaks of human H5N1 and H5N6 avian influenza remain at risk in Hubei province.

7.
Stem Cell Res Ther ; 11(1): 92, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111240

RESUMO

BACKGROUND: As the population ages, an increasing number of postmenopausal women are donors of adipose stromal cells (ASCs) and may benefit from autologous ASC-related treatments. However, the effect of menopausal status on ASCs has not been investigated. METHODS: RNA sequencing data were downloaded, and differentially expressed genes (DEGs) were identified. Hierarchical clustering, Gene Ontology, and pathway analyses were applied to the DEGs. Two gene coexpression network analysis approaches were applied to the DEGs to provide a holistic view and preserve gene interactions. Hub genes of the gene coexpression network were identified, and their expression profiles were examined with clinical samples. ASCs from pre- and postmenopausal women were co-cultured with monocytes and T cells to determine their immunoregulatory role. RESULTS: In total, 2299 DEGs were identified and presented distinct expression profiles between pre- and postmenopausal women. Gene Ontology and pathway analyses revealed some fertility-, sex hormone-, immune-, aging-, and angiogenesis-related terms and pathways. Gene coexpression networks were constructed, and the top hub genes, including TIE1, ANGPT2, RNASE1, PLVAP, CA2, and MPZL2, were consistent between the two approaches. Expression profiles of hub genes from the RNA sequencing data and clinical samples were consistent. ASCs from postmenopausal women elicit M1 polarization, while their counterparts facilitate CD3/4+ T cell proliferation. CONCLUSIONS: The present study reveals the transcriptome differences in ASCs derived from pre- and postmenopausal women and provides holistic views by preserving gene interactions via gene coexpression network analysis. The top hub genes identified by this study could serve as potential targets to enhance the therapeutic potential of ASCs.

8.
Cancer Res ; 80(12): 2484-2497, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32156775

RESUMO

TAp63 is a p53 family member and potent tumor and metastasis suppressor. Here, we show that TAp63-/- mice exhibit an increased susceptibility to ultraviolet radiation-induced cutaneous squamous cell carcinoma (cuSCC). A human-to-mouse comparison of cuSCC tumors identified miR-30c-2* and miR-497 as underexpressed in TAp63-deficient cuSCC. Reintroduction of these miRNAs significantly inhibited the growth of cuSCC cell lines and tumors. Proteomic profiling of cells expressing either miRNA showed downregulation of cell-cycle progression and mitosis-associated proteins. A mouse to human and cross-platform comparison of RNA-sequencing and proteomics data identified a 7-gene signature, including AURKA, KIF18B, PKMYT1, and ORC1, which were overexpressed in cuSCC. Knockdown of these factors in cuSCC cell lines suppressed tumor cell proliferation and induced apoptosis. In addition, selective inhibition of AURKA suppressed cuSCC cell proliferation, induced apoptosis, and showed antitumor effects in vivo. Finally, treatment with miR-30c-2* or miR-497 miRNA mimics was highly effective in suppressing cuSCC growth in vivo. Our data establish TAp63 as an essential regulator of novel miRNAs that can be therapeutically targeted for potent suppression of cuSCC. SIGNIFICANCE: This study provides preclinical evidence for the use of miR-30c-2*/miR-497 delivery and AURKA inhibition in the treatment of cuSCC, which currently has no FDA-approved targeted therapies.See related commentary by Parrales and Iwakuma, p. 2439.

9.
Clin Cancer Res ; 26(9): 2163-2175, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31924735

RESUMO

PURPOSE: The development of leptomeningeal melanoma metastases (LMM) is a rare and devastating complication of the late-stage disease, for which no effective treatments exist. Here, we performed a multi-omics analysis of the cerebrospinal fluid (CSF) from patients with LMM to determine how the leptomeningeal microenvironment shapes the biology and therapeutic responses of melanoma cells. EXPERIMENTAL DESIGN: A total of 45 serial CSF samples were collected from 16 patients, 8 of these with confirmed LMM. Of those with LMM, 7 had poor survival (<4 months) and one was an extraordinary responder (still alive with survival >35 months). CSF samples were analyzed by mass spectrometry and incubated with melanoma cells that were subjected to RNA sequencing (RNA-seq) analysis. Functional assays were performed to validate the pathways identified. RESULTS: Mass spectrometry analyses showed the CSF of most patients with LMM to be enriched for pathways involved in innate immunity, protease-mediated damage, and IGF-related signaling. All of these were anticorrelated in the extraordinary responder. RNA-seq analysis showed CSF to induce PI3K/AKT, integrin, B-cell activation, S-phase entry, TNFR2, TGFß, and oxidative stress responses in the melanoma cells. ELISA assays confirmed that TGFß expression increased in the CSF of patients progressing with LMM. CSF from poorly responding patients conferred tolerance to BRAF inhibitor therapy in apoptosis assays. CONCLUSIONS: These analyses identified proteomic/transcriptional signatures in the CSF of patients who succumbed to LMM. We further showed that the CSF from patients with LMM has the potential to modulate BRAF inhibitor responses and may contribute to drug resistance.See related commentary by Glitza Oliva and Tawbi, p. 2083.

10.
Sci Rep ; 10(1): 417, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31942045

RESUMO

Metasurfaces are made of subwavelength nanoantennas with a flat, ultrathin architecture, and strong capability in manipulating the propagation of light by flexible modulations on its phase, amplitude, and polarization. Conventional metallic metalenses always suffer from its low efficiencies due to large intrinsic loss. Here, we demonstrate a cavity enhanced bilayer metalens composed of aluminum nanobars and its complementary structures. The focusing and imaging experiments definitely show an improved efficiency of such kind of bilayer metalens compared with its single layer counterpart. Detailed theoretical analyses based on full-wave simulations are carried out with respect to different cavity lengthes and working wavelengths, which reveals that the improvement rightly attributes to enhanced cavity mode. Our design will not only improve the working efficiency for metalens with simplified manufacturing procedure, but also indicates more possibilities by employing the metal as electrodes.

11.
Sci Rep ; 10(1): 140, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924846

RESUMO

Macrophage migration inhibitory factor (MIF) has been recognized as a major player in the pathogenesis of atherosclerosis. This study determined the association between polymorphisms of MIF gene and acute coronary syndrome (ACS). The polymorphism of MIF gene (rs755622, rs1007888 and rs2096525) was analyzed in 1153 healthy controls and 699 ACS cases in Chinese Han population. Plasma MIF level was also measured in part of ACS patients (139/19.9%) and healthy controls (129/11.2%) randomly. Most participants including healthy controls and ACS patients carried rs755622 GG (63.1% vs. 56.7%) and CG genotypes (33.1% vs. 38.9%) and G allele of rs755622 (79.6% vs. 76.1%, respectively), while CC genotype (3.8% vs. 4.4%) and C allele (20.4% vs. 23.9%) carriers were the lowest. Multivariate logistic regression analysis showed that carriers with rs755622 C allele had a higher risk of ACS compared to other genotypes (AOR = 1.278, 95% CI: 1.042-1.567). In addition, CC genotype carriers had the highest plasma levels of MIF than other genotype carriers. The MIF level in ACS patients with CC genotype was significantly higher than ACS patients carrying GG genotype and healthy controls carrying 3 different genotypes of MIF gene rs755622. Our findings indicate that MIF gene rs755622 variant C allele is associated with increased risk of ACS. Identification of this MIF gene polymorphism may help for predicting the risk of ACS.

12.
Bioinformatics ; 36(1): 257-263, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199438

RESUMO

MOTIVATION: Missingness in label-free mass spectrometry is inherent to the technology. A computational approach to recover missing values in metabolomics and proteomics datasets is important. Most existing methods are designed under a particular assumption, either missing at random or under the detection limit. If the missing pattern deviates from the assumption, it may lead to biased results. Hence, we investigate the missing patterns in free mass spectrometry data and develop an omnibus approach GMSimpute, to allow effective imputation accommodating different missing patterns. RESULTS: Three proteomics datasets and one metabolomics dataset indicate missing values could be a mixture of abundance-dependent and abundance-independent missingness. We assess the performance of GMSimpute using simulated data (with a wide range of 80 missing patterns) and metabolomics data from the Cancer Genome Atlas breast cancer and clear cell renal cell carcinoma studies. Using Pearson correlation and normalized root mean square errors between the true and imputed abundance, we compare its performance to K-nearest neighbors' type approaches, Random Forest, GSimp, a model-based method implemented in DanteR and minimum values. The results indicate GMSimpute provides higher accuracy in imputation and exhibits stable performance across different missing patterns. In addition, GMSimpute is able to identify the features in downstream differential expression analysis with high accuracy when applied to the Cancer Genome Atlas datasets. AVAILABILITY AND IMPLEMENTATION: GMSimpute is on CRAN: https://cran.r-project.org/web/packages/GMSimpute/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

13.
Biomaterials ; 227: 119552, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31670079

RESUMO

Bone healing is a complex physiological process initiated by early regulation of the inflammatory immunity and entails multiple events including angiogenesis, osteogenic differentiation, and biomineralization. Here, we fabricated an injectable periosteal extracellular matrix (PEM) hydrogel that dynamically integrates multiple biological functions and, therefore, acts at different stages of the fracture healing process. PEM hydrogels were fully characterized compared with a collagen I hydrogel. The effects of PEM hydrogels on the different phases of the healing process were assessed in vitro. PEM hydrogels induced the recruitment and M2-polarization of macrophages, promoted the differentiation of MSCs into endothelial-like cells, HUVEC tube formation, osteogenic differentiation of primary calvarial osteoblasts and MSCs, and mineralization after being immersed in simulated body fluid. The dynamic and multiphase effects of the hydrogels were evaluated using a rat critical-sized calvarial defect model in vivo. During the early phase of repair, PEM hydrogels facilitated the M1-to-M2 transition of macrophages. As bone repair progressed, PEM hydrogels promoted blood vessel migration, the development of relative larger blood vessels, and functional vascularization. These effects were also verified in a subcutaneous embedding model. Eventually, PEM hydrogels promoted mature bone formation in large bone defects to a greater extent than collagen I hydrogels. These biological effects coordinated well with the natural process of bone regeneration. Thus, PEM hydrogels may serve as promising biomaterials in bone tissue engineering.

14.
Parasit Vectors ; 12(1): 542, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727141

RESUMO

BACKGROUND: Larvae of Echinococcus granulosus (sensu lato) dwell in host organs for a long time but elicit only a mild inflammatory response, which indicates that the resolution of host inflammation is necessary for parasite survival. The recruitment of alternatively activated macrophages (AAMs) has been observed in a variety of helminth infections, and emerging evidence indicates that AAMs are critical for the resolution of inflammation. However, whether AAMs can be induced by E. granulosus (s.l.) infection or thioredoxin peroxidase (TPx), one of the important molecules secreted by the parasite, remains unclear. METHODS: The activation status of peritoneal macrophages (PMs) derived from mice infected with E. granulosus (sensu stricto) was analyzed by evaluating the expression of phenotypic markers. PMs were then treated in vivo and in vitro with recombinant EgTPx (rEgTPx) and its variant (rvEgTPx) in combination with parasite excretory-secretory (ES) products, and the resulting activation of the PMs was evaluated by flow cytometry and real-time PCR. The phosphorylation levels of various molecules in the PI3K/AKT/mTOR pathway after parasite infection and antigen stimulation were also detected. RESULTS: The expression of AAM-related genes in PMs was preferentially induced after E. granulosus (s.s.) infection, and phenotypic differences in cell morphology were detected between PMs isolated from E. granulosus (s.s.)-infected mice and control mice. The administration of parasite ES products or rEgTPx induced the recruitment of AAMs to the peritoneum and a notable skewing of the ratio of PM subsets, and these effects are consistent with those obtained after E. granulosus (s.s.) infection. ES products or rEgTPx also induced PMs toward an AAM phenotype in vitro. Interestingly, this immunomodulatory property of rEgTPx was dependent on its antioxidant activity. In addition, the PI3K/AKT/mTOR pathway was activated after parasite infection and antigen stimulation, and the activation of this pathway was suppressed by pre-treatment with an AKT/mTOR inhibitor. CONCLUSIONS: This study demonstrates that E. granulosus (s.s.) infection and ES products, including EgTPx, can induce PM recruitment and alternative activation, at least in part, via the PI3K/AKT/mTOR pathway. These results suggest that EgTPx-induced AAMs might play a key role in the resolution of inflammation and thereby favour the establishment of hydatid cysts in the host.


Assuntos
Echinococcus granulosus/imunologia , Macrófagos Peritoneais/imunologia , Proteína Oncogênica v-akt/metabolismo , Peroxirredoxinas/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Equinococose/parasitologia , Echinococcus granulosus/enzimologia , Feminino , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Peroxirredoxinas/farmacologia , Fenótipo , Fosforilação , Transdução de Sinais , Organismos Livres de Patógenos Específicos
15.
Light Sci Appl ; 8: 99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31728191

RESUMO

Tomography is an informative imaging modality that is usually implemented by mechanical scanning, owing to the limited depth-of-field (DOF) in conventional systems. However, recent imaging systems are working towards more compact and stable architectures; therefore, developing nonmotion tomography is highly desirable. Here, we propose a metalens-based spectral imaging system with an aplanatic GaN metalens (NA = 0.78), in which large chromatic dispersion is used to access spectral focus tuning and optical zooming in the visible spectrum. After the function of wavelength-switched tomography was confirmed on cascaded samples, this aplanatic metalens is utilized to image microscopic frog egg cells and shows excellent tomographic images with distinct DOF features of the cell membrane and nucleus. Our approach makes good use of the large diffractive dispersion of the metalens and develops a new imaging technique that advances recent informative optical devices.

16.
EMBO Mol Med ; 11(12): e10849, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31633874

RESUMO

The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate-limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self-renewal of lung cancer stem-like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self-renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self-renewal through AMPK-YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK-mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline-inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC-mediated therapy resistance and metastatic recurrence.


Assuntos
Neoplasias Pulmonares/enzimologia , Mitocôndrias/enzimologia , Células-Tronco Neoplásicas/enzimologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Células A549 , Linhagem Celular Tumoral , DNA Mitocondrial/genética , Humanos , Imuno-Histoquímica , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
17.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652563

RESUMO

Zhenjiang aromatic vinegar (ZAV) is one of the famous Chinese vinegars, which contains various physicochemical and bioactive compositions. In the present study, physicochemical properties and total antioxidant activity were detected in ZAV samples. The correlation between of organic acids, amino acids, phenolic compounds, and the antioxidant activity of ZAV were explored. The results showed that contents of total acids, soluble solids, reducing sugar and total antioxidant activity in ZAV were increased with aging time, and those in ZAV-5 were the highest. Organic acids and amino acids exhibited weak antioxidant activity, while phenolic compounds had higher antioxidant ability. In addition, amino acids had synergistic effect on the antioxidant activity of phenolic compounds, whereas organic acids inhibited the antioxidant activity of phenolic compounds. Moreover, it was found that phenolic compounds including catechin, vanillic acid and syringic acid showed higher contribution rates to antioxidant activities of mixed phenolic compounds. In conclusion, these findings would provide references to control the antioxidant characteristic of vinegar through regulating the main compositions, and further improve the quality of vinegar production.


Assuntos
Ácido Acético/química , Aminoácidos/química , Antioxidantes/química , Fenóis/química , Ácido Acético/metabolismo , Ácido Acético/farmacologia , Aminoácidos/farmacologia , Antioxidantes/farmacologia , Catequina/metabolismo , Sinergismo Farmacológico , Ácido Gálico/análogos & derivados , Ácido Gálico/metabolismo , Fenóis/metabolismo , Fenóis/farmacologia , Ácido Vanílico/metabolismo
18.
Cell Rep ; 28(11): 2824-2836.e8, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509745

RESUMO

The deregulation of the actin cytoskeleton has been extensively studied in metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton dysregulation is poorly understood. Here, we report that fascin, an actin-bundling protein, promotes lung cancer metastatic colonization by augmenting metabolic stress resistance and mitochondrial oxidative phosphorylation (OXPHOS). Fascin is directly recruited to mitochondria under metabolic stress to stabilize mitochondrial actin filaments (mtF-actin). Using unbiased metabolomics and proteomics approaches, we discovered that fascin-mediated mtF-actin remodeling promotes mitochondrial OXPHOS by increasing the biogenesis of respiratory Complex I. Mechanistically, fascin and mtF-actin control the homeostasis of mtDNA to promote mitochondrial OXPHOS. The disruption of mtF-actin abrogates fascin-mediated lung cancer metastasis. Conversely, restoration of mitochondrial respiration by using yeast NDI1 in fascin-depleted cancer cells is able to rescue lung metastasis. Our findings indicate that the dysregulated actin cytoskeleton in metastatic lung cancer could be targeted to rewire mitochondrial metabolism and to prevent metastatic recurrence.

19.
FASEB J ; 33(12): 13254-13266, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31539281

RESUMO

Macrophages (Mφs) can be used as a part of cell-based cancer immunotherapy. However, they may be hampered by a failure to effectively and stably regulate their polarization state to enhance their tumoricidal effects. In this work, mechanical stretch (MS), as a biology-free modulatory method, was shown to enhance M1 polarization and tumoricidal effects. By using an in vitro Flexcell Tension system, we found that murine Mφ RAW264.7 cells showed higher M1 polarization-related mRNA expression and cytokine release after MS. Further molecular analyses found that focal adhesion kinase and NF-κB activation occurred in the MS-induced M1 polarization. Coculture of MS-preconditioned Mφ with B16F10 skin melanoma cells in vitro showed that the proliferation of B16F10 cells decreased, whereas caspase-3-induced apoptosis increased. Importantly, the injection of MS-preconditioned Mφ into murine skin melanomas in vivo impeded tumor growth; lesions were characterized by increased amounts of M1 Mφ, decreased tumor cell proliferation, and increased tumor cell apoptosis in the tumor microenvironment. Together, our results suggest that MS could be used as a simple preconditioning approach to prepare tumoricidal M1 Mφ for cancer immunotherapy.-Shan, S., Fang, B., Zhang, Y., Wang, C., Zhou, J., Niu, C., Gao, Y., Zhao, D., He, J., Wang, J., Zhang, X., Li, Q. Mechanical stretch promotes tumoricidal M1 polarization via the FAK/NF-κB signaling pathway.

20.
Hepatol Commun ; 3(8): 1085-1097, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31388629

RESUMO

Farnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid-derived FXR agonist obeticholic acid (OCA) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of the novel nonbile acid FXR agonist tropifexor (LJN452) in two distinct preclinical models of NASH. The efficacy of tropifexor at <1 mg/kg doses was superior to that of OCA at 25 mg/kg in the liver in both NASH models. In a chemical and dietary model of NASH (Stelic animal model [STAM]), tropifexor reversed established fibrosis and reduced the nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin-resistant obese NASH model (amylin liver NASH model [AMLN]), tropifexor markedly reduced steatohepatitis, fibrosis, and profibrogenic gene expression. Transcriptome analysis of livers from AMLN mice revealed 461 differentially expressed genes following tropifexor treatment that included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on preclinical validation in animal models, tropifexor is a promising investigational therapy that is currently under phase 2 development for NASH.

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