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1.
J Hazard Mater ; 383: 121117, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31518802

RESUMO

Nitrous oxide (N2O) is an important ozone-depletion substance and greenhouse gas. Selective catalytic reduction (SCR) of N2O by CO is considered an effective method for N2O elimination. However, O2 exhibited a significant inhibition effect on the catalytic performance of N2O reduction by CO. A series of iron-based catalysts were prepared to investigate the effect of O2 in SCR of N2O by CO. The Fe-Z-pH2 (Fe-ZSM-5 ion-exchanged under pH of 2) catalyst manifested superior activity at low temperature and excellent O2 resistance in N2O reduction process. The characterization results from UV-vis DR spectra and XPS indicated that α-sites are the main active sites in Fe-Z-pH2, and they were inert to O2 but highly active to N2O. It could be concluded that the competition effect between N2O and O2 was very important over different catalysts. O2 is more prevalent over α-Fe2O3 catalyst, while N2O dominates over Fe-Z-pH2 catalyst. Moreover, in the presence of O2, Fe-Z-pH2 exhibited better performance for N2O removal than non-noble mixed oxide catalysts, which might broaden the application of low-temperature SCR of N2O by CO.

2.
J Otolaryngol Head Neck Surg ; 48(1): 61, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711544

RESUMO

BACKGROUND: The purpose of this study was to develop an effective management algorithm for lesions of third or fourth branchial sinuses. STUDY DESIGN: Case series with chart review. METHODS: Data from patients who were identified as having third or fourth branchial pouch sinus lesions in a single institution between January 2014 and December 2018 were retrospectively collected. RESULTS: All 67 patients underwent fistulectomy. First, we classified the patients into five types based on their anatomic features. Then, we considered four optimized surgical methods and adopted the appropriate method with full consideration of the patient's clinical characteristics. The great majority of cases occurred on the left side of the neck (68.7%) and most commonly presented as either a recurrent low-neck abscess or cutaneous discharging fistula with neck infection. Effective preoperative examination included administering contrast agent prior to a computed tomography (CT) scan and in-office laryngoscopy during the quiescent period of inflammation. Ultrasound was also very helpful in determining the presence of thyroiditis. The mean follow-up duration after excision of the lesion was 25.8 months. To date, only 1 (1.5%) recurrence and no obvious complications have been observed. CONCLUSION: Refining fistula subtypes and adopting corresponding treatment measures can reduce the recurrence rate and improve curative effects. We propose and advocate this treatment algorithm for all third and fourth branchial pouch lesions.

3.
Drug Des Devel Ther ; 13: 3037-3049, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692505

RESUMO

Purpose: Gastric carcinogenesis is a multistep process and is the second-highest cause of cancer death worldwide with a high incidence of invasion and metastasis. MicroRNAs (miRNAs) engage in complex interactions with the machinery that controls the transcriptome and concurrently target multiple mRNAs. Recent evidence has shown that miRNAs are involved in the cancer progression, including promoting cell-cycle, conferring resistance to apoptosis, and enhancing invasiveness and metastasis. Here, we aim to elucidate the roles of miRNAs, especially microRNA-4665-3p (miR-4665-3p), in the inhibitory effect of arsenic sulfide in gastric cancer (GC). Methods: The arsenic sulfide-induced miRNA expression alterations in AGS cells was determined by miRNA microarray. RT-PCR was used to further verify the arsenic sulfide-regulated miRNAs in GC tissues. The inhibition of miR-4665-3p on the migration and invasion of GC cells were determined by wound healing assay and transwell assay. Western blot analysis was used to detect the expression of EMT related proteins and the putative target of miR-4665-3p. Results: The miR-4665-3p was up-regulated by arsenic sulfide and showed inhibition upon the migration and invasion of GC cells. MiRBase and Western blotting indicated that miR-4665-3p directly down-regulated the oncoprotein GSE1. Morphological observation also indicated that the up-regulation of miR-4665-3p inhibits the EMT in GC cells. Conclusion: Our data demonstrates that the increased expression of miR-4665-3p induced by arsenic sulfide suppresses the cell invasion, metastasis and EMT of GC cells, and has the potential to be a novel therapeutic target in GC.

4.
Proc Natl Acad Sci U S A ; 116(48): 23909-23914, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31699816

RESUMO

Three-dimensional hierarchical morphologies widely exist in natural and biomimetic materials, which impart preferential functions including liquid and mass transport, energy conversion, and signal transmission for various applications. While notable progress has been made in the design and manufacturing of various hierarchical materials, the state-of-the-art approaches suffer from limited materials selection, high costs, as well as low processing throughput. Herein, by harnessing the configurable elastic crack engineering-controlled formation and configuration of cracks in elastic materials-an effect normally avoided in various industrial processes, we report the development of a facile and powerful technique that enables the faithful transfer of arbitrary hierarchical structures with broad material compatibility and structural and functional integrity. Our work paves the way for the cost-effective, large-scale production of a variety of flexible, inexpensive, and transparent 3D hierarchical and biomimetic materials.

5.
BMC Biotechnol ; 19(1): 76, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718625

RESUMO

BACKGROUND: Corynebacterium ammoniagenes is an important industrial organism that is widely used to produce nucleotides and the potential for industrial production of coenzyme A by C. ammoniagenes ATCC 6871 has been shown. However, the yield of coenzyme A needs to be improved, and the available constitutive promoters are rather limited in this strain. RESULTS: In this study, 20 putative DNA promoters derived from genes with high transcription levels and 6 promoters from molecular chaperone genes were identified. To evaluate the activity of each promoter, red fluorescence protein (RFP) was used as a reporter. We successfully isolated a range of promoters with different activity levels, and among these a fragment derived from the upstream sequence of the 50S ribosomal protein L21 (Prpl21) exhibited the strongest activity among the 26 identified promoters. Furthermore, type III pantothenate kinase from Pseudomonas putida (PpcoaA) was overexpressed in C. ammoniagenes under the control of Prpl21, CoA yield increased approximately 4.4 times. CONCLUSIONS: This study provides a paradigm for rational isolation of promoters with different activities and their application in metabolic engineering. These promoters will enrich the available promoter toolkit for C. ammoniagenes and should be valuable in current platforms for metabolic engineering and synthetic biology for the optimization of pathways to extend the product spectrum or improve the productivity in C. ammoniagenes ATCC 6871 for industrial applications.

6.
Drug Des Devel Ther ; 13: 3369-3381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576111

RESUMO

Background: Colorectal cancer is one of the common malignant tumors. Cyanopyridine and aminocyanopyridine having a carbon-nitrogen bond have been shown to have significant anticancer effects. STAT3 is a promising therapeutic target in multiple cancers. However, there are currently no effective STAT3 inhibitors in clinical practice for the treatment of colorectal cancer. Materials and methods: We screened 27 cyanopyridines for their anticancer activity by cell viability. The HCT-116, RKO, and DLD-1 cell lines were used to evaluate the anti-colorectal cancer effect of 3n. Scratch experiments and colony formation assays were used for the assessment of cell migration and proliferation capacity. Phosphorylated STAT3, STAT3, MCL-1, and Survivin levels were assessed by Western blot analysis. Results: In this study, we synthesized 27 cyanopyridines and screened their anticancer activities in three human tumor cells, HCT-116, Hela229, and A375. We found that 2-amino-3-cyanopyridine 3n has better anticancer activity with IC50 values in the low micromolar range. Furthermore, 3n significantly inhibited the migration and colony formation of colorectal cancer cells. Mechanistically, 3n inhibited the expression of STAT3 phosphorylation in a dose- and time-dependent manner. Conclusion: 3n is worth of further investigations toward the discovery of STAT3 inhibitor as a drug candidate for cancer therapy.

7.
Biomed Pharmacother ; 120: 109540, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639648

RESUMO

BACKGROUND: To investigate the effect of hydrogen peroxide (H2S) on myocardial clock gene Bmal1 in ischemic cardiomyocytes. MATERIALS & METHODS: Quantitative PCR (qPCR) was used to detect the expression of Bmal1 at the mRNA level in H9C2 rat cardiomyocytes. The protein expressions of Bax and Bcl-2, PI3K/Akt, caspase-3 were measured by western blotting. The levels of reactive oxygen species (ROS) were determined by ELISA. RESULTS: The expression level of clock gene Bmal1 demonstrated a clock rhythm of periodic oscillation within 24 h. Compared with the control group, H2S treatment maintained the rhythm of the clock gene in ischemic cardiomyocytes and increased the transcription and expression levels of Bmal1. H2S increased cell survival by activating PI3K/Akt signaling pathway, inhibiting mitochondrial apoptosis signaling, and reducing intracellular oxidative stress. PI3K/Akt and Bmal1 were demonstrated to be involved in H2S protection of cardiomyocyte ischemia. Knockout of Bmal1 gene affects the degree of phosphorylation of Akt and Erk proteins, and the level of ROS production, resulting in a decrease in the protective effects of H2S. CONCLUSION: The expression level of Bmal1 has effects on the function of cardiomyocytes such as ROS production. The potential mechanism by which H2S regulates clock genes may be related to the effect of clock genes on protein phosphorylation levels in ischemic cardiomyocytes.

8.
Cell Death Dis ; 10(11): 809, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649256

RESUMO

Novel drugs are urgently needed for gastric cancer (GC) treatment. The thioredoxin-thioredoxin reductase (TRX-TRXR) system has been found to play a critical role in GC tumorigenesis and progression. Thus, agents that target the TRX-TRXR system may be highly efficacious as GC treatments. In this study, we showed that chaetocin, a natural product isolated from the Chaetomium species of fungi, inhibited proliferation, induced G2/M phase arrest and caspase-dependent apoptosis in both in vitro and in vivo models (cell xenografts and patient-derived xenografts) of GC. Chaetocin inactivated TRXR-1, resulting in the accumulation of reactive oxygen species (ROS) in GC cells; overexpression of TRX-1 as well as cotreatment of GC cells with the ROS scavenger N-acetyl-L-cysteine attenuated chaetocin-induced apoptosis; chaetocin-induced apoptosis was significantly increased when GC cells were cotreated with auranofin. Moreover, chaetocin was shown to inactivate the PI3K/AKT pathway by inducing ROS generation; AKT-1 overexpression also attenuated chaetocin-induced apoptosis. Taken together, these results reveal that chaetocin induces the excessive accumulation of ROS via inhibition of TRXR-1. This is followed by PI3K/AKT pathway inactivation, which ultimately inhibits proliferation and induces caspase-dependent apoptosis in GC cells. Chaetocin therefore may be a potential agent for GC treatment.

9.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31601032

RESUMO

Epidermal cell fate determination-including trichome initiation, root hair formation, and flavonoid and mucilage biosynthesis in Arabidopsis (Arabidopsis thaliana)-are controlled by a similar transcriptional regulatory network. In the network, it has been proposed that the MYB-bHLH-WD40 (MBW) activator complexes formed by an R2R3 MYB transcription factor, a bHLH transcription factor and the WD40-repeat protein TRANSPARENT TESTA GLABRA1 (TTG1) regulate the expression of downstream genes required for cell fate determination, flavonoid or mucilage biosynthesis, respectively. In epidermal cell fate determination and mucilage biosynthesis, the MBW activator complexes activate the expression of GLABRA2 (GL2). GL2 is a homeodomain transcription factor that promotes trichome initiation in shoots, mucilage biosynthesis in seeds, and inhibits root hair formation in roots. The MBW activator complexes also activate several R3 MYB genes. The R3 MYB proteins, in turn, competing with the R2R3 MYBs for binding bHLH transcription factors, therefore inhibiting the formation of the MBW activator complexes, lead to the inhibition of trichome initiation in shoots, and promotion of root hair formation in roots. In flavonoid biosynthesis, the MBW activator complexes activate the expression of the late biosynthesis genes in the flavonoid pathway, resulting in the production of anthocyanins or proanthocyanidins. Research progress in recent years suggests that the transcriptional regulatory network that controls epidermal cell fate determination and anthocyanin biosynthesis in Arabidopsis is far more complicated than previously thought. In particular, more regulators of GL2 have been identified, and GL2 has been shown to be involved in the regulation of anthocyanin biosynthesis. This review focuses on the research progress on the regulation of GL2 expression, and the roles of GL2 in the regulation of epidermal cell fate determination and anthocyanin biosynthesis in Arabidopsis.

10.
Int Immunopharmacol ; 76: 105838, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473406

RESUMO

Hepatic fibrosis, a common pathological feature and leading cause of various chronic liver diseases, still lacks effective therapy. Hesperetin derivative (HD) is a derivative of Traditional Chinese Medicine monomer isolated from the fruit peel of Citrusaurantium L. (Rutaceae). In the present study, we revealed the anti-fibrotic effects of HD in CCl4-induced mouse hepatic fibrosis model and in TGF-ß1-activated LX-2 cells, in vivo and in vitro. Results showed that HD prevented CCl4-induced liver injury and histological damage. Consistently, HD inhibited the up-regulation of liver fibrogenesis markers α-SMA, Col1α1, Col3α1 and TIMP-1 in primary hepatic stellate cells (HSCs) and suppressed inflammatory responses in primary liver macrophages from hepatic fibrosis mice. Furthermore, HD promoted the apoptosis of activated HSCs, a key step in the onset of fibrosis regression. Mechanistically, the Hedgehog pathway was involved in HD-treated hepatic fibrosis, and HD specifically contributed to attenuate the aberrant expression of Glioma associated oncogene-1 (Gli-1). Interestingly, blockade of Gli-1 removed the inhibitory effect of HD on activated HSCs, indicating that Gli-1 may play a pivotal role in mediating the anti-fibrotic effect of HD in hepatic fibrosis. Collectively, our results suggest that HD may be a potential anti-fibrotic Traditional Chinese Medicine monomer for the treatment of hepatic fibrosis.

11.
Viruses ; 11(9)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487883

RESUMO

Plants use RNA silencing as a defense against viruses. In response, viruses encode various RNA silencing suppressors to counteract the antiviral silencing. Here, we identified p22 as a silencing suppressor of cucurbit chlorotic yellows crinivirus and showed that p22 interacts with CsSKP1LB1, a Cucumis sativus ortholog of S-phase kinase-associated protein 1 (SKP1). The F-box-like motif of p22 was identified through sequence analysis and found to be necessary for the interaction using a yeast two-hybrid assay. The involvement of the F-box-like motif in p22 silencing suppressor activity was determined. Proteomics analysis of Nicotiana benthamiana leaves expressing p22, and its F-box-like motif deletion mutant showed 228 differentially expressed proteins and five enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways: ABC transporters, sesquiterpenoid and triterpenoid biosynthesis, ubiquitin-mediated proteolysis, riboflavin metabolism, and cysteine and methionine metabolism. Collectively, our results demonstrate the interaction between p22 and CsSKP1LB1 and show that the deletion of F-box-like motif inhibits p22 silencing suppressor activity. The possible pathways regulated by the p22 through the F-box-like motif were identified using proteomics analysis.

12.
Neurosci Lett ; 713: 134493, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31518673

RESUMO

Schizophrenia patients often show deficits in facial emotion recognition, which contributes to their poor social functioning. The present study investigated the time course of categorization of emotional faces in schizophrenia patients by recording and analyzing ERPs elicited by emotional faces. Behavioral data show that in comparison with controls, schizophrenia patients categorized emotional faces more slowly with decreased accuracy and did not show evident positive classification advantage. The ERP data showed that the N170 decreased in schizophrenia patients although it was not modulated by facial emotions. In comparison with controls, schizophrenia patients exhibited the lack of frontal and posterior N2 components and decreased P3 component, without P3 modulation of emotional faces. These data provide new evidence for the dysfunction of processing emotional faces in schizophrenia patients.

13.
Am J Clin Nutr ; 110(5): 1067-1078, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504087

RESUMO

BACKGROUND: Although available data suggest that some dietary flavan-3-ol sources reduce cardiometabolic risk, to our knowledge no review has systematically synthesized their specific contribution. OBJECTIVE: We aimed to examine, for the first time, if there is consistent evidence that higher flavan-3-ol intake, irrespective of dietary source, reduces cardiometabolic risk. METHODS: MEDLINE, Cochrane Central, and Commonwealth Agricultural Bureau abstracts were searched for prospective cohorts and randomized controlled trials (RCTs) published from 1946 to March 2019 on flavan-3-ol intake and cardiovascular disease (CVD) risk. Random-effects models meta-analysis was used. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach assessed the strength of evidence. RESULTS: Of 15 prospective cohorts (23 publications), 4 found highest compared with lowest habitual intakes of flavan-3-ols were associated with a 13% reduction in risk of CVD mortality and 2 found a 19% reduction in risk of chronic heart disease (CHD) incidence. Highest compared with lowest habitual intakes of monomers were associated with a reduction in risk of type 2 diabetes mellitus (T2DM) (n = 5) and stroke (n = 4) (10% and 18%, respectively). No association was found for hypertension. Of 156 RCTs, flavan-3-ol intervention resulted in significant improvements in acute/chronic flow-mediated dilation (FMD), systolic (SBP) and diastolic blood pressure (DBP), total cholesterol (TC), LDL and HDL cholesterol, triglycerides (TGs), hemoglobin A1c (HbA1c), and homeostasis model assessment of insulin resistance (HOMA-IR). All analyses, except HbA1c, were associated with moderate/high heterogeneity. When analyses were limited to good methodological quality studies, improvements in TC, HDL cholesterol, SBP, DBP, HOMA-IR, and acute/chronic FMD remained significant. In GRADE evaluations, there was moderate evidence in cohort studies that flavan-3-ol and monomer intakes were associated with reduced risk of CVD mortality, CHD, stroke, and T2DM, whereas RCTs reported improved TC, HDL cholesterol, SBP, and HOMA-IR. CONCLUSIONS: Available evidence supports a beneficial effect of flavan-3-ol intake on cardiometabolic outcomes, but there was considerable heterogeneity in the meta-analysis. Future research should focus on an integrated intake/biomarker approach in cohorts and high-quality dose-response RCTs. This review was registered at www.crd.york.ac.uk/PROSPERO/ as CRD42018035782.

14.
Eur J Pharm Sci ; 140: 105058, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472255

RESUMO

The biofilm formation of Pseudomonas aeruginosa (P. aeruginosa) is regulated by a phenomenon of quorum sensing (QS). With 5-hydroxyl-3,4-halogenated-5H-furan-2-ones as beginning, analogs bearing alkyl chains, vinyl bromide, or aromatic rings were designed and synthesized. The minimum inhibitory concentration (MIC) of the compounds against P. aeruginosa was assayed and the biofilm inhibition ratio was determined at different concentrations lower than the MIC. C-5 aromatic substituted furanones showed remarkable biofilm formation as well as inhibition of virulence factor production in P. aeruginosa. Fluorescence report analysis identified the QS regulatory mechanism of the most active compound 29. This study provides us a novel candidate for combating drug resistant bacteria strains by merely inhibiting biofilm formation. Without suppressing the regular life cycle of the bacteria, bacterial resistance mechanisms may not be activated.

15.
J Biol Chem ; 294(44): 16141-16151, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31511324

RESUMO

Methanobactins (Mbns) are ribosomally-produced, post-translationally modified peptidic copper-binding natural products produced under conditions of copper limitation. Genes encoding Mbn biosynthetic and transport proteins have been identified in a wide variety of bacteria, indicating a broader role for Mbns in bacterial metal homeostasis. Many of the genes in the Mbn operons have been assigned functions, but two genes usually present, mbnP and mbnH, encode uncharacterized proteins predicted to reside in the periplasm. MbnH belongs to the bacterial diheme cytochrome c peroxidase (bCcP)/MauG protein family, and MbnP contains no domains of known function. Here, we performed a detailed bioinformatic analysis of both proteins and have biochemically characterized MbnH from Methylosinus (Ms.) trichosporium OB3b. We note that the mbnH and mbnP genes typically co-occur and are located proximal to genes associated with microbial copper homeostasis. Our bioinformatics analysis also revealed that the bCcP/MauG family is significantly more diverse than originally appreciated, and that MbnH is most closely related to the MauG subfamily. A 2.6 Å resolution structure of Ms. trichosporium OB3b MbnH combined with spectroscopic data and peroxidase activity assays provided evidence that MbnH indeed more closely resembles MauG than bCcPs, although its redox properties are significantly different from those of MauG. The overall similarity of MbnH to MauG suggests that MbnH could post-translationally modify a macromolecule, such as internalized CuMbn or its uncharacterized partner protein, MbnP. Our results indicate that MbnH is a MauG-like diheme protein that is likely involved in microbial copper homeostasis and represents a new family within the bCcP/MauG superfamily.

16.
J Environ Radioact ; 208-209: 106036, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31493563

RESUMO

In order to develop an artificially constructed plant community plot for the enhanced phytoremediation of uranium contaminated soils, three uranium accumulators including Bamboo-willow (Salix sp.), Paspalum scrobiculatum linn and Macleaya cordata were used to construct four artificial plant community plots, and greenhouse experiments were conducted to investigate the bioaccumulation of uranium by the plants and the organic acid content, enzyme activity, and the change of microbial community structure in their rhizosphere soils. The transfer factor (TF) and the total bioaccumulation amount (TBA) of uranium were used to describe remediation efficiencies in this paper. It was found that their remediation efficiencies were in the order Bamboo-willow (Salix sp.)-Paspalum scrobiculatum linn-Macleaya cordata > Bamboo-willow (Salix sp.)-Macleaya cordata > Paspalum scrobiculatum linn-Macleaya cordata > Bamboo-willow (Salix sp.)-Paspalum scrobiculatum linn. The bioaccumulation amount of uranium by each plant in the Bamboo-willow (Salix sp.)-Paspalum scrobiculatum linn-Macleaya cordata community plot was significantly (P < 0.05) higher than that by its single population, the bioaccumulation amounts of uranium by Bamboo-willow (Salix sp.), Paspalum scrobiculatum linn and Macleaya cordata were 0.29, 0.32 and 2.19 mg/plant, respectively, and they were increased by 31.82%, 77.78% and 146.07%, respectively, and the transfer efficiencies by the plants were increased by 150%, 110% and 52.17%, respectively. The interaction between the plants' roots and the microorganisms in the rhizosphere soil of the Bamboo-willow (Salix sp.)-Paspalum scrobiculatum linn-Macleaya cordata community plot resulted in the high content of organic acids such as oxalic acid in the rhizosphere soil of the plant community plot, which was significantly (P < 0.05) higher than that of its single population. The chelation of the organic acids with uranium led to an increase in the proportion of exchangeable uranium in soil solution. In addition, Burkholderia, which is an iron-producing carrier bacterium and can increase the uptake and accumulation of uranium by plants, and Leptolyngbya, which is a plant growth promoting rhizobacteria and can increase the biomass of plants, emerged in the rhizosphere soil of the plant community plot. These may be the mechanisms by which the phytoremediation of the uranium contaminated soils was enhanced by the plant community plot.


Assuntos
Biodegradação Ambiental , Poluentes Radioativos do Solo/metabolismo , Urânio/metabolismo
17.
Int J Biol Macromol ; 141: 1191-1198, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31518622

RESUMO

To control release of drugs sensitive to gastrointestinal (GI) environmental effects or irritating to stomach, such as diclofenac sodium (DS), sodium alginate (SA) hydrogel beads are gaining considerable attention gradually. However, due to high swelling ratio, the sustained release performance of SA hydrogel is still far from satisfactory. The objective of this research was to develop new drug delivery device based on SA and ZnO nanoparticles (ZnO NPs). ZnO NPs were prepared by direct precipitation method, and carboxymethyl chitosan (CMCS) acted as stabilizing agent to dominate the preparation of ZnO NPs. The incorporation of CMCS-ZnO NPs resulted in slower and sustained release of DS in vitro. In vivo pharmacokinetics studies showed the bioavailability of DS was better after oral administration of DS-loaded SA/CMCS-ZnO hydrogel beads. These results suggested that SA/CMCS-ZnO hydrogel beads will be a prospective material for loading drugs sensitive to GI environmental effects or irritating to stomach.

18.
Nat Commun ; 10(1): 3518, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388006

RESUMO

Diurnal light-dark cycle resets the master clock, while timed food intake is another potent synchronizer of peripheral clocks in mammals. As the largest metabolic organ, the liver sensitively responds to the food signals and secretes hepatokines, leading to the robust regulation of metabolic and clock processes. However, it remains unknown which hepatokine mediates the food-driven resetting of the liver clock independent of the master clock. Here, we identify Angptl8 as a hepatokine that resets diurnal rhythms of hepatic clock and metabolic genes in mice. Mechanistically, the resetting function of Angptl8 is dependent on the signal relay of the membrane receptor PirB, phosphorylation of kinases and transcriptional factors, and consequently transient activation of the central clock gene Per1. Importantly, inhibition of Angptl8 signaling partially blocks food-entrained resetting of liver clock in mice. We have thus identified Angptl8 as a key regulator of the liver clock in response to food.

19.
J Clin Invest ; 130: 4850-4862, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31408442

RESUMO

Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death (ICD)-inducing drugs available that can kill cancer cells, enhance tumor immunogenicity, increase the in vivo immune infiltration, and thereby boosting a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immuno-stimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still investigational. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and T cell activation assay. We identified that teniposide, a DNA topoisomerase II inhibitor, could induce high mobility group box 1 (HMGB1) release and type I interferon signaling in tumor cells, and teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling including NF-κB activation and STING-dependent type I interferon signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 on multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity, and enabled a potential chemo-immunotherapeutic approach to potentiate the therapeutic efficacy of anti-PD1 immunotherapy.

20.
J Clin Invest ; 130: 3786-3791, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31403469

RESUMO

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

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