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1.
Microvasc Res ; : 103988, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32057731

RESUMO

OBJECTIVE: Resveratrol has shown benefit for pulmonary hypertension improvement. Our previous reports showed NR4A3/cyclin D1 pathway promoted pulmonary arterial smooth muscle cells (PASMCs) proliferation. This study tried to explore the mechanism underlying this process, focusing on the role of resveratrol in regulation of miRNA and NR4A3. METHODS: Rats were injected with monocrotaline (MCT) to establish pulmonary hypertension (PH) models. Resveratrol was used to prevent pulmonary vascular remodeling. Primary rat PASMCs were cultured in vitro and stimulated by platelet-derived growth factor (PDGF) with or without resveratrol. Cells proliferation and expression of miR-638 as well as NR4A3 were evaluated. RESULTS: MCT resulted in significant pulmonary vascular remodeling and down-regulation of miR-638, which could be suppressed by resveratrol. Moreover, PDGF-induced PASMC proliferation and miR-638 down-regulation were both significantly prevented by resveratrol treatment in vitro. MiR-638 mimics markedly inhibited PASMC proliferation and percentage of PCNA-positive cells in vitro. But anti-miR-638 could markedly promote cells proliferation and percentage of PCNA-positive cells. The luciferase reporter assay showed that NR4A3 was a direct target of miR-638. The loss-of-function and gain-of-function experiments indicated that NR4A3 promoted proliferation via cyclin D1 pathway. CONCLUSION: Our data indicated that resveratrol prevented MCT-induced pulmonary vascular remodeling via miR-638 regulating NR4A3/cyclin D1 pathway.

2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 242-247, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027284

RESUMO

OBJECTIVE: To investigate the preventive and therapeutic effects of endothelial progenitor cells on monocrotaline-induced hepatic vein occlusion disease in mice. METHODS: C57BL/6 mice were randomly divided into 3 groups: saline group (n=15), monocrotaline group (n=15), and endothelial progenitor cell infusion group (n=15). Liver function (TBIL, ALT, AST), liver index, and serum levels of TNF-α and IL-6 were measured on the 8th day after intragastric administration. Hepatic sinusoidal endothelial cells, hepatic central venous endothelial cells and hepatocytes were observed by both HE and immunohistochemical staining. Hepatic fibrosis was observed by Masson's trichrome staining. RESULTS: By the light microscopy, the liver of the monocrotaline group showed moderate to the severe injuries of hepatic sinusoidal and central venous endothelial cells, and hepatic venous congestion. Masson staining showed moderate to severe hepatic fibrosis of central vein and hepatic sinus. In the endothelial progenitor cell group, hepatic sinusoidal and central venous endothelial cell injuries, and the fibrosis of central hepatic vein and hepatic sinus were mild to moderate. Hepatic venous congestion was reduced in comparison with that in the mice of the monocrotaline group. Compared with the endothelial progenitor cell group, the liver index was higher, the liver function was more abnormal, and the serum expression levels of TNF-α and IL-6 were higher in the monocrotaline group. CONCLUSION: The monocrotaline-induced damage of hepatic sinusoidal and central venous endothelial cells is an linitiating factor for hepatic vein occlusive disease. Infusion of endothelial progenitor cells can play a role in preventing and treating hepatic vein occlusion.

3.
Opt Lett ; 45(3): 722-725, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32004294

RESUMO

We report on the first, to the best of our knowledge, direct generation of pulsed vortex beams at 2 µm from a ${ Q}$Q-switched Tm:LuYAG laser. High-energy Laguerre-Gaussian (${{\rm LG}_{0,l}}$LG0,l) pulsed laser beams with well-defined handedness are selectively excited through spatially matched pump gain distribution and asymmetric cavity loss without using any intracavity handedness-selective optical elements. Pulse energies of 1.48 mJ for the ${{\rm LG}_{0, + 1}}$LG0,+1 mode and 1.51 mJ for the ${{\rm LG}_{0, - 1}}$LG0,-1 mode, respectively, are achieved at a repetition rate of 500 Hz. The pulsed laser beams with helical wavefronts are potentially useful for studying orbital angular momentum transformation dynamics, generation of mid-IR vortex beams, and nanostructuring of organic materials.

4.
Dev Comp Immunol ; : 103634, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32004542

RESUMO

C8α and C9 mediate the membrane attack complex formation and bacterial lysis and are important components in the complement system. The cDNA sequences of the C8α and C9 genes were cloned from Takifugu rubripes. The full-length cDNA of Tr-C8α was 1,893 bp and included a 5'-UTR of 69 bp and 3'-UTR of 83 bp. The full-length cDNA of Tr-C9 was 2083 bp and included a 5'-UTR of 72 bp and 3'-UTR of 250 bp. The expression of Tr-C8α and Tr-C9 was detected in newly fertilized eggs of T. rubripes. The expression of these two genes was at a higher level in the liver than in other tissues tested. After lipopolysaccharide (LPS) challenge, the gene expression of Tr-C8α and Tr-C9 increased more significantly in the liver. With these combined results, we further understood how Tr-C8α and Tr-C9 function in the innate immunity of pufferfish. Our findings could deepen the understanding of immune regulation in pufferfish.

5.
BMC Plant Biol ; 20(1): 52, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005164

RESUMO

BACKGROUND: Carrot (Daucus carota subsp. carota L.) is an important root crop with an available high-quality genome. The carrot genome is thought to have undergone recursive paleo-polyploidization, but the extent, occurrences, and nature of these events are not clearly defined. RESULTS: Using a previously published comparative genomics pipeline, we reanalysed the carrot genome and characterized genomic fractionation, as well as gene loss and retention, after each of the two tetraploidization events and inferred a dominant and sensitive subgenome for each event. In particular, we found strong evidence of two sequential tetraploidization events, with one (Dc-α) approximately 46-52 million years ago (Mya) and the other (Dc-ß) approximately 77-87 Mya, both likely allotetraploidization in nature. The Dc-ß event was likely common to all Apiales plants, occurring around the divergence of Apiales-Bruniales and after the divergence of Apiales-Asterales, likely playing an important role in the derivation and divergence of Apiales species. Furthermore, we found that rounds of polyploidy events contributed to the expansion of gene families responsible for plastidial methylerythritol phosphate (MEP), the precursor of carotenoid accumulation, and shaped underlying regulatory pathways. The alignment of orthologous and paralogous genes related to different events of polyploidization and speciation constitutes a comparative genomics platform for studying Apiales, Asterales, and many other related species. CONCLUSIONS: Hierarchical inference of homology revealed two tetraploidization events that shaped the carrot genome, which likely contributed to the successful establishment of Apiales plants and the expansion of MEP, upstream of the carotenoid accumulation pathway.

6.
J Control Release ; 320: 293-303, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32004584

RESUMO

Treatment of solid tumors by chemotherapy is usually failed in clinical because of its low effectiveness and side effects. Stimulation of immune system in vivo to fight cancer has been proved to be a pleasant complementary to systemic chemotherapy. Herein, we have developed a combination cancer therapy strategy by using polymer nanoparticles to deliver Gd-metallofullerenol and doxorubicin simultaneously. The Gd-metallofullerenol provoked the Th1 immune response by regulating the M1 macrophage polarization and the doxorubicin realized direct tumor cells killing by its cytotoxic effect. Also, the Gd-metallofullerenol as part of component in delivery system enhances the encapsulation efficiency of doxorubicin in polymer cargo for potential passive tumor target. The biocompatible and reliable method by combining nanoparticle-induced immune modulation and chemotherapy triggers systemic antitumor immune responses for the synergistic inhibition of tumor growth in vivo. The integration of Gd-metallofullerenol and doxorubicin with potentially complementary functions in one nanoplatform may provide new opportunities to improve cancer treatments.

7.
J Hazard Mater ; 391: 122206, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32036317

RESUMO

Increasing environmental exposure to silica nanoparticles (SiNPs) and limited cardiotoxicity studies posed a challenge for the safety evaluation and management of these materials. This study aimed to explore the adverse effects and underlying mechanisms of subacute exposure to SiNPs on cardiac function in rats. Results from echocardiographic, ultrastructural and histopathological analysis found that SiNPs induced cardiac contractile dysfunction, accompanied by incomplete myocardial structures, disordered sarcomere segments, interstitial edema and myocyte apoptosis in heart. Levels of myocardial enzymes and inflammatory factors were markedly increased in both serum and heart tissue, accompanied by elevated levels of oxidative damage occurred in the hearts of SiNPs-treated rats. SiNPs significantly upregulated the expressions of inflammation and contraction-related proteins, including JNK, p-JNK, c-Jun, TF and PAR1. Lentivirus transfection of JNK shRNA showed the low-expression of JNK-facilitated F-actin and inhibited TF in the SiNPs-treated cardiomyocytes. Moreover, SiNPs activated the mRNA and protein levels of JNK/TF/PAR1 pathway, and these effects were significantly dampened after JNK knock down. Our results demonstrate that SiNPs trigger myocardial contractile dysfunction via JNK/TF/PAR1 signaling pathway.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32055912

RESUMO

Nitrate accumulation causes long-time threat to aquatic animals in recirculating aquaculture system (RAS); thus, nitrate removal is also required in RASs. However, the lack of carbon sources makes denitrification difficult to function. Nitrate removal performance of an aerobic denitrifying and extracellular polyhydroxyalkanoate depolymerase-producing bacterium, Pseudomonas sp. AOB-7, using polyhydroxyalkanoate (PHA) granules as a solid sustained-release carbon source in RAS was evaluated. With the initial nitrate-N concentration of 140 mg/L, the high denitrification rates of 0.056 g NO3--N L-1 day-1 and 0.035 g NO3--N L-1 day-1 were achieved in denitrification medium containing poly-ß-hydroxybutyrate (PHB) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), respectively. Significant erosions and pits formed on the surface of the granules made them a good biofilm carrier for AOB-7, and 3-hydroxybutyrate (3-HB) monomer was the major product released to aquatic phase, which was benefit to animals. SEM photos showed that AOB-7 entered and attached on the inside of the PHA particle holes. A 4-week application trial was conducted to reveal the effects of PHB (AOB-7) denitrifying agent and 3-HB produced on growth of zebrafish (Brachydanio rerio) by adding 0.1% (w/v) PHB (AOB-7) denitrifying agent. Result indicated that PHB (AOB-7) denitrifying agent can significantly reduce nitrate-N content in RASs. Compared with the control group, feed coefficient ratio reduced by 18% and weight gain ratio increased by 29% in the PHB (AOB-7) denitrifying agent group. 3-HB monomer produced during the denitrification was speculated to function as a prebiotic and promote zebrafish growth. KEY POINTS: • AOB-7 showed a good aerobic denitrifying ability on PHA granules as sustained-release C source. • PHB (AOB-7) denitrifying agent can significantly reduce nitrate content in RAS. • R-3-HB monomer was the major product released to aquatic phase and function as a prebiotic.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32003217

RESUMO

In view of the limitations of practical applications of current triboelectric nanogenerators (TENGs), a new type of coating TENGs with antiwear and healing properties have been fabricated to collect the large-scale dissipative energy in the environment. To enhance the triboelectrification performance of the coating TENG, mesoporous silica filled with perfluorooctylethanol is added to the acrylate resin material, in addition to improving the antiwear properties of the frictional coating. The result shows that when the mesoporous silica is used as a carrier and perfluorooctylethanol is loaded, the short-circuit current (Isc) and output voltage (Vo) of the coating TENG reach as high as 10 µA and 220 V, respectively, which are 4-5 times higher than those of pure acrylate. More importantly, the coefficient of friction of the new coating decreases from 0.11 to 0.04 with the wear volume reducing by approximately 89%, indicating a better friction-reducing property of the coating for long-term working. As a new coating material based on the traditional acrylic resin, it can be widely sprayed onto various walls, metals, and hulls as protection coating as well as power-generation coating. Interestingly, when the coating is damaged due to long-term aging or external mechanical forces, it can restore its triboelectric performance by encapsulating the repair agent within the pore structure of silica. Owing to the large-area fabrication, low cost, high output performance, and antiwear properties, the new coating TENGs have promising potential for practical applications in energy-harvesting, self-energy supplies, and self-powered sensors.

10.
Sci Rep ; 10(1): 1814, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020024

RESUMO

Rice straw was substituted for sawdust at five different ratios of 0, 20%, 40%, 60%, and 80% (Control, RS20, RS40, RS60 and RS80, respectively) to obtain five kinds of Lentinula edodes. The effects of adding cropped rice straw to substrate formulas on the proximate composition and non-volatile taste compounds in mushrooms were investigated. The control group had the highest level of MY and BE among the five formulations. The protein levels in mushrooms decreased with the addition of rice straw and the ash levels increased. We found that trehalose, mannitol, and arabitol were the main soluble sugars in the five kinds of mushrooms. The contents of total free amino acids varied from 16.29 to 24.59 mg/g and the highest level of free amino acids was found in mushrooms cultivated from RS20 and RS40. Moreover, the addition of rice straw improved the contents of monosodium glutamate (MSG)-like amino acids in mushrooms. The 5'-Nucleotide levels ranged from 1.66 to 4.48 mg/g and equivalent umami concentration (EUC) value increased with the addition of rice straw. Our results suggest that rice straw is a potential substitute for sawdust to cultivate L. edodes with more non-volatile taste compounds.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32020783

RESUMO

OBJECTIVE: Sarcopenia in older adults is closely related to vitamin D deficiency and reduced levels of physical activity, but little has been reported on the interaction between physical activity and the positive effects of vitamin D. The purpose of this study was to explore the interactive effect of vitamin D and physical activity on muscle mass and function through animal experiments and population surveys. METHODS: Male 4-week-old C57BL/6J mice were fed different purified diets: a vitamin D-deficient diet (with increased calcium and phosphorus to prevent the effects of abnormal mineral levels on muscle) or a 1,25-dihydroxyvitamin D3 (1,25D)-supplemented diet. After 24 weeks on the assigned diets, the mice were immobilized. The level of skeletal muscle atrophy in the mice was determined by grip strength, gastrocnemius (GA) muscle mass and muscle fiber cross-sectional area (CSA); additionally, the protein expression levels of FOXO3a and the E3 ubiquitin ligases MuRF1 and MAFbx were detected. A cross-sectional study included data from 4139 older adults (64.9% women, 67.9 ± 6.7 years) as part of a survey in Shenyang, Northeast China. The associations of serum 25(OH)D3 and physical activity with timed up and go test (TUG) performance, handgrip strength, calf circumference, and body muscle mass were assessed by a linear regression analysis that was adjusted for covariates. RESULTS: In activity-limited mice, vitamin D deficiency accelerated the decrease in GA muscle weight, muscle fiber CSA, and grip strength and increased the protein expression of MuRF1, MAFbx, and FOXO3a (all P < 0.05). In addition, 1,25D supplementation may inhibit the grip-strength reduction induced by limited activity (P = 0.069). Serum 25(OH)D3 and physical activity were linearly related to TUG time (P < 0.001) and handgrip strength (P < 0.05) after adjustment for sex, age, body mass index (BMI), education level, smoking status, and serum calcium level. Serum 25(OH)D3 and physical activity had interactive effects on TUG (P < 0.001) and handgrip strength (P < 0.05) but not calf circumference or body muscle mass in older adults. CONCLUSIONS: The effect of vitamin D on muscle strength and physical performance depends on physical activity level in the elderly. It is recommended that older adults strive to avoid both physical inactivity and vitamin D deficiency. Because physical inactivity and vitamin D deficiency may exacerbate muscle atrophy, the biological mechanism may involve synergistic effects of vitamin D and physical activity on the promotion of muscle protein ubiquitination and degradation.

12.
Forensic Sci Int Genet ; 46: 102255, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-32007673

RESUMO

Paternity testing involving close relatives is facing challenges in the field of forensic genetics. Microhaplotype has been proposed as a promising genetic marker for their low mutation rates and high discrimination power recently. In this study, we selected 30 microhaplotypes from 1000 genome projects, including one non-binary SNP, and other six microhaplotypes from published studies containing only binary SNPs to established a panel of microhaplotypes for paternity testing. Most microhaplotypes generated a high effective number of alleles (Ae) with the harmonic mean value of Ae of 3.91 and the arithmetic mean value of heterozygosity of 0.74, respectively. We collected 54 unrelated individuals and 53 samples from six extended families. It was noting that 13 samples from six extended families were unrelated so they were also included in unrelated individuals. The pedigrees of 38 parent-child duos, 55 uncle/aunt/grandparent-child duos (non-biological parent-child duos) and 29 full sibling pairs were constructed based on 53 samples from six extended families. The genotype and haplotype results demonstrated that the combined power of discrimination (CPD) reached 0.99999999999999999999999999999999799 and the cumulative probability of exclusion (CPE) reached 0.999999999999548. The combined probability of excluding relatives (uncle/aunt/grandparent) (CPER) was 0.999999993 (>0.9999), indicating that our panel had good effectiveness in preventing the misinterpretation of close relatives being biological parents. For 38 parent-child duos, the CPI by using the microhaplotypes panel was higher than the one by using Goldeneye 20A kit due to higher polymorphism and more loci in our panel. For 55 non-biological parent-child duos, the CPIs by using STR loci could not help determine 9 non-biological parent-child duos as "exclusions" of paternity while the CPIs by using microhaplotype loci could not help exclude the parenthood of 4 non-biological parent-child duos (CPI > 0.0001). Using the CPI derived from both datasets of STRs and microhaplotypes, all the non-biological parent-child duos could be considered as exclusions. The efficiency of excluding close relatives for this panel was evaluated by analyzing the parameters of 2000 simulated pairs, and the effectiveness was 0.988 at the threshold of t1 = 4 and t2 = -4. Moreover, the average Log10 combined full sibling index (CFSI) for all 29 full sibling pairs was about 7.55 after physical linkage taken account. These data demonstrated that this nonbinary SNPs-based microhaplotype panel has advantages in paternity testing, especially in STR mutated or close relatives involved cases.

13.
Lancet ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007143

RESUMO

BACKGROUND: In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. METHODS: In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. FINDINGS: Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. INTERPRETATION: The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. FUNDING: National Key R&D Program of China.

14.
Exp Hematol ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007477

RESUMO

Histone lysine demethylase KDM5 family is implicated in normal development and stem cell maintenance by epigenetic modulation of histone methylation status. Deregulation of KDM5 family was reported in various types of cancers, including hematological malignancies. However, their transcriptional regulatory roles in the context of leukemia remain unclear. Here, we find that KDM5B expression is strongly expressed in normal CD34+ hematopoietic stem/progenitor cells and chronic myeloid leukemia (CML) cells. Knockdown of KDM5B in K562 CML cells reduced leukemia colony-forming potential. Transcriptome profiling of KDM5B knockdown K562 cells demonstrated the deregulation of genes involved in myeloid differentiation and Toll-like receptor signaling. Through the integration of transcriptome and ChIP-seq profiling data, we show that KDM5B is enriched at the binding sites of GATA and AP-1 transcription factor families, suggesting their collaborations in the regulation of transcription. Even though the binding of KDM5B substantially overlapped with H3K4me1 or H3K4me3 mark at gene promoters, only a small subset of the KDM5B targets showed differential expression in association with the histone demethylation activity. By characterizing the interacting proteins in K562 cells, we discover that KDM5B recruits protein complexes involved in the mRNA processing machinery, implying an alternative epigenetic action mediated by KDM5B in gene regulation. Our study highlights the oncogenic functions of KDM5B in CML cells and suggests that KDM5B is vital to the transcriptional regulation via multiple epigenetic mechanisms.

16.
Drug Deliv ; 27(1): 258-268, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32009475

RESUMO

In this paper, we prepared doxorubicin-loaded folic acid-functionalized pH-sensitive photothermal therapy (PTT) traceable hollow mesoporous silica nanoparticles (DOX-HPCF) as a drug carrier for liver cancer treatment. According to TEM characterization, hollow mesoporous silica nanoparticles (HMSN) are monodispersed spherical particles with hollow structure. In vitro drug release experiments showed that HPCF exhibited pH-sensitive release. Cell uptake experiments showed that HPCF was successfully absorbed by SMMC-7721 cells. In addition, DOX-HPCF significantly inhibited the proliferation of SMMC-7721 cells, and the near-infrared (NIR) light group showed a more obvious inhibitory effect. In vivo anti-tumor experiments showed that DOX-HPCF-assisted PTT inhibited tumor growth significantly. Therefore, HPCF is a promising photothermotherapy carrier for the treatment of liver cancer.

17.
Medicine (Baltimore) ; 99(3): e18875, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011513

RESUMO

RATIONALE: In surgery of the lower jaw, the application of computer-assisted navigation is complicated and challenging due to the mobile nature of the mandible. In this study, we presented a computer-assisted navigation surgery for removal of the foreign body in the lower jaw with a mandible reference frame, basing on the strategy that the mandible is independent as an entity. PATIENT CONCERNS: A 41-year-old male patient, identified as having a broken fissure bur that displaced into the mandibular lingual soft tissue, was referred to our department. The fissure bur broke accidentally and then displaced into the soft tissue when the patient underwent extraction of the left mandibular impacted third molar. DIAGNOSIS: A metallic foreign body in the left lower jaw, confirmed by orthopantomography. INTERVENTIONS: A computer-assisted navigation surgery with a customized mandible reference frame. OUTCOMES: The broken bur was removed successfully. Satisfactory wound healing and mouth opening was achieved, without postoperative complications. LESSONS: Surgeons should be alert to the presence of broken bur in the lower jaw and avoid its displacement into deep facial space, and computer-assisted navigation with a mandible reference frame is recommended for removal of the foreign body in the lower jaw.

18.
Cancer Res ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029551

RESUMO

For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC, and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (Hyd) in Drosophila, Hyd suppressed dMyc-dependent overgrowth of wing imaginal discs. In contrast, in cancer cells UBR5 suppressed MYC-dependent priming to therapy-induced apoptosis. Of direct cancer relevance, MYC and UBR5 genes were co-amplified in MYC-driven human cancers. Functionally, UBR5 suppressed MYC-mediated apoptosis in p53-mutant breast cancer cells with UBR5/MYC co-amplification. Further, single-cell immunofluorescence analysis demonstrated reciprocal expression of UBR5 and MYC in human basal-type breast cancer tissues. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC activity. In MYC amplified, and p53-mutant breast cancer cells, UBR5 has an important role in suppressing MYC-mediated apoptosis priming and in protection from drug-induced apoptosis.

19.
Nat Cell Biol ; 22(2): 167-174, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32029896

RESUMO

Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)1-4. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC3,4. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.

20.
Microb Pathog ; : 104045, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32035105

RESUMO

Peste des petits ruminants (PPR) is a highly contagious and fatal disease of small ruminants, particularly sheep and goats. This disease leads to high morbidity and mortality of small ruminants, thus resulting in devastating economic loss to the livestock industry globally. The severe disease impact has prompted the Food and Agriculture Organization of the United Nations (FAO) and the World Organization for Animal Health (OIE) to develop a global strategy for the control and eradication of PPR by 2030. Over the past decades, the control of PPR is mainly achieved through vaccinating the animals with live-attenuated vaccines, e.g., rinderpest vaccines. As a closely related disease to PPR of large ruminants, rinderpest was eradicated in 2011 and its vaccines subsequently got banned in order to keep rinderpest-free zones. Consequently, it is desirable to develop homologous PPR vaccines to control the disease. The present review summarizes the objectives of PPR control and eradication by focusing on the homologous PPR vaccines.

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