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1.
J Virol ; 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896597

RESUMO

TER94 is a multifunctional AAA+ ATPase crucial for diverse cellular processes, especially protein quality control and chromatin dynamics in eukaryotic organisms. Many viruses, including coronavirus, herpesvirus and retrovirus, co-opt host cellular TER94 for optimal viral invasion and replication. Previous proteomics analysis identified the association of TER94 with the budded virions (BVs) of baculovirus, an enveloped insect large DNA virus. Here, the role of TER94 in the prototypic baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) life cycle was investigated. In virus-infected cells, TER94 accumulated in virogenic stroma (VS) at the early stage of infection and subsequently partially rearranged to the ring zone region. In the virions, TER94 was associated with the nucleocapsids of both BV and occlusion-derived virus (ODV). Inhibition of TER94 ATPase activity significantly reduced viral DNA replication and BV production. Electron/immunoelectron microscopy revealed that inhibition of TER94 resulted in the trapping of nucleocapsids within cytoplasmic vacuoles at the nuclear periphery for BV formation and blockage of ODV envelopment at a pre-mature stage within infected nuclei, which appeared highly consistent with its pivotal function in membrane biogenesis. Further analyses showed that TER94 was recruited to the VS or subnuclear structures through interaction with viral early proteins LEF3 and helicase, whereas inhibition of TER94 activity blocked the proper localization of replication-related viral proteins and morphogenesis of VS, providing an explanation for its role in viral DNA replication. Taken together, these data indicated the crucial functions of TER94 at multiple steps of baculovirus life cycle including genome replication, BV formation, and ODV morphogenesis.IMPORTANCE TER94 constitutes an important AAA+ ATPase that associates with diverse cellular processes including protein quality control, membrane fusion of the Golgi apparatus and endoplasmic reticulum network, nuclear envelope reformation, and DNA replication. To date, little is known regarding the role(s) of TER94 in the baculovirus life cycle. In this study, TER94 was found to play a crucial role in multiple steps of baculovirus infection including viral DNA replication and BV- and ODV formation. Further evidence showed that the membrane fission/fusion function of TER94 is likely to be exploited by baculovirus for virion morphogenesis. Moreover, TER94 could interact with the viral early proteins LEF3 and helicase to transport to and further recruit viral replication-related proteins to establish viral replication factories. This study highlights the critical roles of TER94 as an energy-supplying chaperon in the baculovirus life cycle and enriches our knowledge regarding the biological function of this important host factor.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31955337

RESUMO

Thermal desorption (TD) technology is the preferred treatment technology for treating soil contaminated by organic compounds. Under laboratory conditions, eggshell and plant ash were studied as additives during thermal desorption to further improve the soil thermal desorption efficiency and the quality of soil after thermal desorption. The results showed that temperature was still an important factor affecting the soil quality and removal efficiency of PAHs (polycyclic aromatic hydrocarbons). The efficiency of the thermal desorption of soil was significantly improved (from 91.7 to 96.6%) by adding two additives, and the agglomeration of the soil was alleviated to some extent according to the decreased amount of large soil particle (100-400 µm). Moreover, the TOC (total organic carbon) and CEC (cation exchange capacity) of the soil were increased. This work suggested that the addition of similar alkaline additives to the soil during thermal desorption might have a positive impact on both thermal desorption behavior and soil quality.

3.
J Theor Biol ; 486: 110103, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31809719

RESUMO

Altruistic punishment and reward have been proved to promote the evolution of cooperation in the public goods game(PGG), but the punishers and the rewarders have to pay a price for these behaviors and that results in overall loss of interest. In present work, probabilistic punishment and reward are introduced to PGG. Probabilistic punishment and reward mean that punishment and reward are executed with a certain probability. Although that will reduce unnecessary costs, occasional absence of execution can lead to distrust. Thus we focus on how to implement punishment and reward efficiently within the structured populations. Numerical simulations are performed and prove that probabilistic punishment and reward can promote the evolution of cooperation more effectively. Further researches indicate that there is an optimal executing probability to promote cooperation and maximize reduction of cost. In addition, when the unit cost is high, the PGG with probabilistic punishment and reward still helps the evolution of altruistic punishers and rewarders, thereby avoiding collapse of cooperation.

4.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1134-1135: 121854, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785534

RESUMO

Rosmarinus officinalis L., rosemary, is traditionally used to treat headache and improve cardiovascular disease partly due to its vasorelaxant activity, while the vasorelaxant ingredients remain unclear. In this study, chemical spectrum-pharmacological effect relationship (spectrum-effect relationship) was utilized for efficiently discovering the main vasorelaxant ingredients of rosemary. Ten kinds of rosemary extracts were prepared by different extracting solvents and macroporous resin purification, and their chemical components were analyzed by UPLC. At the same time, the vasorelaxant activities of the 10 kinds of rosemary extracts were estimated on isolated rat thoracic aorta, and three chemometrics named partial least squares regression (PLSR), grey correlation analysis (GRA), and the least absolute shrinkage and selection operator (LASSO) were applied to construct spectrum-effect relationship between the UPLC fingerprints and vasorelaxant activity of rosemary extracts. As a result, most rosemary extracts showed dose-dependent increase in vasorelaxant activity and five kinds of ingredients, including carnosol, carnosic acid, epirosmanol methyl ether, carnosol isomer, and augustic acid were screened as vasorelaxant ingredients. Further, the vasorelaxant activities of carnosic acid and carnosol were verified. Moreover, the increase of nitric oxide (NO) and the decrease of angiotensin-II (Ang-II) were thought to contribute to the vasorelaxant activity of rosemary.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31811349

RESUMO

The purpose of the present study was to elucidate the pharmacological effects of Geniposide (GEN) on high diet fed and streptozotocin (STZ)-caused diabetic cognitive impairment. The mice were fed with high fat diet (HFD) for 4 weeks and intraperitoneally injected with 60 mg/kg STZ for three times within 72 h. The mice with glucose level over 15 mmol/l were regarded as diabetic and selected for further studies. The animals were intragastrically treated with metformin or GEN once daily for 4 weeks. Afterwards, the animals were applied for Y maze, novel object recognition (NOR) test, step-through passive avoidance test, and Morris water maze (MWM) test. The blood glucose and body weight were examined. The SH-SY5Y cells were treated with GEN in the presence or absence of ibrutinib and stimulated with high-glucose culture medium. The tumor necrosis factor-a (TNF-α) and interleukin (IL)-6 in serum, hippocampus, and supernatant were measured using ELISA method. The protein expressions of Bruton's tyrosine kinase (BTK), Toll-like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), nuclear factor kappa-B (NF-κB), p-NF-κB, brain-derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB), p-CREB, and glucagon-like peptide-1 receptor (GLP-1R) were detected by western blot analyses. As a result, the GEN treatment notably attenuated the body weight, blood glucose, and cognitive decline. GEN also inhibited the generations of inflammatory cytokines. Furthermore, the administrations of GEN ameliorated the alterations of BTK, TLR4, MyD88, NF-κB, and BDNF in HFD + STZ-induced mice. With the application of ibrutinib, the selective inhibitor of BTK, it was also found that BTK/TLR4/NF-κB pathway was associated with the GEN treatment in high glucose-induced SH-SY5Y cells. In summary, the results suggested that GEN exerted the protective effect on STZ-induced cognitive impairment possibly through the modulation of BTK/TLR4/NF-κB signaling.

6.
Forensic Sci Int Genet ; 45: 102211, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31812097

RESUMO

Whole genome amplification (WGA) allows for multiple genetic analyses with low template DNA, such as DNA derived from a single cell. WGA could increase the amount of input DNA from the pg to the µg level. However, there are no studies comparing the performance of forensic markers with DNA from a single cell after WGA evaluated on both capillary electrophoresis (CE) and massively parallel sequencing (MPS) platforms. In this study, cell lines consisting of female cultured B-lymphoblastoid cells and karyocytes from male venous blood were segregated into one, two, three and five cells. Including the references with the bulk cells, all samples were generated by WGA with the multiple displacement amplification (MDA) strategy in triplicate and genotyped on CE and MPS platforms. Allele balance, stutter ratio, accuracy, repeatability and concordance of short tandem repeat (STR) markers were used to evaluate the genotyping performance on both platforms. Additionally, the sequence coverage ratio (SCR) and SNP genotypes were evaluated for sequence information generated from the MPS. Heterozygous loci showed high allele balance, with an overall average allele balance ratio larger than 0.79 on the CE and 0.75 on the MPS platforms for the venous blood cell samples; the cultured B-lymphoblastoid cell samples had ratios of 0.62 and 0.70, respectively. The stutter ratio of every source and cell number from both cell line samples were very close, ranging from 5.3%-7.2% for autosomal STRs and approximately 10 % of Y chromosomal STRs on the CE platform. The average stutter, allele, and sequence-based and length-based noise ratios were 6.6 %, 88 %, 4.7 % and 0.7 %, respectively, in the single male cell sample. SNPs also showed high consistency and intralocus balance. Our study indicated that WGA with MDA strategy works relatively well of STR and SNP genotyping with low copy number samples on CE and MPS, even with one-cell sample.

7.
Mol Biol Rep ; 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31813129

RESUMO

Bone marrow mononuclear cells (BM-MNCs) transplantation has evolved as a promising experimental treatment in various regenerative therapy fields, especially in clinical hematopoietic stem cells transplantation (HSCT). In vitro methods have mainly been used to study the pre-clinical kinetics of BM-MNCs in mice after transplantation. And it is difficult to monitor the dynamic homing of BM-MNCs in living mice. The present study obtained the kinetics of transplanted BM-MNCs in the peripheral blood (PB) and the dynamic homing of BM-MNCs in the BM in living mice by a combination of in vivo flow cytometry (IVFC) and calvarium intravital microscopy. We found out that BM-MNCs were cleared rapidly from the PB and mainly localized to various hematopoietic tissues after transplantation. The number of BM-MNCs in the PB decreased over time accompanied by an increase in the BM indeed after transplantation. In addition, a lower number of BM-MNCs were found home to calvaria than long bone, probably indicating long bone marrow might also be an important hematopoietic organ. Clinical studies will benefit from non-invasive measurements to monitor the dynamic homing of transplanted cells. Our pre-clinical kinetics of BM-MNCs in living mice will have important clinical guiding significance in HSCT and other regenerative therapy fields.

8.
Endocrine ; 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31786774

RESUMO

PURPOSE: Serum complement C3 has been shown to contribute to the incidence of type 2 diabetes (T2D), but how serum complement C3 affects islet ß-cell function throughout the course of T2D is unclear. This study explored whether serum complement C3 is independently associated with changes in islet ß-cell function over time in patients with T2D. METHODS: Serum complement C3 was measured, and endogenous ß-cell function was evaluated by area under the C-peptide curve (AUCcp) during an oral glucose tolerance test (OGTT) in 411 patients with T2D at baseline from 2011 to 2015. Next, 347 of those patients with available data were pooled for a final follow-up analysis from 2014 to 2018. Changes in islet ß-cell function at follow-up were evaluated by AUCcp percentage changes (ΔAUCcp%). In addition, other possible clinical risks for diabetes were also examined. RESULTS: The 347 patients included in the analysis had a diabetes duration of 4.84 ± 3.63 years at baseline. Baseline serum complement C3 (baseline C3) levels were positively correlated with baseline natural logarithm of AUCcp (lnAUCcp) (n = 347, r = 0.288, p < 0.001), and baseline C3 was independently associated with baseline lnAUCcp (ß = 0.17, t = 3.52, p < 0.001) after adjustment for baseline glycemic status and other clinical confounders by multivariate liner regression analysis. Compared with the baseline values, complement C3 changes (ΔC3) and ΔAUCcp% was -0.15 ± 0.28 mg/ml and -17.2 ± 18.4%, respectively, at a follow-up visit 4.57 ± 0.78 years later. Moreover, ΔC3 was positively correlated with ΔAUCcp% (n = 347, r = 0.302, p < 0.001). Furthermore, each 0.1 mg/ml increase in ΔC3 was associated with a higher ΔAUCcp% (1.41% [95% CI, 0.82-2.00%]) after adjusting for changes in glycemic status and other clinical confounders at follow-up. CONCLUSIONS: In addition to serum complement C3 being independently associated with islet ß-cell function at baseline, its changes were also independently associated with changes in islet ß-cell function over time in patients with T2D.

9.
Biomed Res Int ; 2019: 6764919, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828119

RESUMO

The digestive tract is home to millions of microorganisms and is the main and most important part of bacterial colonization. On one hand, the abundant bacterial community in intestinal tissues may pose potential health challenges such as inflammation and sepsis in cases of opportunistic invasion. Thus, the immune system has evolved and adapted to maintain the symbiotic relationship between host and microbiota. On the other hand, the intestinal microflora also exerts an immunoregulatory function to maintain host immune homeostasis, which cannot be neglected. In addition, the interaction of either microbiota or probiotics with immune system in regard to therapeutic applications is an area of great interest, and novel therapeutic strategies remain to be investigated. The review will elucidate interactions between intestinal microflora/probiotics and the immune system as well as novel therapeutic strategies.

10.
Nat Med ; 25(11): 1739-1747, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31700183

RESUMO

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.

11.
Polymers (Basel) ; 11(11)2019 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-31717853

RESUMO

In this study, composites of poly (hydroxybutyrate-co-valerate) (PHBV) with untreated luffa fibers (ULF) and NaOH-H2O2 treated luffa fibers (TLF) were prepared by hot press forming. The properties of luffa fibers (LFs) and composites were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and other analysis methods. Results showed that pre-treatment effectively removed pectin, hemicellulose, and lignin, thus reducing the moisture absorptivity of LFs. The flexural strength of TLF/PHBV was higher than that of ULF/PHBV. With 60% LF content, the flexural strengths of ULF/PHBV and TLF/PHBV reached 75.23 MPa and 90.73 MPa, respectively, 219.7% and 285.6% more than that of pure PHBV. Water absorptivities of composites increased with increase in LF content. Water absorptivity of TLF/PHBV was lower than that of ULF/PHBV. The flexural strengths of composites decreased after immersion in water at room temperature. Meanwhile, flexural strength of TLF/PHBV was lower than that of ULF/PHBV. Pretreatment of LFs effectively improved the bonding between fibers and PHBV, resulting in enhanced and thus improved the moisture resistance of composites.

12.
Clin Neurol Neurosurg ; 188: 105617, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31775069

RESUMO

OBJECTIVE: This study was performed to explore the efficacy and safety of different surgical interventions in patients with spontaneous supratentorial intracranial hemorrhage (SSICH) and determine which intervention is most suitable for such patients. PATIENTS AND METHODS: We searched the PubMed, Medline, OVID, Embase, and Cochrane Library databases. The quality of the included studies was assessed. Statistical analyses were performed using the software Stata 13.0 and RevMan 5.3. RESULTS: Endoscopic surgery (ES), minimally invasive surgery combined with urokinase (MIS + UK), minimally invasive surgery combined with recombinant tissue plasminogen activator (MIS + rt-PA), and craniotomy were associated with higher survival rates and a lower risk of intracranial rebleeding than standard medical care (SMC) in patients with SSICH, especially in younger patients with few comorbidities. The order from highest to lowest survival rate was ES, MIS + UK, MIS + rt-PA, craniotomy, and SMC. The order from lowest to highest intracranial rebleeding risk was ES, MIS + UK, craniotomy, MIS + rt-PA, and SMC. Additionally, compared with SMC, all four surgical interventions (ES, MIS + rt-PA, MIS + UK, and craniotomy) improved the prognosis and reduced the proportion of patients with serious disability. The order from most to least favorable prognosis was MIS + rt-PA, ES, MIS + UK, craniotomy, and SMC. The order from highest to lowest proportion of patients with serious disability was ES, MIS + rt-PA, MIS + UK, craniotomy, and SMC. CONCLUSIONS: This study revealed that the efficacy and safety of different surgical interventions (ES, MIS + UK, MIS + rt-PA, craniotomy) were superior to those of SMC in the patients with SSICH, especially in younger patients with few comorbidities. Among them, ES was the most reasonable and effective intervention. ES was found not only to improve the survival rate and prognosis but also to have the lowest risk of intracranial rebleeding and the lowest proportion of patients with serious disability.

13.
Front Oncol ; 9: 1195, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781497

RESUMO

Huaier, as known as Trametes robiniophila Murr, is a traditional Chinese medicine. Various studies have demonstrated that Huaier could inhibit cancer progression and improve the prognosis of patients. In the present study, we comprehensively screened the expression profiles of lncRNAs, miRNAs, and mRNAs in Huaier-treated breast cancer cells. Using bioinformatic analysis, hub genes were identified and functionally annotated. Weighted gene coexpression network analysis was applied to construct the molecular network influenced by Huaier. Linc00339 was then found to play a critical role in Huaier-mediated cancer suppression. To validate the effects of linc00339 and identify the downstream targets, we performed in vitro and in vivo experiments. Finally, we identified that Huaier could inhibit the proliferation of breast cancer cells through modulating linc00339/miR-4656/CSNK2B signaling pathway.

14.
Cancer Sci ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31782868

RESUMO

It is an urgent need to find novel potential therapeutic targets for diagnosis and treatment of ccRCC (clear cell renal cell carcinoma ) due to its highly invasive ability as a common urological malignant tumor. CircRNAs (circular RNAs) have been indicated as potentially critical mediator in various tumor progression. We first demonstrated qRT-PCR analysis to find dysregulated circRNAs in ccRCC. A novel circRNA, hsa_circ_001895, was up-regulated in ccRCC specimens and associated with metastatic properties of ccRCC. However, the tumorigenic mechanism of hsa_circ_001895 on ccRCC is yet to be found. We first indicated that hsa_circ_001895 predicted a poor prognosis in ccRCC patients. Additionally, overexpression of hsa_circ_001895 not only promoted cell proliferation, invasion and migration of ccRCC, but also inhibited cell apoptosis, while hsa_circ_001895 knockdown reversed the effect on ccRCC progression. In vivo subcutaneous xenotransplanted tumor model also revealed that silence of hsa_circ_001895 could suppress in vivo ccRCC growth. Mechanistically, hsa_circ_001895 directly bind with miR-296-5p and inhibited its expression. Moreover, SRY (sex determining region Y)-box 12 (SOX12) was identified as targets of miR-296-5p, whose expression was suppressed by miR-296-5p. Notably, the inhibitory effect of hsa_circ_001895 on ccRCC progression was reversed by miR-296-5p inhibitor. In general, our findings indicated hsa_circ_001895 may sponge miR-296-5p and promote SOX12 expression, which is the underlying mechanism of hsa_circ_001895-induced ccRCC progression.

15.
Clin Chim Acta ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31758933

RESUMO

BACKGROUND: The value of urinary mitochondrial DNA (mtDNA) for assessing kidney injury of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) was investigated. METHODS: Thirty-nine kidney biopsy-proved myeloperoxidase (MPO)-ANCA associated AAV patients were enrolled and analyzed. RESULTS: The average urinary mtDNA of patients was significantly higher than that of normal controls (3372.74 ± 1859.72 vs. 474.90 ± 123.59 copy/nmol creatinine, p < 0.001). The patients who needed dialysis at disease onset had the highest levels of urinary mtDNA (5072.23 ± 1302.87 copy/nmol creatinine). Urinary mtDNA positively correlated with urinary neutrophil gelatinase-associated lipocalin (R = 0.661, P < 0.001) and negatively correlated with estimated glomerular filtration rate (R = -0.515, P = 0.001). The urinary mtDNA level of crescentic class (4703.08 ± 1744.31 copy/nmol creatinine) was higher than that of mixed class (3258.14 ± 1158.99 copy/nmol creatinine) and focal class (2268.15 ± 1897.63 copy/nmol creatinine). Univariate correlation analysis showed urinary mtDNA positively correlated with interstitial neutrophils (R = 0.471, P = 0.048) and glomerular neutrophils (R = 0.673, P = 0.002) in kidney biopsy. Among 13 patients who needed hemodialysis at disease onset, 10 patients who got renal recovery had higher urinary mtDNA than 3 patients who remained dialysis dependent (5455.20 ± 1174.64 vs. 3795.67 ± 893.34 copy/nmol creatinine, p = 0.047). CONCLUSIONS: Urinary mtDNA increases in AAV with kidney injury, and its levels correlate with the severity of kidney injury and neutrophils infiltration in pathology.

16.
Twin Res Hum Genet ; : 1-4, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31666146

RESUMO

The Pennsylvania Longitudinal Study of Parents and Children Twin Registry was developed to capture a representative sample of multiple births and their parents in the state of Pennsylvania. The registry has two main efforts. The first began in 2012 through recruitment of adolescents in Pennsylvania schools. The second effort began in January 2019 in partnership with the Pennsylvania Department of Health to capture the birth cohort of twins born from 2007 to 2017. Study recruitment, sample demographics, focus and measures are provided, as well as future directions.

17.
ACS Appl Mater Interfaces ; 11(47): 44430-44437, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31680508

RESUMO

PbS colloidal quantum dots passivated by the thiocyanate anion (SCN-) are developed to combine with perovskite (CH3NH3PbI3) as building blocks for UV-vis-NIR broadband photodetectors. Both high electrical conductivity and appropriate energy-level alignment are obtained by the in situ ligand exchange with SCN-. The PbS-SCN/CH3NH3PbI3 composite photodetectors are sensitive to a broad wavelength range covering the UV-vis-NIR region (365-1550 nm), possessing an excellent responsivity of 255 A W-1 at 365 nm and 1.58 A W-1 at 940 nm, remarkably high detectivity of 4.9 × 1013 Jones at 365 nm and 3.0 × 1011 Jones at 940 nm, and fast response time of ≤42 ms. Furthermore, a 10 × 10 photodetector array is fabricated and integrated, which constitutes a high-performance broadband image sensor. Our approach paves a way for the development of highly sensitive broadband photodetectors/imagers that can be easily integrated.

18.
Chin Med ; 14: 42, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31592267

RESUMO

Background: The dry root and rhizome of Salvia miltiorrhiza Bunge, or Danshen, is a well-known, traditional Chinese medicine. Tanshinones are active compounds that accumulate in the periderm, resulting in red-colored roots. However, lines with orange roots have been observed in cultivated fields. Here, we performed metabolome and transcriptome analyses to investigate the changes of orange-rooted Danshen. Methods: Metabolome analysis was performed by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC/Q-Tof-MS) to investigate the metabolites variation between orange Danshen and normal Danshen. RNA sequencing and KEGG enrichment analysis were performed to analyzing the differentially expressed genes between orange-rooted and normal Danshen. Results: In total, 40 lipophilic components were detected in metabolome analysis, and seven compounds were significantly decreased in the orange Danshen, including the most abundant active compounds, tanshinone IIA and tanshinone I in normal Danshen. Systematic analysis of transcriptome profiles revealed that the down-regulated genes related to catalytic dehydrogenation was not detected. However, two genes related to stress resistance, and four genes related to endoplasmic reticulum (ER)-associated degradation of proteins were up-regulated in orange Danshen. Conclusions: Decreases in the content of dehydrogenated furan ring tanshinones such as tanshinone IIA resulted in phenotypic changes and quality degradation of Danshen. Transcriptome analysis indicated that incorrect folding and ER-associated degradation of corresponding enzymes, which could catalyze C15-C16 dehydrogenase, might be contributed to the decrease in dehydrogenated furan ring tanshinones, rather than lower expression of the relative genes. This limited dehydrogenation of cryptotanshinone and dihydrotanshinone I into tanshinones IIA and I products, respectively, led to a reduced quality of Danshen in cultivated fields.

19.
Onco Targets Ther ; 12: 7637-7647, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571914

RESUMO

Background: The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is implicated in several cancers. AKT allosteric inhibitor MK2206 and dual PI3K and mTOR inhibitor BEZ235 are promising drug candidates with potential anti-tumor effects. Purpose: In this study, we aimed to detect the activation of PI3K/AKT/mTOR pathway and assess the efficacy of MK2206 and BEZ235 in inhibiting esophageal cancer growth. Materials and methods: We used three different systems including carcinogen-induced animal model, human esophageal squamous cell carcinoma (SCC) cell lines, and xenograft mouse model. Results: Our data indicated that components of the PI3K/AKT/mTOR pathway were overexpressed and activated in esophageal SCC. MK2206 and BEZ235 inhibited cell proliferation, enhanced apoptosis, and induced cell-cycle arrest through downstream effectors SKP2, MCL-1, and cyclin D1 in esophageal SCC cells. MK2206 and BEZ235 also inhibited tumor growth in xenograft mice through the inhibition of AKT phosphorylation. MK2206/BEZ235 combination showed greater anti-tumor effect than MK2206 or BEZ235 alone. The enhanced efficacy of the combination was associated with the inhibition of phosphorylation ATK on both Thr308 and Ser473. Conclusion: The combination of MK2206 and BEZ235 exhibits potent antitumor effects and may have important clinical applications for esophageal SCC treatment.

20.
Biochem Biophys Res Commun ; 520(2): 420-427, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31607480

RESUMO

Irradiation induces severe damage in the hematopoietic system, which leads to bone marrow hyperplasia, pancytopenia, and aggravated tissue formation in bone marrow. Studies have shown that Toll-like receptor 4 (TLR4) has a protective effect against irradiation, but the underlying mechanism remains unclear. In this study, we used a TLR4 knockout (TLR4-/-) mouse irradiation model and found that the white blood cell and platelet counts in the peripheral blood of TLR4-/- mice recovered slowly after irradiation, with bone marrow hyperplasia and increased mortality. Additionally, we found that the proportion of CD11b+Gr1+ granulocytes in the peripheral blood and bone marrow of TLR4-/- mice was lower than that of wild-type mice after irradiation. Further, we found that the expression of NADPH Oxidases (NOXs) in the bone marrow was down-regulated after irradiation of TLR4-/- mice, and administration of the NOXs inhibitor VAS2870 reduced the proportion of CD11b+Gr1+ cells in the bone marrow and peripheral blood of wild-type mice after irradiation. Irradiation induced severe marrow adipocytes accumulation in TLR4-/- mice, TLR4 ligand lipopolysaccharide promoted proliferation and inhibited adipogenic differentiation of mesenchymal stromal cells. In summary, our data suggest that TLR4 promotes myeloid hyperplasia by up-regulating the expression of NOXs after irradiation, prohibits marrow adipogensis and increases the tolerance of mice to irradiation.

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