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1.
Pharmacol Res ; 153: 104658, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32001347

RESUMO

Wutou Decoction (WTD) achieves favorable therapeutic response in treating rheumatoid arthritis (RA), especially for wind-cold-dampness stimulating RA. However, its material basis and molecular mechanisms remain unclear. To address this problem, the main bioactive compounds (BACs) of WTD against RA and the candidate targets were identified in the current study via transcriptional regulatory network analysis, computational structure-based methods, as well as in vivo and in vitro experimental validations. As a result, we successfully established a RA rat model named AIA-S, which simulated the clinical manifestations and pathological changes of wind-cold-dampness stimulating RA, and also displayed the distinctive characteristics and biological basis of inflammatory-immune system imbalance and abnormal energy metabolism changes. In addition, ALOX15B-PPAR-γ-PTGS2-FGF2-IL-1ß-c-JUN-MMP13-TGF-ß1 signal axis, involved into thermogenesis and energy metabolism, as well as maintaining the balance of inflammation-immune system, was identified as a candidate target of WTD against RA, according to the transcriptional regulatory network analysis on "RA-related gene-WTD-effective gene interaction network". Moreover, Paeoniflorin (PAE) and Talatizidine (TLT) were demonstrated to be the main BACs of WTD against RA for the following reasons: firstly, both PAE and TLT were the BACs of WTD according to ADME analysis in silico and the pharmacokinetics analysis in vivo. Secondly, both PAE and TLT were able to bind with PPAR-γ, c-JUN, MMP13 and TGF-ß1, which were the candidate targets of WTD against RA, with the strong binding affinity. Thirdly, the PAE and TLT combination exerted significant therapeutic effects on AIA-S rats through reversing the imbalance of inflammatory-immune system, and the disturbance of thermogenesis and energy metabolism, which were similar to WTD. More importantly, the administration of TLT or PAE alone didn't exert as prominently therapeutic effects as that of the two-BAC-combination did. Fourthly, the PAE and TLT combination promoted adipogenesis and lipogenesis by upregulating the PPAR-γ-induced lipogenic proteins. In conclusion, this study identified PAE and TLT as the main BACs of WTD in alleviating the severity of RA, and also developed a novel combination of PAE and TLT as a promising candidate drug for RA therapy.

2.
PLoS One ; 15(1): e0227681, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31940401

RESUMO

BACKGROUND: Older adults with Alzheimer's disease and related dementias (ADRD) are high-risk to experience hospitalizations and emergency room (ER) admissions. Mexican-Americans have a high prevalence of ADRD, but there is limited information on the healthcare use of older Mexican-Americans with ADRD. We used data from a cohort of older Mexican-Americans that has been linked with Medicare files to investigate differences in hospitalizations, ER admissions, and physician visits according to ADRD diagnosis. We also identify sociodemographic, health, and functional characteristics that may contribute to differences in healthcare utilization between Mexican-American Medicare beneficiaries with and without an ADRD diagnosis. METHODS AND FINDINGS: Data came from the Hispanic Established Populations for the Epidemiological Study of the Elderly that has been linked with Medicare Master Beneficiary Summary Files, Medicare Provider Analysis and Review files, Outpatient Standard Analytic files, and Carrier files. The final analytic sample included 1048 participants. Participants were followed for two years (eight quarters) after their survey interview. Generalized estimating equations were used to estimate the probability for one or more hospitalizations, ER admissions, and physician visits at each quarter. ADRD was associated with higher odds for hospitalizations (OR = 1.65, 95%CI = 1.29-2.11) and ER admissions (OR = 1.57, 95%CI = 1.23-1.94) but not physician visits (OR = 1.23, 95%CI = 0.91-1.67). The odds for hospitalizations (OR = 1.24, 95%CI = 0.97-1.60) and ER admissions (OR = 1.27, 95%CI = 1.01-1.59) were reduced after controlling for limitations in activities of daily living and comorbidities. CONCLUSIONS: Mexican-American Medicare beneficiaries with ADRD had significantly higher odds for one or more hospitalizations and ER admissions but similar physician visits compared to beneficiaries without ADRD. Functional limitations and comorbidities contributed to the higher hospitalizations and ER admissions for older Mexican-Americans with ADRD.

3.
Phytomedicine ; 67: 153156, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31901568

RESUMO

BACKGROUND: Baihu-Guizhi decoction (BHGZD) has been extensively used for the treatment of rheumatoid arthritis (RA) with a satisfying therapeutic effect. However, the material basis and the underlying mechanisms of BHGZD against RA have not been fully elucidated. PURPOSE: To investigate the chemical profile and the pharmacological mechanisms of BHGZD against RA. METHODS: The chemical constituents containing in BHGZD were identified using UFLC-Q-TOF-MS/MS system, and the corresponding putative targets were predicted. Then, the differentially expressed genes (DEGs) between adjuvant-induced arthritis (AIA) and normal control groups were identified using microarray analysis. After constructing the interaction network of "RA-related gene-BHGZD putative target", BHGZD candidate targets against RA were screened by topological analysis and further experimentally validated based on AIA rat model. RESULTS: A total of 41 chemical constituents were identified in the water extract of BHGZD, which were predicted to hit 1312 putative targets. Additionally, 26 DEGs between the AIA and normal control groups were defined as "RA-related genes", which were functionally involved into the imbalance of "inflammation-immune" system during RA progression. On the basis of the topological importance in the network of "RA-related gene-BHGZD putative target", 177 BHGZD candidate targets against RA were identified. Among them, TLR4, c-Fos/AP-1, IL2 and TNF had direct interactions with each other and also function as crucial components of toll-like receptor and T cell receptor signaling pathways, which may play important roles in maintaining the balance of "inflammation-immune" system. Experimentally, we verified that BHGZD dose-dependently attenuated the severity, pathological changes, as well as mechanical, cold, and heat hypersensitivities during RA progression based on the AIA rat model. Further western blot analysis demonstrated that BHGZD significantly reduced the protein levels of TLR4, c-Fos/AP-1, IL2 and TNF, which were induced by RA modeling, in the inflamed joints of AIA rats (all p<0.05). CONCLUSION: This study combining the chemical and transcriptomic profilings, target prediction, network calculation and experimental validations identifies the chemical constituents containing in BHGZD and offers the convincing evidence that BHGZD may ameliorate RA partially by restoring the balance of "inflammation-immune" system and subsequently reversing the pathological events during RA progression through regulating the TLR4-c-Fos-IL2-TNF axis.

4.
J Clin Lab Anal ; : e23201, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944387

RESUMO

BACKGROUND: X-linked ichthyosis (XLI) is the second most common type of ichthyosis, which is characterized by wide and symmetric distribution of adherent, dry, and polygonal scales on the skin. Steroid sulfatase (STS) gene, which is located at chromosome Xp22.31, has been identified as the pathogenic gene of XLI. METHODS: In this study, chromosome karyotype analysis, bacterial artificial chromosomes-on-Beads™ (BoBs) assay, fluorescence in situ hybridization (FISH), and single nucleotide polymorphism array (SNP-array) were employed for the prenatal diagnoses in three pregnant women with high-risk serological screening results and a pregnant woman with mental retardation. RESULTS: STS deletion was identified at chromosome Xp22.31 in all four fetuses. Postnatal follow-up confirmed the diagnosis of ichthyosis in two male fetuses and revealed normal dermatological manifestations in other two female fetuses carrying ichthyosis. CONCLUSION: The results of the present study demonstrate that a combination of karyotypying, prenatal BoBs, FISH, and SNP-array may avoid the missed detection of common microdeletions and ensure the accuracy of the detection results, which provides a feasible tool for the reliable etiological diagnosis and better genetic counseling of XLI.

5.
Chem Commun (Camb) ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31967118

RESUMO

The exquisite combination of hetreometallic [TbIIINiII(COO)3(H2O)] clusters with a designed hexatopic ligand generates one highly robust three-dimensional heterometallic TbIII/NiII-organic framework material {[TbNi(HTDP)(H2O)]·3DMF·2H2O}n (NUC-2; H6TDP = 2,4,6-tri(2,4-dicarboxyphenyl)pyridine). Gas adsorption measurements reveal that the activated NUC-2 exhibits ultrahigh C2H2 adsorption capacity but negligible uptake of C2H4, which is ascribed to its high stability and ultrahigh functional internal surface. Furthermore, dynamic breakthrough experiments confirm that NUC-2 can effectively fulfill the separation of a C2H2/C2H4 (1 : 99) mixture. Such excellent performance makes NUC-2 a promising adsorbent for practical C2H2/C2H4 separation and provides new insights into heterometallic MOFs for gas separation.

6.
Cell Death Dis ; 11(1): 44, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969558

RESUMO

Tissue nonspecific alkaline phosphatase (TNAP) is expressed widely in different tissues, modulating functions of metabolism and inflammation. However, the effect of TNAP on cardiac fibrosis remains controversial and needs to be further studied. The present study aims to investigate the role of TNAP on myocardial infarction (MI)-induced fibrosis and its mechanism. TNAP was upregulated in patients with MI, both in serum and injured hearts, and predicted in-hospital mortality. TNAP was also significantly upregulated after MI in rats, mostly in the border zone of the infarcted hearts combined with collagen synthesis. Administration of TNAP inhibitor, tetramisole, markedly improved cardiac function and fibrosis after MI. In the primary cultures of neonatal rat cardiac fibroblasts (CFs), TNAP inhibition significantly attenuated migration, differentiation, and expression of collagen-related genes. The TGF-ß1/Smads signaling suppression, and p-AMPK and p53 upregulation were involved in the process. When p53 inhibitor was administered, the antifibrotic effect of TNAP inhibition can be blocked. This study provides a direct evidence that inhibition of TNAP might be a novel regulator in cardiac fibrosis and exert an antifibrotic effect mainly through AMPK-TGF-ß1/Smads and p53 signals.

7.
Pain Med ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31904839

RESUMO

OBJECTIVE: To examine opioid prescribing frequency and trends to Medicare Part D enrollees from 2013 to 2017 by medical specialty and provider type. METHODS: We conducted a retrospective, cross-sectional, specialty- and provider-level analysis of Medicare Part D prescriber data for opioid claims from 2013 to 2017. We analyzed opioid claims and prescribing trends for specialties accounting for ≥1% of all opioid claims. RESULTS: From 2013 to 2017, pain management providers increased Medicare Part D opioid claims by 27.3% to 1,140 mean claims per provider in 2017; physical medicine and rehabilitation providers increased opioid claims 16.9% to 511 mean claims per provider in 2017. Every other medical specialty decreased opioid claims over this period, with emergency medicine (-19.9%) and orthopedic surgery (-16.0%) dropping opioid claims more than any specialty. Physicians overall decreased opioid claims per provider by -5.2%. Meanwhile, opioid claims among both dentists (+5.6%) and nonphysician providers (+10.2%) increased during this period. CONCLUSIONS: From 2013 to 2017, pain management and PMR increased opioid claims to Medicare Part D enrollees, whereas physicians in every other specialty decreased opioid prescribing. Dentists and nonphysician providers also increased opioid prescribing. Overall, opioid claims to Medicare Part D enrollees decreased and continue to drop at faster rates.

8.
Life Sci ; 242: 117247, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31899223

RESUMO

AIMS: Programmed death ligand 1 (PD-L1, CD274) has been reported to be expressed abnormally in many cancers, nevertheless, effect of PD-L1 on tumor cells remains unclear, especially in gastric cancer (GC). This study aimed to investigate the role of PD-L1 in metastasis and differentiation in GC. MAIN METHODS: Immunohistochemistry was performed on 237 paired GC tissues. shPD-L1 cells were generated by lentivirus shRNA solution and PD-L1-overexpressing cells were constructed by pcDNA3.1. Expression of PD-L1 and E-cadherin in GC cells were detected by western blot. KEY FINDINGS: PD-L1 expression was significantly lower in GC than that in adjacent normal tissues, especially in poorly differentiated and metastatic GC, but was positively correlated to survival time of patients. Moreover, PD-L1 ablation could decrease E-cadherin expression, promote cell migration and wound repair ability. In turn, overexpression of PD-L1 increased E-cadherin expression and inhibited wound repair ability. At the same time, All-trans retinoic acid (ATRA), which has the properties of pro-differentiation and inhibition of invasion and metastasis, upregulated the expression of PD-L1 and E-cadherin. SIGNIFICANCE: These findings not only identify PD-L1 may have a positive role for the treatment of GC, but also implicate that ATRA combined PD-L1 antibody drugs may enhance anti-tumor Immunity in GC.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Gástricas/patologia , Antígeno B7-H1/fisiologia , Western Blotting , Caderinas/metabolismo , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Gástricas/metabolismo
9.
Biomed Pharmacother ; 123: 109812, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31945696

RESUMO

Wu-tou decoction (WTD), a classic Traditional Chinese medicine formula, has been extensively used in the treatment of neuropathic pain (NP) such as chronic inflammatory pain, trigeminal neuralgia, and cancer-induced pain. Our previous studies have shown that the severity of mechanical allodynia and thermo hypersensitivity in NP rats are reduced by WTD, of which analgesic candidates are paeoniflorin (Pae) and liquiritin (Liq). The aim of this study was to clarify the molecular mechanisms of WTD, Pae and Liq against NP based on the primary rat glial cells in vitro. The gene expression levels of neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and Artemin and C-C chemokine receptor type 5 (CCR5) were augmented by inflammatory cytokines, while chemokines increased only CCR5 gene expression. The constitutive and cytokine-augmented neurotrophic factor gene expression was enhanced by WTD, Pae, and Liq through PI3K- and PKA-dependent pathways in rat glial cells, leading to the increase of NGF and BDNF production. Furthermore, the CCR5 gene expression under basal and chemokine-treated conditions was suppressed by these reagents, in which signal pathway(s) was independent on the activation of PI3K and PKA. Moreover, there was no cytotoxicity in the WTD, Pae, and Liq treatments in glial cells. Thus, these results provide a novel evidence that WTD may exert the anti-NP actions by predominantly increasing the production of neurotrophic factors through PI3K- and PKA-signaling pathways in rat glial cells. Furthermore, Pae and Liq may play as analgesic candidates in WTD-mediated NP management.

10.
Science ; 367(6475): 272-277, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31949075

RESUMO

One great challenge in understanding the history of life is resolving the influence of environmental change on biodiversity. Simulated annealing and genetic algorithms were used to synthesize data from 11,000 marine fossil species, collected from more than 3000 stratigraphic sections, to generate a new Cambrian to Triassic biodiversity curve with an imputed temporal resolution of 26 ± 14.9 thousand years. This increased resolution clarifies the timing of known diversification and extinction events. Comparative analysis suggests that partial pressure of carbon dioxide (Pco2) is the only environmental factor that seems to display a secular pattern similar to that of biodiversity, but this similarity was not confirmed when autocorrelation within that time series was analyzed by detrending. These results demonstrate that fossil data can provide the temporal and taxonomic resolutions necessary to test (paleo)biological hypotheses at a level of detail approaching those of long-term ecological analyses.

11.
Mol Ther Nucleic Acids ; 19: 890-904, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31982775

RESUMO

Drug repositioning offers new clinical applications for existing drugs with shorter approval processes and lower costs and risks than de novo experimental drug development. The Fufang-Biejia-Ruangan pill (FBRP) is the first clinically approved anti-fibrosis herbal formula in China. Whether FBRP could be used to treat hepatocellular carcinoma (HCC) remains unclear. Herein, a total of 161 FBRP candidate targets against HCC were identified according to the topological importance in the "hepatic fibrosis-cirrhosis-cancer axis-related gene-FBRP putative target" network, and mostly enriched in phosphatidylinositol 3-kinase (PI3K)/AKT/nuclear factor κB (NF-κB) signaling. Experimentally, FBRP inhibited liver fibrosis and prevented the development of neoplastic lesions at the early stages of hepatocarcinogenesis in a diethylnitrosamine-induced rat HCC model. FBRP inhibited tumor cell proliferation, induced tumor-specific cell death, and suppressed tumor progression in HCC rats while preventing the activation of PI3K, AKT and IKΚB proteins, reducing the nuclear accumulation of NFΚB1 protein, and decreasing the downstream expression of proteins. Consistently, FBRP suppressed HCC cell proliferation and induced cell cycle arrest in vitro. Co-treatment of FBRP with PI3K inhibitor exhibited an additive inhibitory effect on PI3K/AKT/NF-κB activation. Collectively, our data showed the potentials of FBRP in hepatic fibrosis microenvironment regulation and tumor prevention, suggesting that FBRP may be a promising candidate drug for reduction of fibrogenesis and prevention of HCC.

12.
Rehabil Nurs ; 45(1): 45-53, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30095554

RESUMO

PURPOSE: The purposes of the study were to analyze patient use and satisfaction with low vision aids (LVAs) at the Wenzhou Medical University Low Vision and Rehabilitation Center and to assess the promotion of visual rehabilitation services as a new responsibility for nurses in China. METHODS: Records of 178 patients with low vision (LV) from the Low Vision and Rehabilitation Center examined between October 2015 and October 2016 included basic patient information (e.g., age, diagnosis, visual acuity, educational level) and use of LVAs (patients' own aids, daily duration of LVA use, or refusal to use aids). RESULTS: Sixty percent owned LVAs. Of these, 66% were obtained from a hospital, 26% were obtained from commercial stores, and others were obtained from government or gifts. Patients reported that use of LVAs was reduced because of visual fatigue (39%), inconvenience (22%), and lack of benefit (12%). Reasons for the 40% who had never used visual rehabilitation were nonreferral by doctors (76%), refusal because of inconvenience, discomfort and cosmetics (20%), or a preference for other treatments (4%). CONCLUSIONS: Greater awareness of LV rehabilitation by nurses, ophthalmologists, patients, and the public is necessary. Additional government support for LV rehabilitation is also required.

13.
Clin Cancer Res ; 26(2): 384-390, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615934

RESUMO

PURPOSE: To examine whether submucosal saline injection (SSI) can improve traditional endoscopic ultrasound (EUS) accuracy in distinguishing between T1a and T1b stage esophageal squamous cell carcinoma (ESCC). EXPERIMENTAL DESIGN: Patients with T1N0M0 stage ESCC (n = 180) ages 18 to 85 years were enrolled between February 14, 2012 to June 4, 2018 at Sun Yat-sen University Cancer Center (Guangdong, China). They were randomly assigned (1:1) to receive either EUS examination after 3-5 mL SSI or EUS only examination. All the patients were referred to thoracic surgeons to receive endoscopic resection (ER) or esophagectomy 5 to 10 days after EUS examination. Standard EUS criteria were used to preoperatively stage the ESCC cases, and surgical pathology reports after referral were used to postoperatively stage the cases. The primary endpoint was the diagnostic accuracy of T1b staging [defined as the sum of the true positive (T1b) and true negative (T1a) cases divided by the total number of cases]. RESULTS: Among the per-protocol population, the SSI+EUS group (n = 81) was superior to the EUS-only group (n = 85) in terms of the diagnostic accuracy for T1b staging [93.8% (95% confidence interval (CI), 88.6-99.1) vs. 65.9% (95% CI, 55.8-76.0); P < 0.001]. The positive predictive value of SSI+EUS for diagnosing T1b ESCC reached 90.9% (95% CI, 81.1-100), which was significantly superior to that of EUS only [0.576 (0.450-0.702), P = 0.001]. CONCLUSIONS: SSI significantly improves the diagnostic accuracy of EUS in distinguishing between T1a and T1b ESCC, which might help avoid unnecessary esophagectomy and diagnostic ER.

14.
Free Radic Biol Med ; 146: 70-78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31626947

RESUMO

We found recently that benzohydroxamic acid (BHA) could detoxify the chlorinated quinoid carcinogens via an unusual Lossen rearrangement reaction. However, it is not clear what would happen when the nitrogen hydrogen of BHA was substituted with methyl and other alkyl groups. Here we show that N-methyl benzohydroxamic acid (N-MeBHA, a simple model compound for the classic iron-chelator deferoxamine, which is a typical N-alkyl trihydroxamic acid) could react with 2,5-dichloro-1,4-benzoquinone (DCBQ) to form a relatively stable initial carbon-oxygen bonding conjugation intermediate CBQ-O-N-MeBHA. However, the major final product was identified, unexpectedly, as a carbon-nitrogen bonding conjugate CBQ(OH)-N(CH3)-COAr, which is the rearranged isomer of CBQ-O-N-MeBHA. Interestingly, a new 18-line nitrogen-centered radical and a carbon-centered quinone ketoxy radical were observed by the ESR spin-trapping method, which was further confirmed by HPLC-MS and 15N-isotope labeling methods. We further found that both new DNA adducts and DNA strand breaks could be produced by the reactive nitrogen-centered radical. Taken together, we propose that the reaction between DCBQ and N-MeBHA was not via the Lossen rearrangement, but rather through a novel radical homolysis and recoupling pathway. Analogous results were observed for other chlorinated quinones and N-alkyl hydroxamic acids including the widely-used trihydroxamate iron-chelating drug deferoxamine. This represents the first report of unexpected radical pathway for the reaction between chlorinated quinones and N-alkyl hydroxamic acids under normal physiological conditions, which may have broad biological and environmental significance for future study of carcinogenic chloroquinones and hydroxamic acid drugs.

16.
J Clin Lab Anal ; 34(1): e23025, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31506986

RESUMO

BACKGROUND: While congenital anomalies of the kidney and urinary tract (CAKUT) constitute one-third of all congenital malformations, the mechanisms underlying their development are poorly understood. Some studies have reported an association between CAKUT and copy number variations (CNVs) in children and adults, but few have focused on chromosomal microarray analysis (CMA) findings in fetuses with CAKUT. Therefore, we aimed to perform a CMA on fetuses with CAKUT and normal karyotypes in the presence and absence of other structural anomalies. METHOD: The study was conducted in 147 fetuses with CAKUT and normal karyotypes between January 2016 and January 2019 in the Fujian Provincial Maternal and Child Health Hospital. Single nucleotide polymorphism (SNP) analysis was performed using the Affymetrix CytoScan HD platform. RESULTS: The SNP array identified abnormal CNVs in 13 cases (8.8%): Six were pathogenic, and seven were variations of uncertain clinical significance (VOUS). The detection rate of abnormal CNVs in non-isolated CAKUT was higher than that in isolated CAKUT (22.7% vs 6.4%, P = .038). Within the abnormal CNV groups, the highest frequency of CNVs was identified in fetuses with polycystic kidney dysplasia (13.5%), followed by those with renal agenesis (10.5%). CONCLUSION: SNP array is effective for identifying chromosomal abnormalities in CNVs in fetuses with CAKUT and normal karyotypes, and help counseling.

17.
Mol Plant Pathol ; 21(2): 188-205, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31724809

RESUMO

Cymbidium mosaic virus (CymMV) and Odontoglossum ringspot virus (ORSV) are the two most prevalent viruses infecting orchids and causing economic losses worldwide. Mixed infection of CymMV and ORSV could induce intensified symptoms as early at 10 days post-inoculation in inoculated Phalaenopsis amabilis, where CymMV pathogenesis was unilaterally enhanced by ORSV. To reveal the antiviral RNA silencing activity in orchids, we characterized the viral small-interfering RNAs (vsiRNAs) from CymMV and ORSV singly or synergistically infecting P. amabilis. We also temporally classified the inoculated leaf-tip tissues and noninoculated adjacent tissues as late and early stages of infection, respectively. Regardless of early or late stage with single or double infection, CymMV and ORSV vsiRNAs were predominant in 21- and 22-nt sizes, with excess positive polarity and under-represented 5'-guanine. While CymMV vsiRNAs mainly derived from RNA-dependent RNA polymerase-coding regions, ORSV vsiRNAs encompassed the coat protein gene and 3'-untranslated region, with a specific hotspot residing in the 3'-terminal pseudoknot. With double infection, CymMV vsiRNAs increased more than 5-fold in number with increasing virus titres. Most vsiRNA features remained unchanged with double inoculation, but additional ORSV vsiRNA hotspot peaks were prominent. The potential vsiRNA-mediated regulation of the novel targets in double-infected tissues thereby provides a different view of CymMV and ORSV synergism. Hence, temporally profiled vsiRNAs from taxonomically distinct CymMV and ORSV illustrate active antiviral RNA silencing in their natural host, Phalaenopsis, during both early and late stages of infection. Our findings provide insights into offence-defence interactions among CymMV, ORSV and orchids.

18.
J Gerontol A Biol Sci Med Sci ; 75(2): 326-332, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-30855070

RESUMO

BACKGROUND: Little is known about the patterns of end-of-life health care for older Mexican Americans with or without a diagnosis of Alzheimer's disease and related dementias (ADRD). Our objective was to investigate the frequency of acute hospital admissions, intensive care unit use, and ventilator use during the last 30 days of life for deceased older Mexican American Medicare beneficiaries with and without an ADRD diagnosis. METHODS: We used Medicare claims data linked with survey information from 1,090 participants (mean age of death 85.1 years) of the Hispanic Established Populations for the Epidemiologic Studies of the Elderly. Multivariable logistic regression models were used to estimate the odds for hospitalization, intensive care unit use, and ventilator use in the last 30 days of life for decedents with ADRD than those without ADRD. Generalized linear models were used to estimate the risk ratio (RR) for length of stay in hospital. RESULTS: Within the last 30 days of life, 64.5% decedents had an acute hospitalization (59.1% ADRD, 68.3% no ADRD), 33.9% had an intensive care unit stay (31.3% ADRD, 35.8% no ADRD), and 17.2% used a ventilator (14.9% ADRD, 18.8% no ADRD). ADRD was associated with significantly lower hospitalizations (odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.50-0.89) and shorter length of stay in hospital (RR = 0.77, 95% CI = 0.65-0.90). CONCLUSION: Hospitalization, intensive care unit stay, and ventilator use are common at the end of life for older Mexican Americans. The lower hospitalization and shorter length of stay in hospital of decedents with ADRD indicate a modest reduction in acute care use. Future research should investigate the impact of end-of-life planning on acute-care use and quality of life in terminally ill Mexican American older adults.

19.
Free Radic Biol Med ; 146: 150-159, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31302229

RESUMO

We found previously that nitroxide radical of desferrioxamine (DFO•) could be produced from the interaction between the classic iron chelating agent desferrioxamine (DFO, an N-alkyl trihydroxamic acid) and tetrachlorohydroquinone (TCHQ), one of the carconogenic quinoind metabolites of the widely used wood preservative pentachlorophenol. However, the underlying molecular mechanism remains unclear. Here N-methylacetohydroxamic acid (N-MeAHA) was synthesized and used as a simple model compound of DFO for further mechanistic study. As expected, direct ESR studies showed that nitroxide radical of N-MeAHA (Ac-(CH3)NO•) can be produced from N-MeAHA/TCHQ. Interestingly and unexpectedly, when TCHQ was substituted by its oxidation product tetrachloro-1,4-benzoquinone (TCBQ), although Ac-(CH3)NO• could also be produced, no concurrent formation of tetrachlorosemiquinone radical (TCSQ•) and TCHQ was detected, suggesting that Ac-(CH3)NO• did not result from direct oxidation of N-MeAHA by TCSQ• or TCBQ as proposed previously. To our surprise, a new nitrogen-centered amidyl radical was found to be generated from N-MeAHA/TCBQ, which was observed by ESR with the spin-trapping agents and further unequivacally identified as Ac-(CH3)N• by HPLC-MS. The final product of amidyl radical was isolated and identified as its corresponding amine. Analogous radical homolysis mechanism was observed with other halogenated quinoid compounds and N-alkyl hydroxamic acids including DFO. Interestingly, amidyl radicals were found to induce both DNA strand breaks and DNA adduct formation, suggesting that N-alkyl hydroxamic acids may exert their potential side-toxic effects via forming the reactive amidyl radical species. This study represents the first report of an unexpected new pathway for nitroxide radical production via hydrogen abstration reaction of a more reactive amidyl radical intermediate during the detoxification of the carcinogenic polyhalogenated quinones by N-alkyl hydroxamic acids, which provides more direct experimental evidence to better explain not only our previous finding that excess DFO can provide effective but only partial protection against TCHQ (or TCBQ)-induced biological damage, and also the potential side-toxic effects induced by DFO and other N-alkyl hydroxamic acid drugs.

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