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1.
Curr Med Sci ; 41(2): 228-235, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33877539

RESUMO

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) with unknown origin spread rapidly to 222 countries, areas or territories. To investigate the genomic evolution and variation in the early phase of COVID-19 pandemic in Guangdong, 60 specimens of SARS-CoV-2 were used to perform whole genome sequencing, and genomics, amino acid variation and Spike protein structure modeling analyses. Phylogenetic analysis suggested that the early variation in the SARS-CoV-2 genome was still intra-species, with no evolution to other coronaviruses. There were one to seven nucleotide variations (SNVs) in each genome and all SNVs were distributed in various fragments of the genome. The Spike protein bound with human receptor, an amino acid salt bridge and a potential furin cleavage site were found in the SARS-CoV-2 using molecular modeling. Our study clarified the characteristics of SARS-CoV-2 genomic evolution, variation and Spike protein structure in the early phase of local cases in Guangdong, which provided reference for generating prevention and control strategies and tracing the source of new outbreaks.


Assuntos
/genética , Evolução Molecular , Glicoproteína da Espícula de Coronavírus/genética , /epidemiologia , China/epidemiologia , Furina/genética , Genoma Viral/genética , Humanos , Pandemias , Filogenia , Ligação Proteica/genética , /patogenicidade
2.
J Chem Neuroanat ; 114: 101960, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33915267

RESUMO

BACKGROUND: Epilepsy is a common chronic neurological disease caused by the over-synchronization of neurons leading to brain dysfunction. Recurrent seizures can lead to cognitive and behavioral deficits, and irreversible brain damage. While the PI3K/Akt/mTOR pathway regulates various physiological processes of neurons and glia, it may also lead to abnormal neuronal signal transduction under pathological conditions, including that of epilepsy. Everolimus (Eve), an mTOR inhibitor, may modulate neuronal excitability and therefore exert protection against epilepsy. Therefore, this study aimed to investigate the neuroprotective effect of Everolimus on seizure-induced brain injury and its regulation of the PI3K/Akt/mTOR and NF-kB/IL-6 signaling pathway. Kainic acid (KA) 15 mg/kg was used to induce seizures and Everolimus (1, 2, 5 mg/kg) was administered as a pretreatment. Hippocampal tissue was extracted 24 h post-seizure. RESULTS: The protein and mRNA expression levels of PI3K、p-AKt、p-mTOR、NF-kB and IL-6 as well as neuronal apoptosis and microglia activation, significantly increased after KA-induced seizures, however, these effects were inhibited by Everolimus treatment. Furthermore, pretreatment with Everolimus decreased seizure scores and increased seizure latency. CONCLUSIONS: Everolimus can decrease the PI3K/Akt/mTOR and NF-kB/IL-6 signaling pathway, reduce neuronal apoptosis and microglia activation, and attenuate seizure susceptibility and intensity, thus having a protective effect on seizure-induced brain damage.

3.
Sci Total Environ ; 784: 147187, 2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33901960

RESUMO

Pyrite is widely used in Fenton reaction for degradation of pollutants and exhibits great potential for environmental remediation, however, its efficiency is greatly compromised by extra H2O2 and pH adjustment. Herein, a pyrite based green solar photo-Fenton system for carbamazepine (CBZ) treatment is constructed, involving the use of simulated sunlight and natural organic acids with in situ-generated H2O2 and without extra pH adjustment. The addition of organic acids including tartaric acid (TA), citric acid (CA), and ascorbic acid (AA) can form complex with iron in pyrite, which promotes the Fe(II) dissolution. Upon irradiation, pyrite could be excited to produce photoelectrons, which would reduce oxygen to produce H2O2 through a two-step route assisted by organic acids. The simulated sunlight and organic acids promoted the in-situ production of H2O2 and Fe(II) species, sustaining an efficient Fenton reaction. This produced massive hydroxyl radical (OH), as demonstrated by the active species capture experiment. Compared with no degradation of CBZ under pure pyrite, the degradation efficiency of CBZ reached to 70%, 60%, and 53% in pyrite/TA, pyrite/CA, pyrite/AA within 30 min under simulated solar light irradiation, respectively. This work reports the first use of natural pyrite, a typical Fe-mineral semiconductor, to produce OH for CBZ degradation through natural additive assisted Fenton reaction excluding the adding extra H2O2 and pH adjustment.

4.
RNA Biol ; : 1-17, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33749516

RESUMO

Telomere is a specialized DNA-protein complex that plays an important role in maintaining chromosomal integrity. Shelterin is a protein complex formed by six different proteins, with telomeric repeat factors 1 (TRF1) and 2 (TRF2) binding to double-strand telomeric DNA. Telomeric DNA consists of complementary G-rich and C-rich repeats, which could form G-quadruplex and intercalated motif (i-motif), respectively, during cell cycle. Its G-rich transcription product, telomeric repeat-containing RNA (TERRA), is essential for telomere stability and heterochromatin formation. After extensive screening, we found that acridine derivative 2c and acridine dimer DI26 could selectively interact with TRF1 and telomeric i-motif, respectively. Compound 2c blocked the binding of TRF1 with telomeric duplex DNA, resulting in up-regulation of TERRA. Accumulated TERRA could bind with TRF1 at its allosteric site and further destabilize its binding with telomeric DNA. In contrast, DI26 could destabilize telomeric i-motif, resulting in down-regulation of TERRA. Both compounds exhibited anti-tumour activity for A549 cells, but induced different DNA damage pathways. Compound 2c significantly suppressed tumour growth in A549 xenograft mouse model. The function of telomeric i-motif structure was first studied with a selective binding ligand, which could play an important role in regulating TERRA transcription. Our results showed that appropriate level of TERRA transcript could be important for stability of telomere, and acridine derivatives could be further developed as anti-cancer agents targeting telomere. This research increased understanding for biological roles of telomeric i-motif, TRF1 and TERRA, as potential anti-cancer drug targets.

5.
Biosens Bioelectron ; 180: 113121, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33706156

RESUMO

Photoelectrochemical imaging has great potential in the label-free investigation of cellular processes. Herein, we report a new fast photoelectrochemical imaging system (PEIS) for DC photocurrent imaging of live cells, which combines high speed with excellent lateral resolution and high photocurrent stability, which are all crucial for studying dynamic cellular processes. An analog micromirror was adopted to raster the sensor substrate, enabling high-speed imaging. α-Fe2O3 (hematite) thin films synthesized via electrodeposition were used as a robust substrate with high photocurrent and good spatial resolution. The capabilities of this system were demonstrated by monitoring cell responses to permeabilization with Triton X-100. The ability to carry out dynamic functional imaging of multiple cells simultaneously provides improved confidence in the data than could be achieved with the slower electrochemical single-cell imaging techniques described previously. When monitoring pH changes, the PEIS can achieve frame rates of 8 frames per second.

6.
Clin Appl Thromb Hemost ; 27: 1076029621999717, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33749340

RESUMO

Monocyte to lymphocyte ratio (MLR) has been confirmed as a novel marker of poor prognosis in patients with coronary heart disease (CAD). However, the prognosis value of MLR for patients with CAD after percutaneous coronary intervention (PCI) needs further studies. In present study, we aimed to investigate the correlation between MLR and long-term prognosis in patients with CAD after PCI. A total of 3,461 patients with CAD after PCI at the First Affiliated Hospital of Zhengzhou University were included in the analysis. According to the cutoff value of MLR, all of the patients were divided into 2 groups: the low-MLR group (<0.34, n = 2338) and the high-MLR group (≥0.34, n = 1123). Kaplan-Meier curve was performed to compare the long-term outcome. Multivariate COX regression analysis was used to assess the independent predictors for all-cause mortality, cardiac mortality and MACCEs. Multivariate COX regression analysis showed that the high MLR group had significantly increased all-cause mortality (ACM) [hazard ratio (HR) = 1.366, 95% confidence interval (CI): 1.366-3.650, p = 0.001] and cardiac mortality (CM) (HR = 2.379, 95%CI: 1.611-3,511, p < 0.001) compared to the low MLR group. And high MLR was also found to be highly associated with major adverse cardiovascular and cerebrovascular events (MACCEs) (HR = 1.227, 95%CI: 1.003-1.500, p = 0.047) in patients with CAD undergoing PCI. MLR was an independent predictor of ACM, CM and MACCEs in CAD patients who underwent PCI.

7.
Eur Neuropsychopharmacol ; 45: 15-28, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33730683

RESUMO

Physical inactivity, the fourth leading mortality risk factor worldwide, is associated with chronic mental illness. Identifying the mechanisms underlying different levels of baseline physical activity and the effects of these levels on the susceptibility to stress is very important. However, whether different levels of baseline physical activity influence the susceptibility and resilience to chronic social defeat stress (CSDS), and the underlying mechanisms in the brain remain unclear. The present study segregated wild-type mice into low baseline physical activity (LBPA) and high baseline physical activity (HBPA) groups based on short term voluntary wheel running (VWR). LBPA mice showed obvious susceptibility to CSDS, while HBPA mice were resilient to CSDS. In addition, the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) was lower in LBPA mice than in HBPA mice. Furthermore, activation of TH neurons in the VTA of LBPA mice by chemogenetic methods increased the levels of VWR and resilience to CSDS. In contrast, inhibiting TH neurons in the VTA of HBPA mice lowered the levels of VWR and increased their susceptibility to CSDS. Thus, this study suggests that different baseline physical activities might be mediated by the dopamine system. This system also affects the susceptibility and resilience to CSDS, possibly via alteration of the baseline physical activity. This perspective on the neural control and impacts on VWR may aid the development of strategies to motivate and sustain voluntary physical activity. Furthermore, this can maximize the impacts of regular physical activity toward stress-reduction and health promotion.

8.
Medicine (Baltimore) ; 100(8): e24802, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663097

RESUMO

RATIONALE: Clitoris swelling as the initial clinical presentation of acute lymphoblastic leukemia (ALL) is extremely rare. These patients may be misdiagnosed with acute myeloid leukemia or solid tumor, and the main treatment can also be delayed. PATIENT CONCERNS: A 2.10-year-old girl was referred to the pediatric surgery clinic with a worsening onset of clitoris swellings. The patient was afebrile and well appearing. Multiple retroperitoneal mass were confirmed by computed tomography (CT) and high serum neuron-specific enolase level was high. She was scheduled for an abdominal biopsy from the retroperitoneal mass suspicious of neuroblastoma. DIAGNOSES: The child was eventually diagnosed as having precursor B cell ALL with central nervous system involved, with TCF3-PBX1 fusion gene and additional chromosomal aberrations, based on examinations of the bone marrow and brain magnetic resonance imaging. INTERVENTIONS: Before the diagnosis of leukemia, the patient was given symptomatic treatment for 1 week. She was treated with chemotherapy in accordance with the Chinese Children's Cancer Group protocol 2015 after confirmed diagnosis. OUTCOMES: After induction chemotherapy for ALL, although the girl had transiently clinical remission, the bone marrow aspirate indicated a poor outcome. Our patient discontinued treatment and discharged. From literature review, there was only 1 case of in acute myeloid leukemia with clitoris swelling as the initial symptom. LESSONS: The clinical symptoms of ALL with clitoris swelling are not typical, with a high rate of misdiagnosis. When the cause of clitoris swelling is unknown, ALL should be considered. Bone marrow aspiration must be done before doing a more invasive investigation like biopsy.


Assuntos
Clitóris/patologia , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Pré-Escolar , Feminino , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico
9.
Sci Total Environ ; 778: 145812, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33721648

RESUMO

Certain studies suggest that air pollution could be a risk factor for obesity, but the evidence on the association between air pollution exposure and obesity in adults is limited. This study aims to examine the association between long-term exposure to fine particulate matter (PM2.5) and obesity-related traits in Chinese adults. Thus, a cross-sectional study was conducted based on a nationally representative sample of 91, 121 adults from 31 provinces in China. Integrated the data from satellites, chemical transport model, and ground observations, annual average concentrations of PM2.5 was obtained at the township level using a machine learning method. The information on body weight, height, and waist circumference (WC) were obtained from a questionnaire survey. The general obesity and abdominal obesity status were classified based on body mass index (BMI) and WC, respectively. Logistic and multivariate linear regression models were used to examine the association between PM2.5 and obesity-related traits, along with the examination of potential effect modifications. After adjustment for covariates, a 10 µg/m3 increase in PM2.5 concentration was associated with 8.0% [95% confidence interval (CI): 1.0%, 10.0%] and 10% (95% CI: 9.0%, 11.0%) increases in odds for general obesity and abdominal obesity, respectively. The odds ratios associated with per 10 µg/m3 PM2.5 increase were significantly greater in individuals of older age (≥60 years), of Han ethnicity, with lower socioeconomic status (SES), cooking without using a ventilation device, using unclean household fuels, having near-home pollution sources, and doing no physical exercise. These findings suggest that long-term exposure to ambient PM2.5 increase obesity risk in Chinese adults. It has significant significance to reduce air pollution to reducing the burden of obesity, particularly for the susceptible populations.

10.
Science ; 371(6534): 1116, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33707258
11.
Oncol Rep ; 45(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33649828

RESUMO

The cell surface glycoprotein CD44 displays different active statuses; however, it remains unknown whether the activation process of CD44 is critical for tumor development and progression. The aim of the present study was to investigate whether breast cancer (BCa) cells with different activation states of CD44 show similar or distinct functional characteristics and to further examine the mechanisms regulating CD44 activities. A feature for the 'activated' state of CD44 is that it can bind to its principal ligand hyaluronan (HA). The binding of CD44 with HA is usually influenced by CD44 alternative splicing, resulting in multiple CD44 isoforms that determine CD44 activities. Flow cytometry was used to sort BCa cell subsets based on CD44­HA binding abilities (HA­/low vs. HAhigh). Subsequently, cell proliferation and colony formation assays were performed in vitro, and CD44 expression patterns were analyzed via western blotting. The results demonstrated that the CD44 variant isoform 10 (CD44v10) was highly expressed in a HA­/low binding subset of BCa cells, which exhibited a significantly higher proliferation capacity compared with the HAhigh binding subpopulation. Knockdown of CD44v10 isoform in HA­/low binding subpopulation induced an increase in HA binding ability and markedly inhibited proliferation. Furthermore, the mechanistic analysis identified that CD44v10 facilitated cell proliferation via activation of ERK/p38 MAPK and AKT/mTOR signaling. Moreover, the knockdown of CD44v10 expression downregulated the phosphorylation of ERK, AKT and mTOR, while no alteration was observed in p38 phosphorylation. Collectively, the present study identified a subset of fast­growing BCa cells characterized by CD44v10 expression, which may serve as a specific therapeutic target for BCa.

12.
Biosens Bioelectron ; 182: 113191, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33780852

RESUMO

Vibrio parahaemolyticus is one of the foodborne bacteria that widely present in seafood as well as the leading cause of seafood-associated bacterial gastroenteritis. Traditional identification of such pathogens mainly relies on culturing methods, ELISA or PCR. These methods are usually laborious, time-consuming with poor diagnosis competences, or require costly and bulky equipment though of high sensitivity. In this study, a thread-based microfluidic electrochemical aptasensor was designed, fabricated and tested by using label-free aptamer immunosensing technology for rapid and highly sensitive detection of Vibrio parahaemolyticus in seafood. Both the microfluidic channels and electrodes were simply fabricated on threads. Molybdenum disulfide (MoS2) nanosheets were used to obtain enhanced sensitivity of the electrochemical measurement. When used in detecting Vibrio parahaemolyticus, the proposed aptasensor has a dynamic detection range of 10-106 CFU mL-1 with a detection limit of 5.74 CFU mL-1. Compared with traditional plate counting method, the proposed aptasensor has higher detection sensitivity and less assay time (30 min), while high specificity and accuracy are kept. The proposed microfluidic thread-based electrochemical aptasensor grabs the potential to detect other pathogens by simply functionalizing the threaded electrodes with aptamers for targeted biological substances.

13.
J Mol Biol ; 433(13): 166964, 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33781758

RESUMO

Recent years have seen a dramatic improvement in protein-design methodology. Nevertheless, most methods demand expert intervention, limiting their widespread adoption. By contrast, the PROSS algorithm for improving protein stability and heterologous expression levels has been successfully applied to a range of challenging enzymes and binding proteins. Here, we benchmark the application of PROSS as a stand-alone tool for protein scientists with no or limited experience in modeling. Twelve laboratories from the Protein Production and Purification Partnership in Europe (P4EU) challenged the PROSS algorithm with 14 unrelated protein targets without support from the PROSS developers. For each target, up to six designs were evaluated for expression levels and in some cases, for thermal stability and activity. In nine targets, designs exhibited increased heterologous expression levels either in prokaryotic and/or eukaryotic expression systems under experimental conditions that were tailored for each target protein. Furthermore, we observed increased thermal stability in nine of ten tested targets. In two prime examples, the human Stem Cell Factor (hSCF) and human Cadherin-Like Domain (CLD12) from the RET receptor, the wild type proteins were not expressible as soluble proteins in E. coli, yet the PROSS designs exhibited high expression levels in E. coli and HEK293 cells, respectively, and improved thermal stability. We conclude that PROSS may improve stability and expressibility in diverse cases, and that improvement typically requires target-specific expression conditions. This study demonstrates the strengths of community-wide efforts to probe the generality of new methods and recommends areas for future research to advance practically useful algorithms for protein science.

14.
J Glob Antimicrob Resist ; 25: 72-76, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33689828

RESUMO

OBJECTIVES: The aim of this study was to compare the antibiotic susceptibility profiles of Mycobacterium abscessus complex (MABC) isolates and to investigate the relationship between susceptibility profiles and genetic mechanisms of macrolide resistance. METHODS: More than 200 isolates collected from respiratory specimens between 2014 and 2018 were randomly analysed in this study. Minimum inhibitory concentrations (Mics) of ten potential antimicrobial agents were determined by the microplate alamarBlue assay. RESULTS: We identified 43 MABC isolates, including 32 M. abscessus subsp. abscessus (M. abscessus) (6 from immunocompromised patients) and 11 M. abscessus subsp. massiliense (M. massiliense). The majority of MABC isolates were susceptible to amikacin (96.9% and 100.0% for M. abscessus and M. massiliense, respectively), linezolid (96.9% and 100.0%, respectively), cefoxitin (100.0% and 100.0%, respectively), imipenem (90.6% and 72.7%, respectively) and tobramycin (90.6% and 72.7%, respectively). The resistance rates to clarithromycin and doxycycline in isolates of M. abscessus (68.8% and 100.0%) were significantly higher than those in isolates of M. massiliense (18.2% and 63.6%) (P < 0.05), whereas the percentage of tobramycin-resistant isolates among M. abscessus (9.4%) was significantly lower than among M. massiliense (27.3%) (P = 0.007). Sequencing analyses showed significant differences between erm(41) of M. abscessus and M. massiliense. CONCLUSION: Mycobacterium abscessus is the dominant pathogen of pulmonary MABC infections in our hospital. Aminoglycosides (amikacin and tobramycin), ß-lactams (cefoxitin and imipenem) and linezolid exhibited potent inhibitory activity against MABC in vitro. The erm(41) gene may be a promising marker to predict macrolide susceptibility for M. abscessus.

15.
J Clin Neurosci ; 85: 6-12, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33581791

RESUMO

BACKGROUND: Rituximab (RTX) is a mouse-human chimeric anti-CD20 monoclonal antibody and has been increasingly used for preventing relapses in myasthenia gravis (MG). However, the appropriate dose for maximizing the beneficial effects in refractory MG with acetylcholine receptor (AChR) autoantibody is a long-standing and critical debating question. METHODS: We performed a meta-analysis to evaluate the efficacy and safety of the different doses of RTX in 260 refractory AChR-MG patients. RESULTS: The AChR-MG patients were divided into low or routine RTX dose groups. An overall proportion of 77% (p = 0.000) AChR-MG patients demonstrated improved clinical status as indicated by the Myasthenia Gravis Foundation of America post-intervention scale (MGFA-PIS). There were 77.1% patients showed improved clinical status in lower dose of RTX group (p = 0.000) and 76.8% in routine protocol group (p = 0.000). Although we found there was no significant difference in the proportion of AChR-MG patients with improved clinical status or adverse reactions between the two groups, adverse reactions might be lower in the lower dose RTX group. CONCLUSION: Most of refractory MG patients with anti-AChR autoantibody were well responsive and tolerated to RTX treatment. Repeated application of lower dose of RTX was effective and might be more appropriate for refractory AChR-MG patients with potential lower side effects.


Assuntos
Fatores Imunológicos/administração & dosagem , Miastenia Gravis/tratamento farmacológico , Rituximab/administração & dosagem , Adulto , Idoso , Autoanticorpos/imunologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Rituximab/efeitos adversos
16.
Oncol Nurs Forum ; 48(2): 207-228, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33600394

RESUMO

PROBLEM IDENTIFICATION: The aim of this article is to evaluate the effectiveness of yoga on cancer-related fatigue (CRF) in patients undergoing chemotherapy and/or radiation therapy. LITERATURE SEARCH: Relevant English and Chinese articles were retrieved from medical databases and included in this analysis. Standardized critical appraisal instruments from the Joanna Briggs Institute were adopted for the quality assessment. DATA EVALUATION: 16 randomized controlled trials met the inclusion criteria. SYNTHESIS: Yoga interventions had a positive effect in reducing CRF among patients undergoing chemotherapy and/or radiation therapy, but the adherence to yoga was low. Mixed types of yoga, in addition to supervised and self-practicing strategies, were associated with increased patient adherence and improved CRF. IMPLICATIONS FOR PRACTICE: Yoga appears to be a safe and effective exercise for the management of CRF during chemotherapy and/or radiation therapy; however, additional high-quality studies are needed to define an optimal yoga intervention strategy.

17.
Chemosphere ; 273: 129727, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33524747

RESUMO

Thiamethoxam (TMX) is one of the major compounds of neonicotinoids, the most widely used class of insecticides worldwide. Previously, TMX was considered a non-toxic neonicotinoid insecticide to mammals. However, the genotoxicity, cytotoxicity, and hepatotoxicity of TMX in mammals were recently reported. Thus far, the effects of TMX on the mouse liver and its detailed mechanism remain unclear. NNMT, strongly expressed in the liver, plays a critical role in body energy expenditure. To confirm the potential pathogenesis of liver dysfunction induced by TMX, ICR mice were exposed to TMX at a dose of 4 mg/kg and 20 mg/kg by gavage administration for 12 weeks. The data showed that chronic TMX exposure caused dyslipidemia and nonalcoholic fatty liver disease (NAFLD) in mice. Moreover, aggravated oxidative stress, dysfunction, and disorganized structure were also observed in TMX-treated mouse livers. In addition, increases of PPARγ, fatty acid synthase, and NNMT expression, as well as decreases of PPARα and GNMT expression, S-adenosylmethionine deficiency, and methionine metabolism disorder were also observed in TMX-treated mouse livers. These results suggest that chronic TMX exposure induces dyslipidemia and NAFLD in mice. Moreover, inhibition of NNMT in hepatocytes significantly reversed the effects of TMX. The molecular mechanism of TMX-induced NAFLD is mostly through NNMT-mediated methionine metabolism and methyl donor balance, which ultimately regulates PPARα signaling pathway. Inhibition of NNMT could be a potentially novel strategy for blocking the progression of NAFLD induced by TMX.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Fígado , Metionina , Camundongos , Camundongos Endogâmicos ICR , Nicotinamida N-Metiltransferase , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Tiametoxam
18.
J Infect Dis ; 223(8): 1313-1321, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33605423

RESUMO

Domestic cats, an important companion animal, can be infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This has aroused concern regarding the ability of domestic cats to spread the virus that causes coronavirus disease 2019. We systematically demonstrated the pathogenesis and transmissibility of SARS-CoV-2 in cats. Serial passaging of the virus between cats dramatically attenuated the viral transmissibility, likely owing to variations of the amino acids in the receptor-binding domain sites of angiotensin-converting enzyme 2 between humans and cats. These findings provide insight into the transmissibility of SARS-CoV-2 in cats and information for protecting the health of humans and cats.


Assuntos
/transmissão , /patogenicidade , Aminoácidos/metabolismo , Animais , Gatos , Linhagem Celular , Chlorocebus aethiops , Feminino , Humanos , Masculino , Células Vero
19.
Coron Artery Dis ; 32(3): 191-196, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33471466

RESUMO

BACKGROUND: C-reactive protein (CRP) has been proposed as a contributor to the pathogenesis of coronary artery disease (CAD) and inflammatory reactions, which are associated with a decrease in serum albumin, and it has been reported that the CRP-to-serum albumin ratio (CAR) can predict CAD severity in inpatient ischemic cardiomyopathy (ICM) patients. However, the relationship between the CAR and long-term adverse outcomes in CAD patients after percutaneous coronary intervention (PCI) is still unknown. METHODS: A total of 3561 CAD patients enrolled in the Outcomes and Risk Factors of Patients with Coronary Heart Disease after PCI: an investigation based on case records and follow-up (CORFCHD-ZZ), a retrospective cohort study conducted from January 2013 to December 2017, and 1630 patients meeting the study inclusion criteria were divided into two groups based on the CAR (CAR < 0.186; n = 1301 and CAR ≥ 0.186; n = 329). The primary outcome was long-term mortality, including all-cause mortality (ACM) and cardiac mortality. The average follow-up time was 37.59 months. RESULTS: We found that there were significant differences between the two groups in the incidences of ACM (P < 0.001) and cardiac mortality (P = 0.003). Cox multivariate regression analyses demonstrated that CAR was an independent predictor of ACM [hazard ratio, 2.678; (95% confidence interval (CI), 1.568-4.576); P < 0.001] and cardiac mortality (hazard ratio, 2.055; 95% CI, 1.056-3.998; P = 0.034) in CAD patients after PCI. CONCLUSION: This study revealed that the CAR is an independent and novel predictor of long-term adverse outcomes in CAD patients who have undergone PCI.

20.
J Biomol Struct Dyn ; : 1-10, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33459177

RESUMO

ABTRACT The epidermal growth factor receptor (EGFR) kinase inhibitors Gefitinib, Erlotinib, Afatinib and Osimertinib have been approved for the treatments of non-small cell lung cancer patients harboring sensitive EGFR mutations, but resistance arises rapidly. To date all approved EGFR inhibitors are ATP-competitive inhibitors, highlighting the need for therapeutic agents with alternative mechanisms of action. Allosteric kinase inhibitors offer a promising new therapeutic strategy to ATP-competitive inhibitors. The mutant-selective allosteric EGFR inhibitors EAI045 exhibited higher potency for EGFRL858R&T790M compared to WT, which was also effective in EGFR-mutant models including those harboring the C797S mutation. However, it was not effective as a single-agent inhibitor, and require the co-administration of the anti-EGFR antibody Cetuximab. Further efforts produced a more potent analog JBJ-04-125-02, which can inhibit cell proliferation as a single-agent inhibitor. In the present study, molecular dynamics simulations and free energy calculations were performed and revealed the detailed inhibitory mechanism of JBJ-04-125-02 as more potent EGFR inhibitor. Moreover, the energy difference between HOMO and LUMO calculated by DFT implied the higher interaction of JBJ-04-125-02 than EAI045 in the active site of the EGFR. The identified key features obtained from the molecular modeling enabled us to design novel EGFR allosteric inhibitors. Communicated by Ramaswamy H. Sarma.

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