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1.
J Cell Biochem ; 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38720641

RESUMO

Enterovirus A71 (EV-A71) belongs to the genus Enterovirus of the Picornaviridae family and often causes outbreaks in Asia. EV-A71 infection usually causes hand, foot, and mouth disease and can even affect the central nervous system, causing neurological complications or death. The 5'-untranslated region (5'-UTR) of EV-A71 contains an internal ribosome entry site (IRES) that is responsible for the translation of viral proteins. IRES-transacting factors can interact with the EV-A71 5'-UTR to regulate IRES activity. Heterogeneous nuclear ribonucleoprotein (hnRNP) A3 is a member of the hnRNP A/B protein family of RNA-binding proteins and is involved in RNA transport and modification. We found that hnRNP A3 knockdown promoted the replication of EV-A71 in neural calls. Conversely, increasing the expression of hnRNP A3 within cells inhibits the growth of EV-A71. HnRNP A3 can bind to the EV-A71 5'-UTR, and knockdown of hnRNP A3 enhances the luciferase activity of the EV-A71 5'-UTR IRES. The localization of hnRNP A3 shifts from the nucleus to the cytoplasm of infected cells during viral infection. Additionally, EV-A71 infection can increase the protein expression of hnRNP A3, and the protein level is correlated with efficient viral growth. Based on these findings, we concluded that hnRNP A3 plays a negative regulatory role in EV-A71 replication within neural cells.

2.
Arthrosc Sports Med Rehabil ; 6(1): 100842, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38414840

RESUMO

Purpose: To assess the potential of ultraviolet-visible near-infrared spectroscopy to provide quantitative information on the cartilage surface at early osteoarthritis. Methods: We used a similar source and optical path to a standard arthroscope and constraining input to the range available to a standard detector/camera, further capturing and analyzing spectral information quantitatively in terms of specific electronic absorbance bands and scattering from the cartilage surface, with a focus on the early stages of degradation. Results: The ratio of the 320-nm and longer than 500-nm absorbances produced a distinct change from the normal to diseased states. The slopes between the wavelengths of 600 and 980 nm may show the transition of the single fibril to fibril bundles that occurs during early stages disease. Conclusions: Ultraviolet-visible near-infrared spectroscopy has good potential for use in integrated arthroscopic assessment. Clinical Relevance: This raises the possibility of advancing arthroscopy from a qualitative to a quantitative tool, without requiring modification of either the radiation (the light source and path) or instrumentation (the arthroscope itself) delivered to the patient, thus allowing a low-cost yet potentially high-value technology.

3.
Virus Res ; 339: 199284, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38040125

RESUMO

Enterovirus D68 (EV-D68) primarily spreads through the respiratory tract and causes respiratory symptoms in children and acute flaccid myelitis (AFM). Type III interferons (IFNs) play a critical role in inhibiting viral growth in respiratory epithelial cells. However, the mechanism by which EV-D68 induces type III IFN production is not yet fully understood. In this study, we show that EV-D68 infection stimulates Calu-3 cells to secrete IFN-λ. The transfection of EV-D68 viral RNA (vRNA) stimulated IFN-λ via MDA5. Furthermore, our findings provide evidence that EV-D68 infection also induces MDA5-IRF3/IRF7-mediated IFN-λ. In addition, we discovered that EV-D68 infection downregulated MDA5 expression. Knockdown of MDA5 increased EV-D68 replication in Calu-3 cells. Finally, we demonstrated that the IFN-λ1 and IFN-λ2/3 proteins effectively inhibit EV-D68 infection in respiratory epithelial cells. In summary, our study shows that EV-D68 induces type III IFN production via the activated MDA5-IRF3/IRF7 pathway and that type III IFNs inhibit EV-D68 replication in Calu-3 cells.


Assuntos
Enterovirus Humano D , Infecções por Enterovirus , Doenças Neuromusculares , Criança , Humanos , Enterovirus Humano D/genética , Interferon lambda , Sistema Respiratório
5.
Microbes Infect ; 25(7): 105171, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37321390

RESUMO

Mesenchymal stem cells (MSCs) comprise a primitive cell population and reside in various tissues and organs. These cells exhibit immunomodulatory activity and are effective in treating respiratory viral infections. The activation of type I and III interferons, which protect cells against viral infections, can be induced after pattern recognition receptors (PRRs) recognize viral nucleic acid species. Although certain viruses can upregulate IFN-ß expression in MSCs, the underlying mechanisms and responsiveness to different IFNs are unclear. We found that foreskin-derived fibroblast-like stromal cells (FDSCs), a kind of functional MSC, were permissive to IAV PR8, HCoV-229E, and EV-D68. Infection by IAV PR8 and HCoV-229E increased the expression of IFN-ß and IFN-λ species in FDSCs in an IRF-3-dependent manner. RIG-I was critical for detecting IAV PR8 in FDSCs, and IAV PR8 infection induced a significant increase in the expression of interferon signaling genes (ISGs). Interestingly, only IFN-ß, but not IFN-λ species, could induce the expression of ISGs, a finding supported by our observation that only IFN-ß induced STAT1 and STAT2 phosphorylation in FDSCs. We also proved that treatment with IFN-ß suppressed the propagation of IAV PR8 and promoted the survival of virus-infected FDSCs. Respiratory viruses could infect FDSCs and induce the expression of IFN-ß and IFN-λ1, but only IFN-ß could protect FDSCs against viral infection.


Assuntos
Células-Tronco Mesenquimais , Viroses , Vírus , Humanos , Interferons/genética , Interferons/metabolismo , Interferon lambda , Transdução de Sinais , Vírus/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator Regulador 3 de Interferon/metabolismo
6.
Int J Gen Med ; 16: 1653-1659, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37168532

RESUMO

Background: Traumatic brain injury (TBI) can result in functional impairments. Many patients with TBI require post-acute care to improve their functional skills and allow for greater self-independence and a better quality of life. Taiwan's National Health Insurance proposed a nationwide post-acute care program in 2017 for patients with traumatic brain injury. The program's goal was to maximize patients' functional recovery and make it possible for them to return to their homes and communities. This study aimed to explore the effectiveness of such programs in Taiwan. Methods: This pilot study retrospectively evaluated a de-identified database that contained the scores of various assessments evaluated at admission and discharge. It used the data to determine the functional improvement of patients with traumatic brain injury after participating in post-acute care programs. Results: This study collected complete data from 27 patients. After an average of 45.11 days in the program, the patients showed significant improvement in the Barthel Activity Daily Living Index, the Lawton-Brody Instrumental Activity Daily Living Scale, the Mini Nutrition Assessment, the EuroQol Five Dimensions Questionnaire, the Berg Balance Scale, the Galveston Orientation and Amnesia Test, the Rancho Los Amigos Scale, the Concise Chinese Aphasia Test, and the Mini Mental State Examination. After discharge, 96% of the patients could return to their community. Conclusion: This pilot study concluded that the program significantly promoted functional recovery for patients and could help patients with traumatic brain injury return to their communities and reduce the risk of institutionalization. Thus, patients with the potential for functional recovery could receive post-acute care in regional or community hospitals immediately after being discharged from acute wards. In the future randomized controlled trials are needed to further confirm the clinical impact of this program.

7.
PLoS One ; 18(3): e0275884, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36996063

RESUMO

For the assessment of sarcopenia or other geriatric frailty syndromes, psoas major area may be one of the primary indicators. Aim to develop and cross-validate the psoas cross-sectional area estimation equation of L3-L4 of the elderly over 60 years old by bioelectrical impedance analysis (BIA). Ninety-two older adults with normal mobility were enrolled (47 females, 45 males), and were randomly divided into a modeling group (MG, n = 62) and validation group (VG, n = 30). Computed tomography (CT) was used to measure the psoas major area at the' L3-L4 lumbar vertebrae height as a predictor. Estimated variables were height (h), whole body impedance (Zwhole), whole body impedance index (h2/Zwhole, WBI), age, gender (female = 0, male = 1), and body weight (weight) by standing BIA. Relevant variables were estimated using stepwise regression analysis. Model performance was confirmed by cross-validation. BIA estimation equation for PMM obtained from the MG was: (PMMBIA = 0.183 h2/Z- 0.223 age + 4.443 gender + 5.727, r2 = 0.702, n = 62, SEE = 2.432 cm2, p < 0.001). The correlation coefficient r obtained by incorporating the VG data into the PMM equation was 0.846, and the LOA ranged from -4.55 to 4.75 cm2. PMMBIA and PMMCT both correlate highly with MG or VG with small LOA. The fast and convenient standing BIA for measuring PMM may be a promising method that is worth developing.


Assuntos
Composição Corporal , Sarcopenia , Humanos , Masculino , Feminino , Idoso , Pré-Escolar , Pessoa de Meia-Idade , Composição Corporal/fisiologia , Peso Corporal , Músculos Psoas/diagnóstico por imagem , Sarcopenia/diagnóstico por imagem , Análise de Regressão , Impedância Elétrica
8.
Sci Rep ; 13(1): 4626, 2023 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-36944855

RESUMO

Maintenance of normothermia is a critical perioperative issue. The warming process after hypothermia tends to increase oxygen demand, which may lead to myocardial ischemia. This study explored whether hypothermia was an independent risk factor for increased morbidity and mortality in patients receiving CABG. We conducted a retrospective observational study of CABG surgeries performed from January 2018 to June 2019. The outcomes of interest were mortality, surgical site infection rate, ventilator dependent time, intensive care unit (ICU) stay, and hospitalization duration. Data from 206 patients were analysed. Hypothermic patients were taller (p = 0.012), had lower left ventricular ejection fraction (p = 0.016), and had off-pump CABG more frequently (p = 0.04). Our analysis noted no incidence of mortality within 30 days. Hypothermia was not associated with higher surgical site infection rate or longer intubation time. After adjusting for sex, age, cardiopulmonary bypass duration, left ventricular ejection fraction, and EuroSCORE II, higher EuroSCORE II (p < 0.001; odds ratio 1.2) and hypothermia upon ICU admission (p = 0.04; odds ratio 3.8) were independent risk factors for prolonged ICU stay. In addition to EuroSCORE II, hypothermia upon ICU admission was an independent risk factor for prolonged ICU stay in patients receiving elective CABG.


Assuntos
Infecção da Ferida Cirúrgica , Função Ventricular Esquerda , Humanos , Infecção da Ferida Cirúrgica/etiologia , Volume Sistólico , Tempo de Internação , Ponte de Artéria Coronária/efeitos adversos , Fatores de Risco , Estudos Retrospectivos , Unidades de Terapia Intensiva
9.
Angew Chem Int Ed Engl ; 62(16): e202300815, 2023 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-36825300

RESUMO

The exploration of deactivation mechanisms for near-infrared(NIR)-emissive organic molecules has been a key issue in chemistry, materials science and molecular biology. In this study, based on transient absorption spectroscopy and transient grating photoluminescence spectroscopy, we demonstrate that the aggregated PtII complex 4H (efficient NIR emitter) exhibits collective out-of-plane motions with a frequency of 32 cm-1 (0.96 THz) in the excited states. Importantly, similar THz characteristics were also observed in analogous PtII complexes with prominent NIR emission efficiency. The conservation of THz motions enables excited-state deactivation to proceed along low-frequency vibrational coordinates, contributing to the suppression of nonradiative decay and remarkable NIR emission. These novel results highlight the significance of excited-state vibrations in nonradiative processes, which serve as a benchmark for improving device performance.

10.
Mol Divers ; 2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36735167

RESUMO

A series of 1-benzo[1,3]dioxol-5-yl-indoles bearing 3-N-fused heteroaryl moieties have been designed based on literature reports of the activity of indoles against various cancer cell lines, synthesized via a Pd-catalyzed C-N cross-coupling, and evaluated for their anticancer activity against prostate (LNCaP), pancreatic (MIA PaCa-2), and acute lymphoblastic leukemia (CCRF-CEM) cancer cell lines. A detailed structure-activity relationship study culminated in the identification of 3-N-benzo[1,2,5]oxadiazole 17 and 3-N-2-methylquinoline 20, whose IC50 values ranged from 328 to 644 nM against CCRF-CEM and MIA PaCa-2. Further mechanistic studies revealed that 20 caused cell cycle arrest at the S phase and induced apoptosis in CCRF-CEM cancer cells. These 1-benzo[1,3]dioxol-5-yl-3-N-fused heteroaryl indoles may serve as a template for further optimization to afford more active analogs and develop a comprehensive understanding of the structure-activity relationships of indole anticancer molecules.

11.
Sci Rep ; 12(1): 21425, 2022 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-36503883

RESUMO

Enterovirus A71 (EV-A71) is an emerging enterovirus that can cause neurological complications. Enhanced serum IL-1ß levels were observed in EV-A71 patients with severe neurological symptoms. However, the roles of sensors in enterovirus-induced IL-1ß production are unclear. In this study, we identified that pattern recognition receptors, including RIG-I, TLR3, and TLR8, are implicated in EV-A71-triggered IL-1ß release in human macrophages. EV-A71 infection results in caspase-1 and caspase-8, which act as regulators of EV-A71-induced NLRP3 and RIG-I inflammasome activation. Moreover, knockdown of the expression of TLR3 and TLR8 decreased the released IL-1ß in an NLRP3-dependent manner. Since TLR3 and TLR8 ligands promote NLRP3 inflammasome activation via caspase-8, the alternative pathway may be involved. In summary, these results indicate that activation of the NLRP3 and RIG-I inflammasomes in EV-A71-infected macrophages is mediated by caspase-1 and caspase-8 and affected by TLRs, including TLR3 and TLR8.


Assuntos
Infecções por Enterovirus , Enterovirus , Humanos , Antígenos Virais , Caspase 1 , Caspase 8 , Inflamassomos , Macrófagos , Receptor 3 Toll-Like
12.
Front Aging Neurosci ; 14: 961515, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36247991

RESUMO

Introduction: Losing balance or tripping over obstacles is considered one of the most common causes of falls in the elderly. Tai-Chi Chuan (TCC) has been shown to improve muscle strength, inter-joint coordination and balance control in the elderly. This study aimed to determine whether older long-term TCC practitioners would show multi-joint kinematic strategies that would reduce the risk of tripping during obstacle-crossing compared to peers without TCC experience. Methods: Three-dimensional motions of the pelvis and lower extremities were measured using a motion capture system in fifteen older long-term TCC practitioners (TCC group) and 15 healthy controls without TCC experience during walking and crossing obstacles of three different heights. Crossing angles of the pelvis and lower limbs and toe-obstacle clearances were obtained and analyzed using two-way analyses of variance to study the between-subject (group) and within-subject (height) effects. A multi-link system approach was used to reveal the relationship between joint angular changes and toe-obstacle clearances. Results: Compared to the controls, the TCC group showed increased leading and trailing toe-obstacle clearances (p < 0.05) with increased pelvic hiking and hip flexion but decreased hip adduction on the swing side and decreased knee flexion on the stance side during leading-limb crossing (p < 0.05), and increased pelvic hiking and anterior tilt but decreased hip adduction on the swing side, and decreased knee flexion on the stance side during trailing limb crossing (p < 0.05). All significant joint angular changes contributed to the increases in the toe-obstacle clearances. Conclusion: The current study identified the kinematic changes of the pelvis and the lower limb joints and revealed a specific synergistic multi-joint kinematic strategy to reduce tripping risks during obstacle-crossing in older long-term TCC practitioners as compared to non-TCC controls. The observed multi-joint kinematic strategies and the associated increases in toe-obstacle clearances appeared to be related to the training characteristics of TCC movements. Long-term TCC practice may be helpful for older people in reducing the risk of tripping and the subsequent loss of balance.

13.
Opt Lett ; 47(17): 4423-4426, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36048669

RESUMO

The vortex beam (Laguerre-Gaussian, LG10 mode) is employed to alleviate crystal damage in multiple-plate continuum generation. We successfully compressed 190-fs, 1030-nm pulses to 42 fs with 590 µJ input pulse energy, which is 5.5 times higher than that obtained by a Gaussian beam setup of the same footprint. High throughput (86%) and high intensity-weighted beam homogeneity (>98%) have also been achieved. This experiment confirms the great potential of beam shaping in energy up-scaling of nonlinear pulse compression.

14.
Medicine (Baltimore) ; 101(37): e30468, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36123870

RESUMO

Studies have shown aspirin decreases the risk of some cancers. However, the evidence reported the association between aspirin and cancer risk in the diabetic population. In this study, we investigate whether aspirin and dipyridamole decrease the risk of cancer in patients with type 2 diabetes. A total of 5308 patients with type 2 diabetes were identified by the National Health Insurance from 1998 to 2000 and followed up until 2013. The demographic characteristics among nondipyridamole nor aspirin, aspirin, and dipyridamole users were analyzed by using the χ(2) test. Cox proportional hazard regression models were used to determine the independent effects of no aspirin nor dipyridamole, aspirin, and dipyridamole users on the risk of different cancer. After adjustment with multiple covariates, both low and high doses of aspirin and dipyridamole decrease liver cancer with risk ratios of 0.56 (95% CI, 0.37-0.83), 0.14 (95% CI, 0.05-0.39), 0.61 (95% CI, 0.38-0.99), and 0.28 (95% CI, 0.12-0.66), respectively. Both low and high doses of aspirin decrease any types of cancer with risk ratios of 0.79 (95% CI, 0.64-0.98) and 0.49 (95% CI, 0.34-0.70), respectively. Therefore, we conclude aspirin may decrease any types of cancer and liver cancer, and dipyridamole may decrease the risk of liver cancer in patients with type 2 diabetes.


Assuntos
Carcinoma , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Aspirina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Dipiridamol/uso terapêutico , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/epidemiologia , Inibidores da Agregação Plaquetária/uso terapêutico , Estudos Retrospectivos , Taiwan/epidemiologia
15.
ACS Omega ; 7(23): 20059-20080, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35722020

RESUMO

We extend our previous quantum chemistry calculations of interaction energies for 31 homodimers of small organic functional groups (the SOFG-31 data set) by including 239 heterodimers with monomers selected within the SOFG-31 data set, thus resulting in the SOFG-31+239 data set. The minimum-level theoretical scheme contains (1) the basis set superposition error corrected supermolecule (BSSE-SM) approach for intermolecular interactions; (2) the second-order Møller-Plesset perturbation theory (MP2) with the Dunning's aug-cc-pVXZ (X = D, T, Q) basis sets for the geometry optimization and correlation energy calculations; and (3) the single-point energy calculations with the coupled cluster with single, double, and perturbative triple excitations method at the complete basis set limit [CCSD(T)/CBS] using the well-tested extrapolation methods for the MP2 energy calibrations. In addition, we have performed a parallel series of energy decomposition calculations based on the symmetry adapted perturbation theory (SAPT) in order to gain chemical insights. That the above procedure cannot be further reduced has been proven to be very crucial for constructing reliable data sets of interaction energies. The calculated CCSD(T)/CBS interaction energy data can serve as a benchmark for testing or training less accurate but more efficient calculation methods, such as the electronic density functional theory. As an application, we employ a segmental SAPT model previously developed for the SOFG-31 data set to predict binding energies of large heterodimer complexes. These model energy "quanta" can be used in coarse-grained molecular dynamics simulations by avoiding large-scale calculations.

16.
Front Physiol ; 13: 775631, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35574491

RESUMO

Background: Unstable hemodynamics are not uncommon during hemodialysis (HD), which involves a rapid volume depletion, taking the patient from hypervolemia toward euvolemia. Since uremic patients commonly have cardiovascular comorbidities, hemodynamic changes during HD may reflect interactions among the volemic, cardiac, and autonomic responses to gradual volume depletion during ultrafiltration. Accurate identification of inappropriate responses helps with precisely managing intradialytic hypotension. Recently, the non-invasive ClearSight was reported to be able to detect causes of intraoperative hypotension. In this prospective observational study, we aimed to determine whether ClearSight could be used to detect patterns in stroke volemic, cardiac, and vasoreactive responses during HD. Methods: ClearSight was used to monitor chronic stable patients receiving maintenance HD. Data of mean arterial blood pressure (MAP), heart rate (HR), stroke volume index (SVI), cardiac index (CI), and calculated systemic vascular resistance index (SVRI) were obtained and analyzed to examine patterns in volemic, cardiac, and vasoreactive changes from T0 (before HD) until T8 in 30-min intervals (total 4 h). Results: A total of 56 patients with a mean age of 60.5 years were recruited, of which 40 of them were men. The average ultrafiltration volume at T8 was 2.1 ± 0.8 L. The changes in MAP and HR from T0 to T8 were non-significant. SVI at T7 was significantly lower than that at T1, T2, and T3. CI at T4 to T8 was significantly lower than that at T0. SVRI was significantly higher at T3 to T8 than at T0. Pearson's correlation coefficients between SVI and CI and between SVRI and MAP were positive at all time points. The correlation coefficients between SVRI and SVI and between CI and SVRI were significant and negative for all time points. Conclusion: ClearSight was able to detect patterns in hypervolemia during HD and was well tolerated for 4 h. CI decreased significantly after T4, with slightly decreased SVI. Ultrafiltration volume was not correlated with changes in SVI or CI. The vascular tone increased significantly, and this counteracted the reduced cardiac output after T4. With simultaneous monitoring on SVI, CI, and SVRI during HD, therefore, hypotension could be detected and managed by reducing the filtration rate or administering inotrope or vasopressors. Trial Registration: clinicaltrials.gov, ID: NCT03901794.

17.
J Formos Med Assoc ; 121(11): 2152-2160, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35331621

RESUMO

BACKGROUND: The purpose of this study is to compare the clinical characteristics and surgical outcomes of thoracotomy and video-assisted thoracoscopic surgery (VATS) in children with congenital lung malformations (CLMs) in a tertiary referring center and to report our modified biportal VATS setting. METHODS: This is a single-center retrospective chart review study including children who underwent surgical resection for CLMs between January 2007 and December 2020. Patient characteristics and surgical outcomes were compared between open and thoracoscopy, as well as conventional VATS and biportal VATS. Biportal setting included an anterior utility wound and a camera trocar wound with one-lung ventilation. RESULTS: A total of 100 patients were identified. Twenty patients received thoracotomy, and 80 patients received VATS (67 conventional and 13 biportal VATS). The median age at operation was 0.4 months in the thoracotomy group and 4.7 months in the VATS group. More patients in the thoracotomy group had preoperative symptoms, comorbidities, and emergent operations. The patients who underwent thoracotomy had significantly longer postoperative ICU stays, chest tube durations, hospital stays, and more complications. The pathological analysis revealed 67 congenital pulmonary airway malformations, 27 pulmonary sequestration, 6 hybrid lesions, and one accompanying pleuropulmonary blastoma. Compared to conventional VATS, the ICU stay was shorter in the biportal VATS group, with comparable operative durations, hospital stay and complications. CONCLUSION: VATS for CLMs is associated with better postoperative recovery and fewer complications. Biportal VATS is also a safe and feasible approach.


Assuntos
Pneumopatias , Neoplasias Pulmonares , Ventilação Monopulmonar , Criança , Humanos , Tempo de Internação , Pulmão/cirurgia , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Cirurgia Torácica Vídeoassistida , Toracotomia , Resultado do Tratamento
19.
Antiviral Res ; 195: 105184, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34627935

RESUMO

Hepatitis B virus (HBV) infection leads to severe liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). More than 257 million individuals are chronically infected, particularly in the Western Pacific region and Africa. Although nucleotide and nucleoside analogues (NUCs) and interferons (IFNs) are the standard therapeutics for HBV infection, none eradicates HBV covalently closed circular DNA (cccDNA) from the infected hepatocytes. In addition, long-term treatment with NUCs increases the risk of developing drug resistance and IFNs may cause severe side effects in patients. Thus, a novel HBV therapy that can achieve a functional cure, or even complete elimination of the virus, is highly desirable. Regarding the HBV life cycle, agents targeting the entry step of HBV infection reduce the intrahepatic cccDNA pool preemptively. The initial entry step in HBV infection involves interaction between the pre-S1 domain of the large hepatitis B surface protein (LHBsAg) and the sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor for HBV. In this study, ergosterol peroxide (EP) was identified as a new inhibitor of HBV entry. EP inhibits an early step of HBV entry into DMSO-differentiated immortalized primary human hepatocytes HuS-E/2 cells, which were overexpressed NTCP. Also, EP interfered directly with the NTCP-LHBsAg interaction by acting on the NTCP. In addition, EP had no effect on HBV genome replication, virion integrity or virion secretion. Finally, the activity of EP against infection with HBV genotypes A-D highlights the therapeutic potential of EP for fighting HBV infection.


Assuntos
Ergosterol/análogos & derivados , Vírus da Hepatite B/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Internalização do Vírus/efeitos dos fármacos , DNA Circular/metabolismo , Ergosterol/farmacologia , Células Hep G2 , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Humanos , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/genética , Replicação Viral
20.
Mol Brain ; 14(1): 152, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607601

RESUMO

The glutamatergic signaling pathway is involved in molecular learning and human cognitive ability. Specific single variants (SNVs, formerly single-nucleotide polymorphisms) in the genes encoding N-methyl-D-aspartate receptor subunits have been associated with neuropsychiatric disorders by altering glutamate transmission. However, these variants associated with cognition and mental activity have rarely been explored in healthy adolescents. In this study, we screened for SNVs in the glutamatergic signaling pathway to identify genetic variants associated with cognitive ability. We found that SNVs in the subunits of ionotropic glutamate receptors, including GRIA1, GRIN1, GRIN2B, GRIN2C, GRIN3A, GRIN3B, and calcium/calmodulin-dependent protein kinase IIα (CaMK2A) are associated with cognitive function. Plasma CaMK2A level was correlated positively with the cognitive ability of Taiwanese senior high school students. We demonstrated that elevating CaMK2A increased its autophosphorylation at T286 and increased the expression of its downstream targets, including GluA1 and phosphor- GluA1 in vivo. Additionally, methyl-CpG binding protein 2 (MeCP2), a downstream target of CaMK2A, was found to activate the expression of CaMK2A, suggesting that MeCP2 and CaMK2A can form a positive feedback loop. In summary, two members of the glutamatergic signaling pathway, CaMK2A and MeCP2, are implicated in the cognitive ability of adolescents; thus, altering the expression of CaMK2A may affect cognitive ability in youth.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Cognição/fisiologia , Proteína 2 de Ligação a Metil-CpG/fisiologia , Psicologia do Adolescente , Receptores Ionotrópicos de Glutamato/genética , Transdução de Sinais/fisiologia , Adolescente , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/sangue , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Linhagem Celular Tumoral , Ativação Enzimática , Retroalimentação Fisiológica/fisiologia , Feminino , Ácido Glutâmico/fisiologia , Células HEK293 , Humanos , Masculino , Neuroblastoma , Fosforilação , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional , Receptores Ionotrópicos de Glutamato/fisiologia , Valores de Referência , Taiwan
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