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1.
Cytokine ; 149: 155725, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34634653

RESUMO

BACKGROUND: Over-activation of the NLRP3 inflammasome can lead to sepsis. NLRP3 is an essential protein in the classical pathway of pyroptosis. This study assessed the use of serum NLRP3 level as a potential inflammatory biomarker in septic patients. METHODS: Patients were categorized into five groups: healthy controls (n = 30), ICU controls (n = 22), infection (n = 19), septic non-shock (n = 33), and septic shock (n = 83). Serum NLRP3 levels were measured by enzyme-linked immunosorbent assay for all patients upon enrollment. Clinical parameters and laboratory test data (APACHE II, SOFA, and lactate) were also assessed. Moreover, the ability of serum NLRP3 levels to predict sepsis was determined by the area under the curve (AUC) analysis. RESULTS: The NLRP3 levels in the septic shock group was significantly higher (431.89, 386.61-460.21 pg/mL) than that in the healthy control group (23.24, 9.38-49.73 pg/mL), ICU control group (74.82, 62.71-85.93 pg/mL), infection group (114.34, 99.21-122.56 pg/mL), and septic non-shock group (136.99, 128.80-146.98 pg/mL; P<0.001 for all comparisons). Additionally, the AUC indicated that the ability of serum NLRP3 levels to predict sepsis and septic shock incidences was not lower than that of the SOFA score. Patients with higher NLRP3 serum levels (>147.72 pg/mL) had significantly increased 30-day mortality rate. CONCLUSIONS: NLRP3 is useful for the early identification of high-risk septic patients, particularly septic shock patients. Moreover, elevated NRLP3 levels could result in poor septic prediction outcomes.

2.
J Phys Chem Lett ; : 9188-9196, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34528804

RESUMO

Cation or anion vacancies in semiconducting oxides usually benefit activity for CO oxidation. To study the nature of vacancy engineering for a thermocatalytic reaction, we adopted lattice doping of cations with varied valence states to construct anion and cation vacancies in n-type and p-type semiconducting CeO2 and NiO, respectively. Doping cations can effectively regulate the number of the vacancies, thus tailoring the activity for CO oxidation. The strong correlation of activation energy and specific activity with a catalyst band gap verified that the nature of vacancy engineering for activity of CeO2 and NiO for CO oxidation can be attributed to tailoring of the band gap. The larger the vacancy amount, the smaller the band gap, and the lower the activation energy, thus giving a higher specific activity. Band-gap engineering, widely used for photocatalytic processes, can be a new tool for tailoring the activity of semiconducting oxide catalysts for thermocatalytic reactions.

3.
Ann Intensive Care ; 11(1): 108, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34255224

RESUMO

INTRODUCTION: Right ventricle (RV) dilation in combination with elevated central venous pressure (CVP), which is a state of RV congestion, is seen as a sign of RV failure (RVF). On the other hand, RV systolic function is usually assessed by tricuspid annular plane systolic excursion (TAPSE) and fractional area change (FAC). This study aimed to investigate the prevalence and prognostic value of RVF and RV systolic dysfunction (RVSD) in septic patients. METHODS: Mechanically ventilated sepsis and septic shock patients were included. We collected haemodynamic and echocardiographic parameters as well as prognostic information including mechanical ventilation duration, length of ICU stay and 30-day mortality. RVF was defined as a right and left ventricular end-diastolic area ratio ≥ 0.6 in combination with CVP ≥ 8 mmHg. RVSD was defined as TAPSE < 16 mm or FAC < 35%. RESULTS: A total of 215 patients were enrolled in this study, and the patients were divided into 4 groups: patients with normal RV function (normal, n = 101), patients with RVF but without RVSD (RVF only, n = 38), patients with RVSD but without RVF (RVSD only, n = 44), and patients with combined RVF-RVSD (RVF/RVSD, n = 32). The RVF/RVSD group and RVSD only group had a lower cardiac index than the RVF only group and normal groups (p < 0.05). At 30 days after ICU admission, 50.0% of patients had died in the RVF/RVSD group, which was much higher than the mortality in the RVF only group (13.2%) and normal group (13.9%) (p < 0.05). In a Cox regression analysis, the presence of RVF/RVSD was independently associated with 30-day mortality (HR 3.004, 95% CI:1.370-6.587, p = 0.006). In contrast, neither the presence of RVF only nor the presence of RVSD only was associated with 30-day mortality (HR 0.951, 95% CI:0.305-2.960, p = 0.931; HR 1.912, 95% CI:0.853-4.287, p = 0.116, respectively). CONCLUSION: The presence of combined RVF-RVSD was associated with 30-day mortality in mechanically ventilated septic patients. Additional studies are needed to confirm and expand this finding.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34296404

RESUMO

Natural bornite (NBo), a sulfide mineral of copper and iron, is one of the main mineral raw materials for copper extraction. In this study, NBo-activated hydrogen peroxide (H2O2) and persulfate processes (PS) for the degradation of minocycline (MNC) in aqueous solution were systemically investigated and compared. The MNC removal rates with the NBo/PS and NBo/H2O2 processes were 86.40% and 87.50%, respectively. The mineralization rate of NBo/PS (33.96%) was higher than that of NBo/H2O2 (29.94%) after reaction for 180 min. The effects of oxidant and activator dosage, pH, common inorganic anions (i.e., Cl-, NO3-, and HCO3-), and water composition on MNC degradation were systematically evaluated. In addition, the degradation of MNC in natural water matrix and toxicity evaluation was also studied to better evaluate the feasibility of practical application of those two processes. The results of free radical quenching experiments and electron paramagnetic resonance spectroscopy (EPR) showed that HO· was the main activated species in the NBo/H2O2 system, while SO4·- and HO· were the main activated species in the NBo/PS system. The degradation of MNC in the NBo/PS system was achieved through electron transfer, while the degradation of MNC in the NBo/H2O2 system was mainly achieved through free radical addition. The degradation pathway mainly included deamidation reactions, C-C bond breakage and hydroxylation. Reusability of NBo showed that NBo was considerably stable in activating PS and H2O2 for degradation of MNC, which was cost-effective activator. This work provides a new perspective on the degradation mechanism of pollutants by Fe-Cu bimetallic sulfide activation of PS and H2O2.

5.
J Clin Ultrasound ; 49(7): 704-714, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34117639

RESUMO

PURPOSE: The primary objective was to demonstrate the relationship between lung ultrasound (LUS) manifestations and the outcomes of intensive care unit (ICU) patients. The secondary objective was to determine the characteristics of LUS manifestations in different subgroups of ICU patients. METHODS: This prospective multi-center cohort study was conducted in 17 ICUs. A total of 1702 patients admitted between August 31, 2017 and February 16, 2019 were included. LUS was performed according to the bedside lung ultrasound in emergency (BLUE)-plus protocol, and LUS scores were calculated. Data on the outcomes and oxygenation indices were analyzed and compared between different primary indication groups. RESULTS: The LUS scores were significantly higher for non-survivors than for survivors and were significantly different between the oxygenation index groups, with higher scores in the lower oxygenation index groups. The LUS score was an independent risk factor for the 28-day mortality. The area under the receiver operating characteristic curve was 0.663 for prediction of the 28-day mortality and 0.748 for prediction of an oxygenation index ≤100. CONCLUSIONS: The LUS score based on the BLUE-plus protocol was an independent risk factor for the 28-day mortality and was important for the prediction of an oxygenation index ≤100. An early LUS score within 24 hours of ICU admission helps predicting the outcome of ICU patients.


Assuntos
Unidades de Terapia Intensiva , Pulmão , Estudos de Coortes , Humanos , Pulmão/diagnóstico por imagem , Estudos Prospectivos , Ultrassonografia
7.
J Int Med Res ; 49(5): 3000605211013176, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33990145

RESUMO

OBJECTIVE: To investigate the effect of focused ultrasonography on clinical outcomes of septic shock. METHODS: Patients with septic shock were randomized into an integrated cardiopulmonary ultrasonography (ICUS) group and conventional (CON) group. Within 1 hour of admission, the ICUS group underwent ICUS examination for hemodynamic decision-making, while the CON group received standard treatment. The primary endpoint was 28-day mortality after admission. The secondary endpoints were cumulative fluid administration in the first 6, 24, and 72 hours; use of vasoactive drugs; lactate clearance; duration of ventilation; and ICU stay. RESULTS: Ninety-four qualified patients were enrolled (ICUS group, 49; CON group, 45). ICUS showed no significant effect on 28-day mortality. Within the initial 6 hours, the ICUS group tended to have a higher fluid balance and fluid intake than the CON group. The duration of vasopressor support was shorter in the ICUS group. There were no differences in the cumulative fluid infusion within 24 or 72 hours, lactate clearance, ICU stay, or duration of ventilation. CONCLUSIONS: The initially focused ICUS did not affect the clinical outcomes of septic shock, but it tended to be associated with a higher fluid balance within the initial 6 hours and shorter duration of vasopressor support.


Assuntos
Choque Séptico , Hidratação , Hemodinâmica , Humanos , Choque Séptico/diagnóstico por imagem , Choque Séptico/tratamento farmacológico , Ultrassonografia , Vasoconstritores/uso terapêutico
8.
Elife ; 102021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33944777

RESUMO

SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine (NSDP) as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.

9.
Am J Respir Cell Mol Biol ; 65(2): 189-200, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33861690

RESUMO

Strict control of iron homeostasis is critical for the maintenance of normal lung function. Iron accumulates in the lungs of patients with idiopathic pulmonary fibrosis (PF), but the characteristics of iron metabolism in the pathogenesis of PF and related targeting therapeutics are not well studied. In this study, we investigated the cellular and molecular characteristics of iron metabolism in fibrotic lungs and further explored the efficacy of clioquinol (CQ) for the treatment of PF as well as its functional mechanism. Iron aggregates accumulated in the lungs of patients with idiopathic PF, and FTL (ferritin light chain) transcripts were increased in their pulmonary fibroblasts. In the bleomycin (BLM)-induced PF (BLM-PF) mouse model, pulmonary iron accumulation is a very early and concomitant event of PF. Labile iron pool levels in both fibroblasts and macrophages from the BLM-PF model were elevated, and iron metabolism was dysregulated. CQ attenuated PF induced by BLM and FITC, and iron-saturated CQ did not alleviate BLM-PF. Furthermore, CQ inhibited the activation of fibroblasts, including proliferation, fibrotic differentiation, proinflammatory cytokine secretion, and migration. In conclusion, our study demonstrated that CQ, acting as an iron chelator, attenuates experimental PF through inactivation of fibroblasts, providing support for targeting iron metabolism as a basis for PF treatment.


Assuntos
Quelantes/farmacologia , Clioquinol/farmacologia , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Ferro/metabolismo , Animais , Bleomicina/efeitos adversos , Bleomicina/farmacologia , Modelos Animais de Doenças , Feminino , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Masculino , Camundongos
10.
Analyst ; 146(11): 3617-3622, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-33928968

RESUMO

An enhanced photothermal signal detection method based on graphene oxide (GO) integrated long period fiber grating (LPFG) for on-site sodium copper chlorophyllin (SCC) quantification is proposed. SCC, as a porphyrin compound, can be photonically excited to induce a stronger photothermal effect. GO offers superior molecular adsorption and thermal conductivity properties; depositing it on the LPFG surface significantly improves the sensitivity and detection efficiency of the SCC photothermal signal, when irradiated with a 405 nm laser. The experimental results showed improved performance compared with those from uncoated LPFG, with a sensitivity of 0.0587 dB (mg L-1)-1 and a limit of detection (LOD) of 0.17 mg kg-1, which is also an order of magnitude lower than that of traditional high-performance liquid chromatography. The proposed method has potential applications in the fields of real-time food safety monitoring, environmental pollutant detection, and disease diagnosis.

11.
Nutrition ; 87-88: 111193, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33774421

RESUMO

OBJECTIVE: Information is limited regarding the possible relationship between diet-related inflammation and the risk of gestational diabetes mellitus (GDM). This study investigated the association between the inflammatory potential of the diet, measured by the dietary inflammatory index (DII), and GDM risk in pregnant Chinese women. METHODS: This study included 2639 eligible women from the Tongji Maternal and Child Health Cohort. Dietary intake was assessed by a validated semiquantitative food frequency questionnaire and was used to calculate the DII score. The DII was then validated using C-reactive protein measurements in a subsample of 133 pregnant women. GDM diagnoses were collected from medical records based on the results of a 75 g oral glucose tolerance test at 24 to 28 wk gestation. Multivariable-adjusted logistic regression models were performed to estimate the odds ratios (ORs) for GDM risk by DII score, modeled continuously and in tertiles. RESULTS: Of the 2639 participants, 13.1% were diagnosed with GDM. DII scores ranged from -4.45 to 3.15 and were positively associated with C-reactive protein (adjusted ß : 1.28, 95% confidence interval [CI]: 0.16, 2.40; P trend = 0.023) when comparing DII tertile 3 (most pro-inflammatory) to tertile 1 (most anti-inflammatory). A significant and positive association was observed between DII scores and GDM risk (adjusted OR: 1.43; 95% CI: 1.05, 1.95; P trend = 0.022) comparing the highest versus lowest tertiles. The stratified analysis showed that this association was stronger in pregnant women who were overweight or obese before pregnancy (adjusted OR: 2.20; 95% CI: 1.03, 4.69). CONCLUSIONS: These findings suggest that a higher DII score, corresponding to a more proinflammatory diet, is associated with a higher risk of GDM, particularly in pregnant women who were overweight or obese before pregnancy.


Assuntos
Diabetes Gestacional , Criança , Estudos de Coortes , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/etiologia , Dieta , Feminino , Humanos , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Estudos Prospectivos , Fatores de Risco
12.
Shock ; 56(3): 412-418, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33534397

RESUMO

BACKGROUND: To investigate the feasibility and the value of using mitochondrial quality control (MQC)-related proteins as biomarkers in septic patients. METHODS: The enrolled subjects were divided into four groups: healthy control group (n = 30), intensive care unit (ICU) control group (n = 62), septic nonshock group (n = 40), and septic shock group (n = 94). Serum levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), fission protein 1 (Fis1), mitofusin2 (Mfn2), and Parkin were measured by enzyme-linked immunosorbent assay at the time of enrollment for all groups. Clinical parameters and laboratory test results were also collected. RESULTS: The levels of MQC-related biomarkers between any two of the four groups were significantly different (P < 0.001 for all). The serum levels of PGC-1α, Mfn2, and Parkin were lowest in healthy individuals; the levels were dramatically higher in the ICU control group compared with the others, and they decreased progressively from the septic nonshock group to the septic shock group. However, the pattern for Fis1 was inverse; the more severe the condition was, the higher the level of Fis1. Moreover, there was moderate correlation between MQC-related biomarkers and the SOFA score (PGC-1α, r = -0.662; Fis1, r = 0.609; Mfn2, r = -0.677; Parkin, r = 0.-0.674, P < 0.001 for all). CONCLUSIONS: The serum levels of PGC-1α, Fis1, Mfn2, and Parkin were significantly correlated with organ dysfunction and reflected the disease progression and severity. The dynamic surveillance of these four biomarkers could be beneficial to predict outcome and guide treatment.

13.
ESC Heart Fail ; 8(2): 1007-1017, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33576177

RESUMO

AIMS: Sarcopenia has been found to be frequently associated with co-morbidity among patients with heart failure (HF). However, there remain insufficient data to accurately estimate the global prevalence of sarcopenia in HF. Therefore, the purpose of this research was to conduct a systematic review and meta-analysis to estimate the current overall prevalence of sarcopenia in patients with HF. METHODS AND RESULTS: We searched relevant databases for studies published up to 13 July 2020, assessing sarcopenia in vpatients with HF. After careful screening, data of included articles were extracted with a predesigned Excel form. Then the pooled prevalence of sarcopenia in patients with HF was calculated using the random-effects model. The Q test was used to assess the heterogeneity, and I2 statistic was calculated to quantify and evaluate the heterogeneity. Subgroup analyses were conducted to determine potential sources of heterogeneity. A total of 2852 articles were initially identified, and after removing duplicate publications and applying the selection criteria, we reviewed 79 full-text articles. Finally, 11 articles (n = 1742 patients with HF) were included in this systematic review and meta-analysis. The pooled prevalence of sarcopenia in patients with HF was 34% [95% confidence interval (CI): 22-47%, I2  = 96.59%] and ranged from 10% to 69%. However, substantial heterogeneity between studies (I2  = 96.59%, P < 0.001) was observed. There was no significant heterogeneity between subgroups by sex (P = 0.803) or the method used to define sarcopenia (P = 0.307). While the heterogeneity between subgroups by population setting was statistically significant (P < 0.001), the pooled prevalence of sarcopenia was 55% (95% CI: 43-66%) for hospitalized patients with HF and 26% (95% CI: 16-37%) for ambulatory patients. CONCLUSIONS: Sarcopenia was a common condition in patients with HF, and the prevalence of hospitalized patients was higher than for ambulatory patients. Early detection of sarcopenia was therefore important in patients with HF, and it was important to implement interventions so that physical therapists or managerial dieticians can easily be introduced into clinical practice.


Assuntos
Insuficiência Cardíaca , Sarcopenia , Comorbidade , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/epidemiologia , Humanos , Prevalência , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia , Sarcopenia/etiologia
14.
J Virol ; 95(9)2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33627391

RESUMO

Influenza A viruses (IAVs) continue to pose an imminent threat to humans due to annual influenza epidemic outbreaks and episodic pandemics with high mortality rates. In this context, the suboptimal vaccine coverage and efficacy, coupled with recurrent events of viral resistance against a very limited antiviral portfolio, emphasize an urgent need for new additional prophylactic and therapeutic options, including new antiviral targets and drugs with new mechanisms of action to prevent and treat influenza virus infection. Here, we characterized a novel influenza A virus nucleoprotein (NP) inhibitor, FA-6005, that inhibited a broad spectrum of human pandemic and seasonal influenza A and B viruses in vitro and protects mice against lethal influenza A virus challenge. The small molecule FA-6005 targeted a conserved NP I41 domain and acted as a potentially broad, multimechanistic anti-influenza virus therapeutic since FA-6005 suppressed influenza virus replication and perturbed intracellular trafficking of viral ribonucleoproteins (vRNPs) from early to late stages. Cocrystal structures of the NP/FA-6005 complex reconciled well with concurrent mutational studies. This study provides the first line of direct evidence suggesting that the newly identified NP I41 pocket is an attractive target for drug development that inhibits multiple functions of NP. Our results also highlight FA-6005 as a promising candidate for further development as an antiviral drug for the treatment of IAV infection and provide chemical-level details for inhibitor optimization.IMPORTANCE Current influenza antivirals have limitations with regard to their effectiveness and the potential emergence of resistance. Therefore, there is an urgent need for broad-spectrum inhibitors to address the considerable challenges posed by the rapid evolution of influenza viruses that limit the effectiveness of vaccines and lead to the emergence of antiviral drug resistance. Here, we identified a novel influenza A virus NP antagonist, FA-6005, with broad-spectrum efficacy against influenza viruses, and our study presents a comprehensive study of the mode of action of FA-6005 with the crystal structure of the compound in complex with NP. The influenza virus inhibitor holds promise as an urgently sought-after therapeutic option offering a mechanism of action complementary to existing antiviral drugs for the treatment of influenza virus infection and should further aid in the development of universal therapeutics.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Proteínas do Nucleocapsídeo , Replicação Viral/efeitos dos fármacos , Animais , Cães , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Camundongos Endogâmicos BALB C , Proteínas do Nucleocapsídeo/antagonistas & inibidores , Proteínas do Nucleocapsídeo/metabolismo , Infecções por Orthomyxoviridae/prevenção & controle , Ligação Proteica
15.
BMC Pulm Med ; 21(1): 66, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632166

RESUMO

BACKGROUND: Mitochondrial DNA (mtDNA) is a critical activator of inflammation. Circulating mtDNA released causes lung injury in experimental models. We hypothesized that elevated plasma mtDNA levels are associated with acute lung injury (ALI) in septic patients. METHODS: We enrolled 66 patients with sepsis admitted to the Department of Critical Care Medicine of Peking Union Medical College Hospital between January 2019 and October 2019. Respiratory, hemodynamic and bedside echocardiographic parameters were recorded. Plasma mtDNA, procalcitonin, interleukin 6, and interleukin 8 levels were examined. RESULTS: Plasma mtDNA levels within 24 h after admission were significantly increased in the group of septic patients with ALI [5.01 (3.38-6.64) vs 4.13 (3.20-5.07) log copies/µL, p 0.0172]. mtDNA levels were independently associated with mortality (hazard ratio, 3.2052; 95% CI 1.1608-8.8500; p 0.0253) and ALI risk (odds ratio 2.7506; 95% CI 1.1647-6.4959; p 0.0210). Patients with high mtDNA levels had worse outcomes, and post hoc tests showed significant differences in 28-day survival rates. Increased mtDNA levels were seen in patients with abdominal infection. CONCLUSIONS: Increased plasma mtDNA levels within 24 h after admission were significantly associated with ALI incidence and mortality in septic patients.


Assuntos
Lesão Pulmonar Aguda/sangue , DNA Mitocondrial/sangue , Sepse/sangue , Lesão Pulmonar Aguda/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Sepse/mortalidade , Índice de Gravidade de Doença , Análise de Sobrevida
16.
Oncogene ; 40(10): 1775-1791, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33564074

RESUMO

Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have previously found that small chemical vacuolin-1 (V1) potently inhibits autophagosome-lysosome fusion and general endosomal-lysosomal degradation. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zß (CapZß) as a V1 binding protein and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that V1 targets CapZß to inhibit endosomal trafficking and metastasis.

17.
BMC Anesthesiol ; 21(1): 25, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482733

RESUMO

BACKGROUND: Serum lactate has long been used to evaluate hypoxia and predict prognosis in critically ill patients, however, discrepancy in lactate measurements between different sites have not been recognized as a useful tool for monitoring hypoxia and evaluating outcome. METHODS: Data were obtained from the clinical information system of the intensive care unit (ICU) in a tertiary academic hospital for 1582 ICU patients with vasoactive drug requirement and valid paired blood gas. The mortality rates were compared between patients with sustained negative venous to arterial lactate gradient (VALac) and the others using the Cox proportional hazard model. Predictive factors associated with negative VALac were searched. RESULTS: A sustained negative VALac was significantly associated with higher 30 day ICU mortality [Adjusted hazard ratio (HR) = 2.31, 95% confidence interval (CI), 1.07-4.99; p = 0.032. Propensity score- weighted HR: 2.57; 95% CI, 1.17-5.64; p = 0.010]. Arterial lactate in the first blood gas pair, 24-h arterial lactate clearance, use of epinephrine, mean positive end-expiratory pressure level, and extracorporeal membrane oxygenation initiation showed statistically significant association with sustained negative VALac during the first 24 h. CONCLUSION: The sustained negative VALac in the early stage of treatment may suggest additional information about tissue hypoxia than arterial lactate alone. Critical care physicians should pay more attention to the lactate discrepancy between different sites in their clinical practice.

18.
Bioorg Med Chem ; 29: 115902, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33302045

RESUMO

ß-lactam antibiotics have long been the mainstay for the treatment of bacterial infections. New Delhi metallo-ß-lactamase 1 (NDM-1) is able to hydrolyze nearly all ß-lactam antibiotics and even clinically used serine-ß-lactamase inhibitors. The wide and rapid spreading of NDM-1 gene among pathogenic bacteria has attracted extensive attention, therefore high potency NDM-1 inhibitors are urgently needed. Here we report a series of structure-guided design of D-captopril derivatives that can inhibit the activity of NDM-1 in vitro and at cellular levels. Structural comparison indicates the mechanisms of inhibition enhancement and provides insights for further inhibitor optimization.

19.
Pulm Circ ; 10(4): 2045894020970363, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33282200

RESUMO

Inappropriate mechanical ventilation may induce hemodynamic alterations through cardiopulmonary interactions. The aim of this study was to explore the relationship between airway pressure and central venous pressure during the first 72 h of mechanical ventilation and its relevance to patient outcomes. We conducted a retrospective study of the Department of Critical Care Medicine of Peking Union Medical College Hospital and a secondary analysis of the MIMIC-III clinical database. The relationship between the ranges of driving pressure and central venous pressure during the first 72 h and their associations with prognosis were investigated. Data from 2790 patients were analyzed. Wide range of driving airway pressure (odds ratio, 1.0681; 95% CI, 1.0415-1.0953; p < 0.0001) were independently associated with mortality, ventilator-free time, intensive care unit and hospital length of stay. Furthermore, wide range of driving pressure and elevated central venous pressure exhibited a close correlation. The area under receiver operating characteristic demonstrated that range of driving pressure and central venous pressure were measured at 0.689 (95% CI, 0.670-0.707) and 0.681 (95% CI, 0.662-0.699), respectively. Patients with high ranges of driving pressure and elevated central venous pressure had worse outcomes. Post hoc tests showed significant differences in 28-day survival rates (log-rank (Mantel-Cox), 184.7; p < 0.001). In conclusion, during the first 72 h of mechanical ventilation, patients with hypoxia with fluctuating driving airway pressure have elevated central venous pressure and worse outcomes.

20.
Ann Transl Med ; 8(20): 1317, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33209897

RESUMO

Background: Cardiovascular disease (CVD) and stroke are leading causes of death. It has several risk factors, including stress and pressure. Stock volatility can cause acute stress for stockholders so that it can cause CVD events. Recently, the spread of new coronaviruses worldwide has affected economic development greatly, leading to more severe stock market fluctuations, so we systematically quantify the short-term effect of stock volatility and CVD events. Methods: Time-series analysis on the effect of stock volatility and cardiovascular events were concluded. We conducted a systematic literature search for studies published in PubMed, Embase, and Cochrane Data up to the date February 9, 2020. We assessed publication bias using Egger's test. Overall analysis and sensitivity analysis were conducted separately. Results: Four studies were finally included. Every 100-point increase in the stock market will bring about 1.01% increases in cardiovascular mortality [95% confidence intervals (CI), -0.18% to 2.21%]. The meta-analysis showed no statistical significance for cardiovascular mortality. Every 100-point increase in the stock market brought 1.01% increases in the cardiovascular mortality [95% CI, -0.18% to 2.21%]. In terms of stroke events, the estimated effect was 2.999% (95% CI, 0.325% to 5.673%). Different lag patterns also have effects on cardiovascular mortality. Every 100-point increase brought about 4.026% (95% CI, 1.516% to 6.536%) and 4.424% (95% CI, 1.145% to 7.703%) for lag 01 and 04 separately. Conclusions: Though our study has a number of limitations due to the limited studies included, it suggested that stock volatility had a lagging effect on CVD mortality, which may last for several days. Also, it might increase the incidence of stroke.

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