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1.
Huan Jing Ke Xue ; 43(1): 349-362, 2022 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-34989519

RESUMO

In this study, 50 surface water and sediment samples were collected from 25 sampling points in Qingpu District (including Taipu River basin, Jinze Reservoir, and Qingxi country park) in the Yangtze River Delta integration demonstration area, and 22 pharmaceuticals and personal care products (PPCPs) in the samples were analyzed using high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS). The distribution characteristics, sources, and influencing factors of targeted PPCPs in the study area were studied in detail. The ecological and health risks of the target PPCPs were evaluated using the quotients method. The results showed that a total of 19 PPCPs were detected in the surface water and sediment samples from 25 sampling points in Qingpu District, with total concentrations ranging from 0.06 to 178.67 ng·L-1 and 0.07 to 37.68 ng·g-1, respectively. The average value of sulfachloropyridazine (SCP) in the surface water was the highest with a concentration of 129.54 ng·L-1, whereas the average value of sulfamethoxazole (SMX) in the sediment was the highest with a concentration of 70.62 ng·g-1. The spatial distribution of the total amount of PPCPs showed a trend of Qingxi country park > Jinze Reservoir > Taipu River basin. Principal component analysis showed that the main sources of pollution were animal antibiotics used in aquaculture and the discharge of domestic sewage. There was a significant correlation between lg Koc and lg Kd (P<0.05), indicating that the organic carbon plays an important role in the distribution of the target PPCPs in water and sediments. The ecological risk assessment results revealed that the fungicides (TCC and TCS) in the surface waters showed a moderate risk to aquatic organisms of different trophic levels. The Qingxi country park and Jinze Reservoir were the regions with the highest ecological risks of PPCPs in surface water and sediment. The health risk entropy (HQ) of people of all age groups exposed through drinking was less than 1; however, with the continuous emission and accumulation of PPCPs, the pollution control of PPCPs in the environment still requires further attention.


Assuntos
Cosméticos , Preparações Farmacêuticas , Poluentes Químicos da Água , Animais , China , Cosméticos/análise , Monitoramento Ambiental , Humanos , Multimídia , Medição de Risco , Rios , Água , Poluentes Químicos da Água/análise
2.
Sci Total Environ ; 805: 150258, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-34543787

RESUMO

Due to the widespread consumption of antibiotics by humans and animals, antibiotic residues from human and animal excrements are released into the environment through domestic sewage and breeding wastewater, which ultimately affect the ecological environment and human health. In this study, the concentrations of 10 antibiotics in the air, water, soil, and sediment from 2013 to 2019 in Qingpu District of the integrated demonstration zone of the Yangtze River Delta were predicated by developing a dynamic Level IV fugacity model. The influence of seasonal environmental factors (e.g., temperature, rainfall) on the distribution and migration of antibiotics in multi-media was also explored. The simulation results show that the 10 antibiotics mainly existed in water and sediment. The concentrations of antibiotics in air, water, soil, and sediment were 0-7.629 × 10-14 ng/L, 1.187 × 10-10-16.793 ng/L, 1.042 × 10-14-3.500 × 10-11 ng/g and 8.015 × 10-12-14.188 ng/g, respectively. It was also found that the increase in temperature and rainfall can reduce the migration rate of some antibiotics into the water and sediment phases. The flux analysis of the cross-media migration and transformation of antibiotics in Qingpu District shows that advection was the prime input and output paths of antibiotics in the water. Moreover, the prime input and output paths of antibiotics in sediment were sedimentation from water to sediment and degradation. Sensitivity analysis shows that the characteristics of antibiotic emission, degradation rate, and Koc were the most influential parameters for target chemicals. The results of risk assessment based on Monte Carlo method reveal that the overall risk level of antibiotics in sediment was relatively risk-free, and the risk of antibiotics in water decreased in the order of tetracyclines > ß-lactams > fluoroquinolones > macrolides > sulfonamides.


Assuntos
Rios , Poluentes Químicos da Água , Animais , Antibacterianos/análise , China , Monitoramento Ambiental , Humanos , Multimídia , Medição de Risco , Poluentes Químicos da Água/análise
3.
Int J Oncol ; 59(6)2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34726248

RESUMO

Signal transducer and activator of transcription 3 (STAT3) activation is associated with drug resistance induced by anti­epidermal growth factor receptor (anti­EGFR) therapy in the treatment of colon cancer. Thus, the combined inhibition of EGFR and STAT3 may prove beneficial for this type of cancer. STAT3 has been proven to play a critical role in colon cancer initiation and progression, and is considered the primary downstream effector driven by interleukin­6 (IL­6). A disintegrin and metalloproteinase 17 (ADAM17), documented as an oncogene, catalyzes the cleavage of both EGF and IL­6R, inducing EGFR signaling and enabling IL­6 trans­signaling to activate STAT3 in a wide range of cell types to promote inflammation and cancer development. As a natural product, shikonin (SKN) has been found to function as an antitumor agent; however, its role in the regulation of ADAM17 and IL­6/STAT3 signaling in colon cancer cells remains unknown. In the present study, it was found that SKN inhibited colon cancer cell growth, suppressed both constitutive and IL­6­induced STAT3 phosphorylation, and downregulated the expression of ADAM17. ADAM17 expression was not altered in response to STAT3 knockdown, while IL­6­induced STAT3 activation did not induce ADAM17 transcripts. Furthermore, it was demonstrated that SKN did not affect the expression of key proteins involved in the maturation and degradation of ADAM17. SKN decreased ADAM17 expression possibly through reactive oxygen species (ROS)­mediated translational inhibition, as evidenced by the increased ADAM17 mRNA and phosphorylation levels of eukaryotic initiation factor 2α (eIF2α). The expression of ADAM17 and p­eIF2α was reversed by N­acetylcysteine (NAC, a ROS scavenger). Taken together, these results indicate that the concurrent inhibition of ADAM17 and IL­6/STAT3 signaling by SKN may synergistically contribute to the suppression of colon cancer cell growth.

4.
Oxid Med Cell Longev ; 2021: 5546711, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239689

RESUMO

Vascular endothelial cell senescence is involved in human aging and age-related vascular disorders. Guidance receptor UNC5B is implicated in oxidative stress and angiogenesis. Nonetheless, little is known about the role of UNC5B in endothelial cell senescence. Here, we cultured primary human umbilical vein endothelial cells to young and senescent phases. Subsequently, the expression of UNC5B was identified in replicative senescent cells, and then, its effect on endothelial cell senescence was confirmed by UNC5B-overexpressing lentiviral vectors and RNA interference. Overexpression of UNC5B in young endothelial cells significantly increased senescence-associated ß-galactosidase-positive cells, upregulated the mRNAs expression of the senescence-associated secretory phenotype genes, reduced total cell number, and inhibited the potential for cell proliferation. Furthermore, overexpression of UNC5B promoted the generation of intracellular reactive oxygen species (ROS) and activated the P53 pathway. Besides, overexpression of UNC5B disturbed endothelial function by inhibiting cell migration and tube formation. Nevertheless, silencing UNC5B generated conflicting outcomes. Blocking ROS production or inhibiting the function of P53 rescued endothelial cell senescence induced by UNC5B. These findings suggest that UNC5B promotes endothelial cell senescence, potentially by activating the ROS-P53 pathway. Therefore, inhibiting UNC5B might reduce endothelial cell senescence and hinder age-related vascular disorders.

5.
Am J Chin Med ; 49(5): 1063-1092, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34107858

RESUMO

Coronavirus disease (COVID-19) is a new infectious disease associated with high mortality, and traditional Chinese medicine decoctions (TCMDs) have been widely used for the treatment of patients with COVID-19 in China; however, the impact of these decoctions on severe and critical COVID-19-related mortality has not been evaluated. Therefore, we aimed to address this gap. In this retrospective cohort study, we included inpatients diagnosed with severe/critical COVID-19 at the Tongren Hospital of Wuhan University and grouped them depending on the recipience of TCMDs (TCMD and non-TCMD groups). We conducted a propensity score-matched analysis to adjust the imbalanced variables and treatments and used logistic regression methods to explore the risk factors associated with in-hospital death. Among 282 patients with COVID-19 who were discharged or died, 186 patients (66.0%) received TCMD treatment (TCMD cohort) and 96 (34.0%) did not (non-TCMD cohort). After propensity score matching at a 1:1 ratio, 94 TCMD users were matched to 94 non-users, and there were no significant differences in baseline clinical variables between the two groups of patients. The all-cause mortality was significantly lower in the TCMD group than in the non-TCMD group, and this trend remained valid even after matching (21.3% [20/94] vs. 39.4% [37/94]). Multivariable logistic regression model showed that disease severity (odds ratio: 0.010; 95% CI: 0.003, 0.037; [Formula: see text]¡ 0.001) was associated with increased odds of death and that TCMD treatment significantly decreased the odds of in-hospital death (odds ratio: 0.115; 95% CI: 0.035, 0.383; [Formula: see text]¡ 0.001), which was related to the duration of TCMD treatment. Our findings show that TCMD treatment may reduce the mortality in patients with severe/critical COVID-19.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/mortalidade , Medicamentos de Ervas Chinesas/administração & dosagem , Idoso , COVID-19/patologia , Estado Terminal , Feminino , Humanos , Masculino , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença
6.
Oxid Med Cell Longev ; 2021: 6699054, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33824698

RESUMO

Background: Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. Methods and Results: Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6, respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. Conclusion: Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cardiomegalia/metabolismo , Insuficiência Cardíaca/metabolismo , Interleucina-6/metabolismo , Estresse Oxidativo , Cloridrato de Raloxifeno/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Cardiomegalia/prevenção & controle , Linhagem Celular , Insuficiência Cardíaca/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitofagia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Cloridrato de Raloxifeno/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
7.
Curr Med Res Opin ; 37(6): 917-927, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33729889

RESUMO

BACKGROUND: To develop a sensitive and clinically applicable risk assessment tool identifying coronavirus disease 2019 (COVID-19) patients with a high risk of mortality at hospital admission. This model would assist frontline clinicians in optimizing medical treatment with limited resources. METHODS: 6415 patients from seven hospitals in Wuhan city were assigned to the training and testing cohorts. A total of 6351 patients from another three hospitals in Wuhan, 2169 patients from outside of Wuhan, and 553 patients from Milan, Italy were assigned to three independent validation cohorts. A total of 64 candidate clinical variables at hospital admission were analyzed by random forest and least absolute shrinkage and selection operator (LASSO) analyses. RESULTS: Eight factors, namely, Oxygen saturation, blood Urea nitrogen, Respiratory rate, admission before the date the national Maximum number of daily new cases was reached, Age, Procalcitonin, C-reactive protein (CRP), and absolute Neutrophil counts, were identified as having significant associations with mortality in COVID-19 patients. A composite score based on these eight risk factors, termed the OURMAPCN-score, predicted the risk of mortality among the COVID-19 patients, with a C-statistic of 0.92 (95% confidence interval [CI] 0.90-0.93). The hazard ratio for all-cause mortality between patients with OURMAPCN-score >11 compared with those with scores ≤ 11 was 18.18 (95% CI 13.93-23.71; p < .0001). The predictive performance, specificity, and sensitivity of the score were validated in three independent cohorts. CONCLUSIONS: The OURMAPCN score is a risk assessment tool to determine the mortality rate in COVID-19 patients based on a limited number of baseline parameters. This tool can assist physicians in optimizing the clinical management of COVID-19 patients with limited hospital resources.


Assuntos
COVID-19 , Medição de Risco/métodos , COVID-19/epidemiologia , COVID-19/mortalidade , China , Hospitalização/estatística & dados numéricos , Humanos , Itália , Fatores de Risco
8.
Oxid Med Cell Longev ; 2021: 6621232, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33574976

RESUMO

Pulmonary hypertension (PH) is a progressive and life-threatening chronic disease in which increased pulmonary artery pressure (PAP) and pulmonary vasculature remodeling are prevalent. Inhaled nitric oxide (NO) has been used in newborns to decrease PAP in the clinic; however, the effects of NO endogenous derivatives, S-nitrosothiols (SNO), on PH are still unknown. We have reported that S-nitroso-L-cysteine (CSNO), one of the endogenous derivatives of NO, inhibited RhoA activity through oxidative nitrosation of its C16/20 residues, which may be beneficial for both vasodilation and remodeling. In this study, we presented data to show that inhaled CSNO attenuated PAP in the monocrotaline- (MCT-) induced PH rats and, moreover, improved right ventricular (RV) hypertrophy and fibrosis induced by RV overloaded pressure. In addition, aerosolized CSNO significantly inhibited the hyperactivation of signal transducers and activators of transduction 3 (STAT3) and extracellular regulated protein kinases (ERK) pathways in the lung of MCT-induced rats. CSNO also regulated the expression of smooth muscle contractile protein and improved aberrant endoplasmic reticulum (ER) stress and mitophagy in lung tissues following MCT induction. On the other hand, CSNO inhibited reactive oxygen species (ROS) production in vitro, which is induced by angiotensin II (AngII) as well as interleukin 6 (IL-6). In addition, CSNO inhibited excessive ER stress and mitophagy induced by AngII and IL-6 in vitro; finally, STAT3 and ERK phosphorylation was inhibited by CSNO in a concentration-dependent manner. Taken together, CSNO led to pulmonary artery relaxation and regulated pulmonary circulation remodeling through anti-ROS and anti-inflammatory pathways and may be used as a therapeutic option for PH treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cisteína/análogos & derivados , Hipertensão Pulmonar/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , S-Nitrosotióis/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Colágeno/metabolismo , Cisteína/farmacologia , Cisteína/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/complicações , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metaloproteinases da Matriz/metabolismo , Mitofagia/efeitos dos fármacos , Monocrotalina , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , S-Nitrosotióis/farmacologia , Fator de Transcrição STAT3/metabolismo , Remodelação Vascular/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
9.
Eur J Pharmacol ; 893: 173822, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33347820

RESUMO

Atherosclerosis is regarded as chronic inflammatory disease. The IL-6/STAT3 pathway plays an important role in inflammation. We previously described a small-molecule compound, Bazedoxifene, which target IL-6/STAT3 pathway and has been approved for clinical use for osteoporosis in postmenopausal women. The aim of this study is to evaluate the effect of Bazedoxifene in the progression of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Five-week-old male ApoE-/- mice were fed with High-fat diet (HFD) containing 5 mg/kg Bazedoxifene or a matching control for 12 weeks. Oil red O (ORO) staining was used to detect plaque size; immunohistochemical staining was used to detect the presence of endothelial cells, vascular muscle cells and phosphorylated STAT3 (P-STAT3) in localized plaques. The potential underlying mechanisms in human umbilical vein endothelial cells (HUVECs) and vascular muscle cells (VSMCs) was detected by Western blot analysis, Wound healing assay and Elisa assay. In the ApoE-/- mice fed with HFD, daily Bazedoxifene administration effectively attenuated atherosclerotic plaque area (P < 0.01), down-regulated IL-6 levels (P < 0.01), decreased STAT3 phosphorylation, reduced VSMCs proliferation and increased endothelial coverage in aortic vessels. Interestingly, we found HUVECs lack of membrane IL-6 receptor (IL-6R) compared to VSMCs (P < 0.01). Furthermore, we found that the soluble IL-6 receptor (sIL6R) participates in the activation of STAT3 induced by IL-6 or TNF-α in HUVECs and primary HUVECs. Bazedoxifene did not inhibit the growth of HUVECs while suppressing the proliferation of VSMCs. Bazedoxifene is an attractive novel therapeutic reagent for atherosclerosis diseases. This mechanism may be partially attributed to regulating IL-6/IL-6R/STAT3 signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Aterosclerose/prevenção & controle , Indóis/farmacologia , Interleucina-6/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos Knockout para ApoE , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Fosforilação , Placa Aterosclerótica , Ratos , Transdução de Sinais
10.
J Investig Med ; 69(1): 75-85, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33051358

RESUMO

The study aimed to compare the clinical characteristics and outcomes of patients with different types (ordinary, severe, and critical) of COVID-19. A total of 1280 patients diagnosed with COVID-19 were retrospectively studied, including 793 ordinary patients, 363 severe patients and 124 critical patients. The impact of comorbidities on prognosis in ordinary, severe, and critical patients were compared and analyzed. The most common comorbidities were hypertension (33.0%), followed by diabetes (14.4%). The length of hospital stay and time from the onset to discharge were significantly longer in ordinary patients with comorbidities compared with those without comorbidities. Critical patients with comorbidities had significantly lower cure rate (19.3% vs 38.9%, p<0.05) and significantly higher mortality rate (53.4% vs 33.3%, p<0.05) compared with those without comorbidities. The time from onset to discharge was significantly longer in ordinary patients with hypertension compared with those without hypertension. The mortality rate of critical patients with diabetes was higher than that of patients without diabetes (71.4% vs 42.7%, p<0.05). Men had a significantly increased risk of death than women (OR=4.395, 95% CI 1.896 to 10.185, p<0.05); patients with diabetes had higher risk of death (OR=3.542, 95% CI 1.167 to 10.750, p<0.05). Comorbidities prolonged treatment time in ordinary patients, increased the mortality rate and reduced the cure rate of critical patients; hypertension and diabetes may be important factors affecting the clinical course and prognosis of ordinary and critical patients, respectively.


Assuntos
COVID-19/complicações , COVID-19/diagnóstico , Adulto , Idoso , COVID-19/mortalidade , Comorbidade , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
11.
Life Sci ; 261: 118304, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32828944

RESUMO

AIMS: The signal transducer and activator of transcription 3 (STAT3) pathway plays an important role in inflammatory cascade process. Our previous studies found that Raloxifene targeted against IL-6/GP130 protein-protein interface and inhibited STAT3 phosphorylation induced by IL-6 in cancer cells. However, whether Raloxifene could suppress IL-6/STAT3 signaling pathway and attenuate atherosclerosis in high-fat diet (HFD)-induced mice remains unknown. The objective of this study was to explore the potential effect of Raloxifene on the prevention of atherosclerosis. MAIN METHODS: HFD-induced atherosclerosis was established in apoliprotein E-deficient (ApoE -/-) mice. Mice by daily intragastric gavage with Raloxifene or vehicle as controls were provided. The human umbilical vein endothelial cells (HUVEC), Rat VSMC and RAW264.7 cell lines were used to evaluate the effect of Raloxifene in vitro. KEY FINDINGS: We demonstrated that Raloxifene was effective in ameliorating HFD- induced atherosclerosis plaque burden and size. Histological analysis showed that the expression of IL-6, P-STAT3, ICAM-1, VCAM-1, CD68 and α-SMA were significantly decreased in the Raloxifene intervention group compared to HFD group. Moreover, we observed that IL-6 increased migration and cell viability of VSMCs and RAW264.7 cells, while Raloxifene treatment decreased migration and reduced cell viability of VSMCs and RAW264.7 cells stimulated by IL-6. Furthermore, this effect was related to blocking IL-6/STAT3 pathway. SIGNIFICANCE: Raloxifene has effects on inhibiting atherosclerosis development, the underlying mechanisms might involve in inhibiting inflammation-related IL-6/STAT3 signaling pathway.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/prevenção & controle , Placa Aterosclerótica/prevenção & controle , Cloridrato de Raloxifeno/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dieta Hiperlipídica , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/patologia , Inflamação/prevenção & controle , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Knockout , Células RAW 264.7 , Ratos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Hypertension ; 76(4): 1104-1112, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32673499

RESUMO

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P<0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P<0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P<0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P<0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P<0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials.


Assuntos
Infecções por Coronavirus , Creatina Quinase Forma MB/sangue , Cardiopatias , Peptídeo Natriurético Encefálico/sangue , Pandemias , Fragmentos de Peptídeos/sangue , Pneumonia Viral , Troponina I/sangue , Betacoronavirus/isolamento & purificação , Biomarcadores/sangue , COVID-19 , China/epidemiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Feminino , Cardiopatias/sangue , Cardiopatias/mortalidade , Cardiopatias/virologia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Avaliação de Resultados em Cuidados de Saúde , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , SARS-CoV-2
13.
Cell Metab ; 31(6): 1068-1077.e3, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32369736

RESUMO

Type 2 diabetes (T2D) is a major comorbidity of COVID-19. However, the impact of blood glucose (BG) control on the degree of required medical interventions and on mortality in patients with COVID-19 and T2D remains uncertain. Thus, we performed a retrospective, multi-centered study of 7,337 cases of COVID-19 in Hubei Province, China, among which 952 had pre-existing T2D. We found that subjects with T2D required more medical interventions and had a significantly higher mortality (7.8% versus 2.7%; adjusted hazard ratio [HR], 1.49) and multiple organ injury than the non-diabetic individuals. Further, we found that well-controlled BG (glycemic variability within 3.9 to 10.0 mmol/L) was associated with markedly lower mortality compared to individuals with poorly controlled BG (upper limit of glycemic variability exceeding 10.0 mmol/L) (adjusted HR, 0.14) during hospitalization. These findings provide clinical evidence correlating improved glycemic control with better outcomes in patients with COVID-19 and pre-existing T2D.


Assuntos
Glicemia/análise , Infecções por Coronavirus/mortalidade , Diabetes Mellitus Tipo 2/sangue , Índice Glicêmico/fisiologia , Hiperglicemia/sangue , Pneumonia Viral/mortalidade , Idoso , Betacoronavirus/patogenicidade , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Diabetes Mellitus Tipo 2/complicações , Suscetibilidade a Doenças/patologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hiperglicemia/complicações , Hipoglicemiantes/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/complicações , Insuficiência de Múltiplos Órgãos/mortalidade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Estudos Retrospectivos , SARS-CoV-2
14.
Hepatology ; 72(2): 389-398, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32359177

RESUMO

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) is a new infectious disease. To reveal the hepatic injury related to this disease and its clinical significance, we conducted a multicenter retrospective cohort study that included 5,771 adult patients with COVID-19 pneumonia in Hubei Province. APPROACH AND RESULTS: We reported the distributional and temporal patterns of liver injury indicators in these patients and determined their associated factors and death risk. Longitudinal liver function tests were retrospectively analyzed and correlated with the risk factors and death. Liver injury dynamic patterns differed in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL). AST elevated first, followed by ALT, in severe patients. ALP modestly increased during hospitalization and largely remained in the normal range. The fluctuation in TBIL levels was mild in the non-severe and the severe groups. AST abnormality was associated with the highest mortality risk compared with the other indicators of liver injury during hospitalization. Common factors associated with elevated liver injury indicators were lymphocyte count decrease, neutrophil count increase, and male gender. CONCLUSION: The dynamic patterns of liver injury indicators and their potential risk factors may provide an important explanation for the COVID-19-associated liver injury. Because elevated liver injury indicators, particularly AST, are strongly associated with the mortality risk, our study indicates that these parameters should be monitored during hospitalization.


Assuntos
Betacoronavirus , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Fígado/fisiopatologia , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Adulto , Idoso , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Biomarcadores , COVID-19 , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Retrospectivos , SARS-CoV-2
15.
Front Pharmacol ; 11: 392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362823

RESUMO

Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by aortic dilatation and predominantly affects an elderly population. Accumulating evidence suggests that Interleukin-6 (IL-6) and the signal transducer and activator of transcription 3 (STAT3) play an important role in formation of AAAs. However, it remains unclear whether Bazedoxifene (BAZ) could suppress the activation of IL-6/GP130/STAT3 in vascular cells and the formation of AAA. Here we explored the effect of BAZ on AngII-stimulated AAA formation. ApoE-/- mice infused with AngII for 28 days using osmotic minipumps were treated with placebo or 5mg/kg BAZ. In our results most of the AngII-induced mice developed AAA with exacerbated inflammation, degradation of elastin fibers, STAT3 phosphorylation, and increased expression of matrix metalloproteinases (MMPs). These effects were markedly attenuated by BAZ. Furthermore, BAZ suppressed the stimuli-induced (IL-6 or AngII) expression of P-STAT3, MMP2 and MMP9 in vascular smooth muscle cells (VSMCs). BAZ inhibited wound healing, colony formation and suppressed STAT3 nuclear translocation in vitro. In conclusion, these results indicated that BAZ downregulated IL-6/GP130/STAT3 signaling and interfered with AAA formation induced by AngII in ApoE-/- mice, which indicates a novel potential strategy for the prevention and therapy of AAA.

16.
Circ Res ; 126(12): 1671-1681, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32302265

RESUMO

RATIONALE: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. OBJECTIVE: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. METHODS AND RESULTS: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. CONCLUSIONS: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.


Assuntos
Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Infecções por Coronavirus/epidemiologia , Mortalidade Hospitalar , Hipertensão/epidemiologia , Pneumonia Viral/epidemiologia , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , COVID-19 , Infecções por Coronavirus/complicações , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações
17.
J Cell Mol Med ; 24(10): 5740-5750, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32253812

RESUMO

Renal fibrosis acts as a clinical predictor in patients with chronic kidney disease and is characterized by excessive extracellular matrix (ECM) accumulation. Our previous study suggested that mindin can function as a mediator for liver steatosis pathogenesis. However, the role of mindin in renal fibrosis remains obscure. Here, tumour necrosis factor (TGF)-ß-treated HK-2 cells and global mindin knockout mouse were induced with renal ischaemia reperfusion injury (IRI) to test the relationship between mindin and renal fibrosis. In vitro, mindin overexpression promoted p65-the hub subunit of the NF-κB signalling pathway-translocation from the cytoplasm into the nucleus, resulting in NF-κB pathway activation in TGF-ß-treated HK-2 cells. Meanwhile, mindin activated the TGF-ß/Smad pathway, thereby causing fibrotic-related protein expression in vitro. Mindin-/- mice exhibited less kidney lesions than controls, with small renal tubular expansion, inflammatory cell infiltration, as well as collagen accumulation, following renal IRI. Mechanistically, mindin-/- mice suppressed p65 translocation and deactivated NF-κB pathway. Simultaneously, mindin disruption inhibited the TGF-ß/Smad pathway, alleviating the expression of ECM-related proteins. Hence, mindin may be a novel target of renal IRI in the treatment of renal fibrogenesis.


Assuntos
Proteínas da Matriz Extracelular/deficiência , Nefropatias/etiologia , Nefropatias/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Biomarcadores , Biópsia , Modelos Animais de Doenças , Fibrose , Técnicas de Silenciamento de Genes , Inflamação/etiologia , Inflamação/metabolismo , Nefropatias/patologia , Masculino , Camundongos
18.
J Cell Mol Med ; 24(8): 4748-4761, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32164044

RESUMO

The role of IL-6 signalling in hypertensive heart disease and its sequelae is controversial. Our group demonstrated that Bazedoxifene suppressed IL-6/gp130 signalling in cancer cells but its effect on myocardial pathology induced by pressure overload is still unknown. We explored whether Bazedoxifene could confer benefits in wild-type C57BL/6J mice suffering from transverse aortic constriction (TAC) and the potential mechanisms in H9c2 myoblasts. Mice were randomized into three groups (Sham, TAC, TAC+Bazedoxifene, n = 10). Morphological and histological observations suggested TAC aggravated myocardial remodelling while long-term intake of Bazedoxifene (5 mg/kg, intragastric) attenuated pressure overload-induced pathology. Echocardiographic results indicated Bazedoxifene rescued cardiac function in part. We found Bazedoxifene decreased the mRNA expression of IL-6, MMP2, Col1A1, Col3A1 and periostin in murine hearts after 8-week surgery. By Western blot detection, we found Bazedoxifene exhibited an inhibition of STAT3 activation in mice three hours and 8 weeks after TAC. Acute TAC stress (3 hours) led to down-regulated ratio of LC3-Ⅱ/LC3-Ⅰ, while in mice after long-term (8 weeks) TAC this ratio becomes higher than that in Sham mice. Bazedoxifene inverted the autophagic alteration induced by TAC at both two time-points. In H9c2 myoblasts, Bazedoxifene suppressed the IL-6-induced STAT3 activation. Moreover, IL-6 reduced the ratio of LC3-Ⅱ/LC3-Ⅰ, promoted P62 expression but Bazedoxifene reversed both changes in H9c2 cells. Our data suggested Bazedoxifene inhibited IL-6/gp130 signalling and protected against cardiac remodelling together with function deterioration in TAC mice.


Assuntos
Receptor gp130 de Citocina/genética , Hipertensão/tratamento farmacológico , Indóis/farmacologia , Interleucina-6/genética , Fator de Transcrição STAT3/genética , Animais , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Hipertensão/genética , Hipertensão/patologia , Camundongos , Ratos , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/genética
19.
Cancer Gene Ther ; 27(7-8): 607-618, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31570754

RESUMO

Patients with renal cell carcinoma (RCC) usually develop drug resistance and have poor prognosis owing to its insensitive property. However, the underlying mechanisms of RCC are still unclear. We implemented an integrative analysis of The Cancer Genome Atlas and Gene Expression Omnibus datasets. Three genes (CRHBP, RAB25 and PSAT1) were found to be potential biomarkers in ccRCC and validated by four independent cohorts. Then, ccRCC patients with a decreased expression of CRHBP in tumor tissues had significantly poor survival by TCGA ccRCC datasets and verified by clinical samples as well as RCC cell lines. Overexpression of CRHBP suppressed cell proliferation, migration, invasion as well as apoptosis in vitro and in vivo. Moreover, the results of western blot analysis showed the effects of CRHBP via upregulating NF-κB and p53-mediated mitochondria apoptotic pathway. Our results suggested that CRHBP may be an effective target to treat ccRCC patients.


Assuntos
Apoptose , Carcinoma de Células Renais/metabolismo , Proteínas de Transporte/metabolismo , Inflamação , Neoplasias Renais/metabolismo , Animais , Carcinoma de Células Renais/fisiopatologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/fisiopatologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cancer Sci ; 110(3): 950-961, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30648776

RESUMO

The interleukin (IL)-6/glycoprotein (GP)130/signal transducer and activator of transcription (STAT)3 pathway is emerging as a target for the treatment of hepatocellular carcinoma. IL-6 binds to IL-6R, forming a binary complex, which further combines with GP130 to transduce extracellular signaling by activating STAT3. Therefore, blocking the interaction between IL-6 and GP130 may inhibit the IL-6/GP130/STAT3 signaling pathway and its biological effects. It has been reported that bazedoxifene acetate (BAZ), a selective estrogen receptor modulator approved by the US Food and Drug Administration, could inhibit IL-6/GP130 protein-protein interactions. Western blot, immunofluorescence staining, wound healing and colony formation assays were used to detect the effect of BAZ on liver cancer cells. Cell viability was evaluated by MTT assay. Apoptosis of cells was determined using the Annexin V-FITC detection kit. Mouse xenograft tumor models were utilized to evaluate the effect of BAZ in vivo. Our data showed that BAZ inhibited STAT3 phosphorylation (P-STAT3) and expression of STAT3 downstream genes, inducing apoptosis in liver cancer cells. BAZ inhibited P-STAT3 induced by IL-6, but not by leukemia inhibitory factor. BAZ inhibited P-STAT1 and P-STAT6 less significantly as elicited by interferon-α, interferon-γ and IL-4. In addition, pretreatment of BAZ impeded the translocation of STAT3 to nuclei induced by IL-6. BAZ inhibited cell viability, wound healing and colony formation in vitro. Furthermore, tumor growth in HEPG2 mouse xenografts were significantly inhibited by daily intragastric gavage of BAZ. Our results suggest that BAZ inhibited the growth of hepatocellular carcinoma in vitro and in vivo, indicating another potential strategy for HCC prevention and therapy.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Glicoproteínas/metabolismo , Indóis/farmacologia , Interleucina-6/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células Hep G2 , Humanos , Interleucina-4/metabolismo , Fator Inibidor de Leucemia/metabolismo , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Receptores de Interleucina-6/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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