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1.
Front Cardiovasc Med ; 9: 870341, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35669468

RESUMO

Background: The positive relationship between metabolic healthy obesity (MHO) and cardiovascular risk has been under debate in recent years. Previously, strong evidence supported the causal role of increased plasma lipoprotein(a) [Lp(a)] levels in cardiovascular disease (CVD). The current study aimed to investigate the different associations of Lp(a) and cardiovascular events (CVEs) in patients with coronary artery disease (CAD) and different metabolic phenotypes. Methods: A total of 5,089 patients who were angiography-proven CAD were consecutively included and followed up for CVEs. Obesity was defined as a body mass index (BMI) ≥25 kg/m2 according to Asia-specific BMI criteria. Patients were divided into four groups according to metabolic phenotypes, namely metabolically healthy/unhealthy non-obese and metabolically healthy/unhealthy obese [metabolically healthy non-obese (MHN), MHO, metabolically unhealthy non-obese (MUN), and metabolically unhealthy obesity (MUO)]. Comparisons of CAD severity and outcomes were performed among four groups. Cox regression analyses and cubic spline models were used to examine the relationship between Lp(a) and CVEs in patients with different metabolic phenotypes. Results: During a median of 7.5 years' follow-up, 540 (10.6%) CVEs occurred. MUN and MUO populations had more severe coronary stenosis than MHN ones, while no significant difference in the Gensini score (GS) was observed between MHN and MHO. Patients with MUN and MUO presented a higher risk of CVEs than patients with MHN (hazard ratio [HR]: 1.414, 95% CI: 1.024-1.953-1.556 and HR: 1.747, 95% CI: 1.295-1.363, p < 0.05). In subgroup analysis, restricted cubic spline models showed that there was no association between Lp(a) and CVEs in patients in MHN and MHO, while the MUN and MUO groups presented increasing associations between Lp(a) and CVEs and such association was stronger in the MUO group. In Cox regression analysis, Lp(a) >50 mg/dl was associated with a 2.032- and 2.206-fold higher risk of subsequent CVEs in the MUO and MUN subgroups, respectively. Conclusion: Among patients with angiography-proven stable CAD, Lp(a) had a more significant prognostic value in both MUO and MUN individuals regardless of obesity, suggesting the importance of screening for cardiovascular risk with Lp(a) in metabolically unhealthy patients.

2.
Acta Pharm Sin B ; 12(5): 2417-2428, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35646546

RESUMO

Glycosite-specific antibody‒drug conjugatess (gsADCs), harnessing Asn297 N-glycan of IgG Fc as the conjugation site for drug payloads, usually require multi-step glycoengineering with two or more enzymes, which limits the substrate diversification and complicates the preparation process. Herein, we report a series of novel disaccharide-based substrates, which reprogram the IgG glycoengineering to one-step synthesis of gsADCs, catalyzed by an endo-N-acetylglucosaminidase (ENGase) of Endo-S2. IgG glycoengineering via ENGases usually has two steps: deglycosylation by wild-type (WT) ENGases and transglycosylation by mutated ENGases. But in the current method, we have found that disaccharide LacNAc oxazoline can be efficiently assembled onto IgG by WT Endo-S2 without hydrolysis of the product, which enables the one-step glycoengineering directly from native antibodies. Further studies on substrate specificity revealed that this approach has excellent tolerance on various modification of 6-Gal motif of LacNAc. Within 1 h, one-step synthesis of gsADC was achieved using the LacNAc-toxin substrates including structures free of bioorthogonal groups. These gsADCs demonstrated good homogeneity, buffer stability, in vitro and in vivo anti-tumor activity. This work presents a novel strategy using LacNAc-based substrates to reprogram the multi-step IgG glycoengineering to a one-step manner for highly efficient synthesis of gsADCs.

3.
Blood Adv ; 6(11): 3386-3397, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35671062

RESUMO

Understanding the genomic and epigenetic mechanisms of drug resistance in pediatric acute lymphoblastic leukemia (ALL) is critical for further improvements in treatment outcomes. The role of transcriptomic response in conferring resistance to l-asparaginase (LASP) is poorly understood beyond asparagine synthetase (ASNS). We defined reproducible LASP response genes in LASP-resistant and LASP-sensitive ALL cell lines as well as primary leukemia samples from newly diagnosed patients. Defining target genes of the amino acid stress response-related transcription factor activating transcription factor 4 (ATF4) in ALL cell lines using chromatin immunoprecipitation sequencing (ChIP-seq) revealed 45% of genes that changed expression after LASP treatment were direct targets of the ATF4 transcription factor, and 34% of these genes harbored LASP-responsive ATF4 promoter binding events. SLC7A11 was found to be a response gene in cell lines and patient samples as well as a direct target of ATF4. SLC7A11 was also one of only 2.4% of LASP response genes with basal level gene expression that also correlated with LASP ex vivo resistance in primary leukemia cells. Experiments using chemical inhibition of SLC7A11 with sulfasalazine, gene overexpression, and partial gene knockout recapitulated LASP resistance or sensitivity in ALL cell lines. These findings show the importance of assessing changes in gene expression following treatment with an antileukemic agent for its association with drug resistance and highlight that many response genes may not differ in their basal expression in drug-resistant leukemia cells.


Assuntos
Aspartato-Amônia Ligase , Leucemia-Linfoma Linfoblástico de Células Precursoras , Fator 4 Ativador da Transcrição/genética , Aminoácidos/uso terapêutico , Asparaginase/farmacologia , Asparaginase/uso terapêutico , Aspartato-Amônia Ligase/genética , Aspartato-Amônia Ligase/metabolismo , Linhagem Celular Tumoral , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
4.
Food Res Int ; 157: 111405, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35761659

RESUMO

Acrylamide (AA) is a common food contaminant that causes glucose metabolism disorders (GMD). However, the underlying mechanism remains unclear. Female Sprague Dawley (SD) rats were treated with AA via gavage for 21 days, and the glucose and insulin levels, gut microbiota, intestinal barrier, and metabolism were analyzed. The results revealed that AA elevated serum glucose levels, reduced insulin levels and caused intestinal barrier injury. The 16S amplicon sequencing and non-targeted metabolomics showed that AA induced gut microbiota dysbiosis and bile acids (BAs) metabolism disorder. Specifically, AA decreased the abundance of Lactobacillus and Bacteroides in the cecal contents, and increased the cholic acid (CA) content in feces. Meanwhile, the expression of ileum apical sodium-dependent bile acid transporter (ASBT) responsible for CA reabsorption was suppressed. Further analysis indicated that BAs sensing nuclear receptor farnesoid X receptor (FXR) gene was activated and glucagon-like peptide-1 (GLP-1) which stimulates insulin secretion was downregulated. In addition, activation of FXR increased the expression of fibroblast growth factor 15 (FGF15), which resulted in the inhibition of hepatic BAs synthesis. Overall, this study demonstrated that AA-induced GMD is associated with the gut-microbiota-CA-FXR/GLP-1 axis. These findings add new knowledge to the AA-induced GMD and provide a basis for potential AA toxicity mitigation by manipulation of the gut microbiota.


Assuntos
Microbioma Gastrointestinal , Transtornos do Metabolismo de Glucose , Insulinas , Acrilamida/toxicidade , Animais , Ácidos e Sais Biliares , Glicemia , Disbiose/induzido quimicamente , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares
5.
Artigo em Inglês | MEDLINE | ID: mdl-35737596

RESUMO

Direct chemical modification of native antibodies in a site-specific manner remains a great challenge due to the complicated structural characteristics of antibodies. Ligand-directed conjugation can achieve the selective modification of antibodies, but usually requires multiple extra steps for ligand release and cargo assembly. Herein, we report a novel, traceless strategy to enable the facile and efficient one-step synthesis of site-specific antibody-drug conjugates (ADCs) by harnessing a thioester-based acyl transfer reagent. The designed reagent, consisting of an optimized Fc-targeting ligand, a thioester bridge and a toxin payload, directly assembles the toxin precisely onto the K251 position of native IgGs and simultaneously self-releases the affinity ligand in one step. With this traceless, one-step method, we successfully synthesized a series of K251-linked ADCs from native Trastuzumab. These ADCs demonstrated excellent homogeneity, thermal stability, and both in vitro and in vivo anti-tumor activity. This strategy is equally efficient for IgG1, IgG2, and IgG4 subtypes. The current work presents a robust, traceless, site-specific antibody functionalization via a self-releasing strategy, and offers a novel acyl transfer design for broad potential application in ligand-directed protein modifications.

6.
BMC Cardiovasc Disord ; 22(1): 246, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35655132

RESUMO

BACKGROUND: The relationship between ambulatory arterial stiffness index (AASI) and left ventricular diastolic dysfunction (LVDD) in patients with heart failure with preserved ejection fraction (HFpEF) is unknown. We aimed to investigate the association between the AASI and LVDD in HFpEF. METHODS: We prospective enrolled consecutive patients with HFpEF in Chongqing, China. Twenty-four-hour ambulatory blood pressure monitoring (24 h-ABPM) and echocardiography were performed in each patient. AASI was obtained through individual 24 h-ABPM. The relationship between AASI and LVDD was analyzed. RESULTS: A total of 107 patients with HFpEF were included. The mean age was 68.45 ± 14.02 years and 63 (59%) were women. The patients were divided into two groups according to the upper normal border of AASI (0.55). AASI > 0.55 group were more likely to be older, to have higher mean systolic blood pressure and worsen left ventricular diastolic function than AASI group ≤ 0.55. AASI was closely positive related to the diastolic function parameters, including mean E/e' (r = 0.307, P = 0.001), septal E/e' (r = 0.290, P = 0.002), lateral E/e' (r = 0.276, P = 0.004) and E (r = 0.274, P = 0.004). After adjusting for conventional risk factors, AASI was still an independent risk factors of mean E/e' > 10 in patients with HFpEF (OR: 2.929, 95%CI: 1.214-7.064, P = 0.017), and the association between AASI and mean E/e' > 14 was reduced (OR: 2.457, 95%CI: 1.030-5.860, P = 0.043). AASI had a partial predictive value for mean E/e' > 10 (AUC = 0.691, P = 0.002), while the predictive value for mean E/e' > 14 was attenuated (AUC = 0.624, P = 0.034). CONCLUSION: AASI was positive related to E/e' in HFpEF and might be an independent risk factor for the increase of mean E/e'.


Assuntos
Insuficiência Cardíaca , Hipertensão , Rigidez Vascular , Disfunção Ventricular Esquerda , Idoso , Idoso de 80 Anos ou mais , Monitorização Ambulatorial da Pressão Arterial , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Volume Sistólico , Rigidez Vascular/fisiologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia
7.
Front Surg ; 9: 908381, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35722529

RESUMO

Purpose: This study aims to explore the clinical value of a computer-assisted surgery system (Hisense CAS) in hepatoblastoma (HB) surgery in children after neoadjuvant chemotherapy. Patients and Methods: The clinical medical records of children with HB treated after neoadjuvant chemotherapy at the Affiliated Hospital of Qingdao University from January 2016 to January 2019 were analyzed retrospectively. Results: A total of 21 children were enrolled in this study, including 13 boys and 8 girls. All cases successfully underwent three-dimensional (3D) reconstruction of the liver and tumor using Hisense CAS, simulated hepatectomy, and hepatectomy according to the preoperative operation plan. There were twelve cases of right hemihepatectomy, four cases of right trefoil hepatectomy, one case of left lobe hepatectomy, and three cases of middle lobe hepatectomy, and one case of V and VI segment hepatectomy. All children recovered well after the operation. The follow-up ranged from 5 months to 3 years. One child died of systemic metastasis 8 months after the operation. One child received one course of chemotherapy after the operation. Due to the serious reaction to the chemotherapy, the family refused further treatment and follow-up. The remaining 19 children had no complications or recurrence. Conclusion: Hisense CAS can clearly and intuitively display the position and shape of the HB before and after chemotherapy and its relationship with the intrahepatic pipeline system and accurately evaluate the changes in tumor volume and the distance between important blood vessels, which is conducive to the operator selecting the best operation opportunity, timely formulating the best operation plan and implementing individualized and accurate liver tumor resection.

8.
Front Immunol ; 13: 894002, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634320

RESUMO

Macrophages play an important role in clearing necrotic myocardial tissues, myocardial ischemia-reperfusion injury, and ventricular remodeling after myocardial infarction. M1 macrophages not only participate in the inflammatory response in myocardial tissues after infarction, which causes heart damage, but also exert a protective effect on the heart during ischemia. In contrast, M2 macrophages exhibit anti-inflammatory and tissue repair properties by inducing the production of high levels of anti-inflammatory cytokines and fibro-progenitor cells. Interleukin (IL)-38, a new member of the IL-1 family, has been reported to modulate the IL-36 signaling pathway by playing a role similar to that of the IL-36 receptor antagonist, which also affects the production and secretion of macrophage-related inflammatory factors that play an anti-inflammatory role. IL-38 can relieve myocardial ischemia-reperfusion injury by promoting the differentiation of M1 macrophages into M2 macrophages, inhibit the activation of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, and increase the secretion of anti-inflammatory cytokines, such as IL-10 and transforming growth factor-ß. The intact recombinant IL-38 can also bind to interleukin 1 receptor accessory protein-like 1 (IL-1RAPL1) to activate the c-jun N-terminal kinase/activator protein 1 (JNK/AP1) pathway and increase the production of IL-6. In addition, IL-38 regulates dendritic cell-induced cardiac regulatory T cells, thereby regulating macrophage polarization and improving ventricular remodeling after myocardial infarction. Accordingly, we speculated that IL-38 and macrophage regulation may be therapeutic targets for ameliorating myocardial ischemic injury and ventricular remodeling after myocardial infarction. However, the specific mechanism of the IL-38 action warrants further investigation.


Assuntos
Traumatismos Cardíacos , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Traumatismos Cardíacos/metabolismo , Humanos , Interleucinas/metabolismo , Macrófagos/metabolismo , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Remodelação Ventricular
9.
Int J Biol Sci ; 18(7): 2759-2774, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35541911

RESUMO

The current performance of nature compounds in antitumor field is gradually attracted more and more attention, we discovered a nature active ingredient alizarin possess potent natural reductive NF-κB activity to against pancreatic cancer. However, the preclinical pharmacology and therapeutic effect, and the underlying mechanisms of alizarin in inhibiting pancreatic cancer are still unclear. After high-throughput screening, this is the first report that alizarin can induce a potent inhibitory effect against pancreatic cancer cells. Alizarin induced cell cycle arrest and promoted cell apoptosis by inhibiting TNF-α-stimulated NF-κB activity and nuclear translocation, and inactivated its related TNF-α-TAK1-NF-κB signaling cascade followed by downregulation of NF-κB target genes involved in cell apoptosis (Bcl-2, Bcl-xL, XIAP) and in the cell cycle and growth (cyclin D, c-myc). Due to the abrogation of NF-κB activity, combination of alizarin and gemcitabine exerted a better inhibitory effect on pancreatic cancer. In summary, natural component alizarin, inhibited cell proliferation and induced apoptosis in vitro and in vivo through targeting of the NF-κB signaling cascade with minimal toxicity, which combine with gemcitabine, can significantly enhance the antitumor capability, playing a synergistic effect. Therefore, alizarin may play a role in reversing gemcitabine resistance caused by overactivated NF-κB in clinical application in the future.


Assuntos
NF-kappa B , Neoplasias Pancreáticas , Antraquinonas , Apoptose , Linhagem Celular Tumoral , Humanos , NF-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Microb Pathog ; 167: 105566, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35568092

RESUMO

Aeromonas veronii (A. veronii) is a pathogen that can infect aquatic organisms and mammals and has caused irrecoverable economic losses to the aquaculture industry. The results of an epidemiological investigation showed that the number of cases of A. veronii have increased gradually in recent years, and its drug resistance and virulence has shown an upward trend. In this study, we constructed an A. veronii mutant strain Δlip, by homologous recombination and studied its function. The results showed that there was no significant difference in the biofilm formation ability between the Δlip and the wild-type strain, but the toxicity of the Δlip to EPC cells and its ability to adhere to EPC cells were significantly reduced. The LD50 value of the Δlip to zebrafish was 7.40-fold higher than that of the wild-type strain. In addition, after 24 h and 72 h, the bacterial loads of the Δlip in the organs of crucian carp were significantly lower than those in the wild-type strain. In conclusion, the mutant strain Δlip led to a decrease in the adhesion and virulence of the wild-type strain, which lays a foundation to further understand lip gene function and the pathogenic mechanism of A. veronii.


Assuntos
Aeromonas , Carpas , Doenças dos Peixes , Infecções por Bactérias Gram-Negativas , Aeromonas/genética , Aeromonas veronii/genética , Animais , Doenças dos Peixes/microbiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/veterinária , Lábio , Mamíferos , Virulência/genética , Peixe-Zebra/microbiologia
11.
J Transl Med ; 20(1): 243, 2022 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-35619146

RESUMO

BACKGROUND: Currently, remnant cholesterol (RC), lipoprotein(a) [Lp(a)], and inflammation are considered the principal residual cardiovascular risk (RCVR) factors. This study sought to evaluate the combined impact of RC, Lp(a), and inflammation on prognosis of statin-treated patients with chronic coronary syndrome (CCS), which has not been investigated. METHODS: A total of 6839 patients with CCS were consecutively enrolled. Baseline RC, Lp(a), and high-sensitivity C-reactive protein (hsCRP) concentrations were measured and their medians were used for categorizations. All patients were followed for the major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal myocardial infarction, and stroke. The individual and combined effects of RC, Lp(a), and hsCRP on MACEs were examined and stratification analysis according to low-density lipoprotein cholesterol (LDL-C) was performed. RESULTS: Over an average of 54.93 ± 18.59 months follow-up, 462 MACEs were recorded. Multivariate Cox analysis showed that elevated RC and Lp(a) levels were significantly associated with an increased risk of MACEs, while high hsCRP levels were related to a slightly but non-significantly increased MACEs risk. Moreover, when participants were subgrouped according to RC, Lp(a), and hsCRP levels together, only High RC-High Lp(a)-High hsCRP group had significantly higher risk of MACEs [hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.15-3.47] compared with the reference group (Low RC-Low Lp(a)-Low hsCRP), especially in patients with LDL-C < 2.6 mmol/L. CONCLUSIONS: The combination of elevated levels of RC, Lp(a), and hsCRP potentiated the adverse effect on MACEs among statin-treated patients with CCS, suggesting that multiple RCVR factors assessment may be a better strategy to improve stratification in very-high risk population.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Lipoproteína(a) , Proteína C-Reativa/metabolismo , LDL-Colesterol , Progressão da Doença , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inflamação/complicações , Prognóstico , Fatores de Risco , Síndrome
12.
Sci Rep ; 12(1): 8281, 2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35585136

RESUMO

Based on the standards of ISO11704-2018 and ASTM D7283-17, a method for simultaneous determination of gross alpha and gross beta activity concentrations in water by liquid scintillation counting (LSC) was established, which can be applied to various types of water samples in routine monitoring, such as drinking water, groundwater, geothermal water, seawater, and radioactive wastewater. The sample's pH value and concentrated volume must be controlled to avoid quenching as much as possible. The validation tests show that the deviations of gross alpha and gross beta activities can satisfy quality control requirements in a wide range of activity ratios from 1:102 to 67:1. For the actual samples, the measurement results of the LSC method are in good agreement with those of the thick source method, in which the relative deviations of gross alpha and gross beta are both less than 15% for these two methods. Moreover, the LSC method performs better in detection limit and has a simpler pretreatment process than the thick source method.


Assuntos
Água Potável , Monitoramento de Radiação , Poluentes Radioativos da Água , Partículas alfa , Partículas beta , Monitoramento de Radiação/métodos , Contagem de Cintilação/métodos , Poluentes Radioativos da Água/análise
13.
J Transl Med ; 20(1): 233, 2022 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-35590369

RESUMO

BACKGROUND: Familial hypercholesterolemia (FH) is a metabolic disease in which patients are prone to develop premature atherosclerosis (AS). Sorbin and SH3 Domain Containing 2 (SORBS2) is known to play a role in coronary heart disease (CHD). However, the mechanism underlying SORBS2 involvement in the development of hypercholesterolemia remains unknown. Here, we investigated the effects of SORBS2 on inflammation and foam cell formation and its underlying mechanisms. METHODS: Using Bioinformatics analysis, we established that SORBS2 is upregulated in patients with FH. Circulating concentrations of SORBS2 were measured using ELISA kit (n = 30). The association between circulating SORBS2 levels and inflammatory factors or lipid indexes were conducted using Spearman correlation analysis. We further conducted in vitro experiments that the expression of SORBS2 were analyzed, and SORBS2 siRNA were transfected into oxidized LDL (OxLDL)-induced macrophages, followed by western blot and immunofluorescence. RESULTS: Circulating SORBS2 levels were positively associated with inflammatory factors and lipid indexes. We also observed that high in vitro expression of SORBS2 in OxLDL-induced macrophages. After SORBS2 silencing, Nod like receptor family pyrin domain-containing 3 protein(NLRP3)-Caspase1 activation and NF-κB activation were attenuated, and secretion of pro-inflammatory cytokines (IL-1ß and IL-18) was decreased. Moreover, SORBS2 silencing blocked reactive oxygen species (ROS) production and lipid accumulation, and promoted cholesterol efflux through ABCG1-PPARγ pathway. CONCLUSIONS: SORBS2 regulates lipid-induced inflammation and foam cell formation, and is a potential therapeutic target for hypercholesterolemia.


Assuntos
Aterosclerose , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aterosclerose/complicações , Aterosclerose/metabolismo , Humanos , Hipercolesterolemia/complicações , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/genética , Inflamassomos/metabolismo , Inflamação/complicações , Inflamação/metabolismo , Lipoproteínas LDL/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Ligação a RNA , Espécies Reativas de Oxigênio/metabolismo
14.
Front Endocrinol (Lausanne) ; 13: 860698, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35574011

RESUMO

Background and Aims: Heterogeneity exists among patients with atherosclerotic cardiovascular disease (ASCVD) with regard to the risk of recurrent events. Current guidelines have definitely refined the disease and we aimed to examine the practicability in Chinese population. Methods: A cohort of 9944 patients with ASCVD was recruited. Recurrent events occurred during an average of 38.5 months' follow-up were collected. The respective and combinative roles of major ASCVD (mASCVD) events and high-risk conditions, being defined by 2018 AHA/ACC guideline, in coronary severity and outcome were studied. Results: The number of high-risk conditions was increased with increasing number of mASCVD events (1.95 ± 1.08 vs. 2.16 ± 1.10 vs. 2.42 ± 1.22). Trends toward the higher to the highest frequency of multi-vessel coronary lesions were found in patients with 1- (71.1%) or ≥2 mASCVD events (82.8%) when compared to those without (67.9%) and in patients with 2- (70.5%) or ≥3 high-risk conditions (77.4%) when compared to those with 0-1 high-risk condition (61.9%). The survival rate was decreased by 6.2% between none- and ≥2 mASCVD events or by 3.5% between 0-1 and ≥3 high-risk conditions. Interestingly, diabetes was independently associated with outcome in patients with 1- [1.54(1.06-2.24)] and ≥2 mASCVD events [1.71(1.03-2.84)]. The positive predictive values were increased among groups with number of mASCVD event increasing (1.10 vs. 1.54 vs. 1.71). Conclusion: Propitious refinement of ASCVD might be reasonable to improve the survival. Concomitant diabetes was differently associated with the incremental risk among different ASCVD categories, suggesting the need of an appropriate estimate rather than a 'blanket' approach in risk stratification.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Aterosclerose/complicações , Aterosclerose/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , China/epidemiologia , Humanos , Medição de Risco , Fatores de Risco
15.
Cell Calcium ; 104: 102590, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35439615

RESUMO

The incidence of atrial fibrillation (AF) increases after surgery and is associated with the activation of NLRP3-inflammation. Our previous studies have found that transient receptor potential vanilloid 4 (TRPV4) blockade reduces the susceptibility to AF, but its molecular mechanisms remains unclear. Therefore, we hypothesized that blockage of TRPV4 reduces the incidence of AF by inhibiting NLRP3-inflammasome in sterile pericarditis (SP) mice. In this study, we established SP mice by dusting talcum powder on atrial surfaces. We first confirmed that genetic or pharmacological TRPV4 inhibition reduced the susceptibility to AF in SP mice. We also found that the expression level of NLRP3-inflammasome and inflammatory cytokines significantly increased in the atria of SP mice, which further increased in application the TRPV4 agonist GSK1016790A (GSK101) and decreased in application the TRPV4 antagonist GSK2193874. More importantly, ERK inhibitor (U0126) or NF-κB inhibitor (Bay11-7082) could partially reverse GSK101-induced NLRP3-inflammasome up-regulation. Interestingly, U0126 can reversed GSK101-induced NF-κB phosphorylation, but Bay11-7082 cannot change GSK101-induced ERK phosphorylation. Finally, we shown that the activation of NLRP3-inflammasome and ERK/NF-κB signaling pathway significantly reduced in TRPV4-knockout SP mice. Collectively, our studies indicate that blockage of TRPV4 prevents AF in SP mice by inhibiting NLRP3-inflammasome through the ERK/NF-κB signaling pathway.


Assuntos
Fibrilação Atrial , Pericardite , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/prevenção & controle , Inflamassomos/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pericardite/complicações , Pericardite/metabolismo , Canais de Cátion TRPV/metabolismo
16.
Biochem Biophys Res Commun ; 610: 1-7, 2022 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-35461070

RESUMO

Inevitable emergence of drug resistance is the biggest hurdle to both chemotherapies and targeted therapies. Understanding the resistance mechanisms will contribute to identification of biomarkers for predicting response to therapy and design new therapeutic strategies to overcome drug resistance in human cancers. The type II transforming growth factor (TGF)-ß receptor gene (TGFBR2) is frequently frameshift mutated in several cancer types, especially in colorectal, endometrium and gastric cancers cells. Here, we found that Med12, a component of the transcriptional mediator complex, plays a role in modulating chemosensitivity in TGFBR2 deficient cancer cells. Loss of Med12 leads to chemoresistance in multiple TGFBR2 deficient cancer cells. Interestingly, RNA sequencing data revealed that interferon IFN-related DNA damage resistance signature (IRDS) is upregulated in Med12 knockdown cancer cells. And the expression of IRDS pattern is negatively correlated with chemosensitivity. Therefore, our study identifies a novel mechanism of Med12-mediated drug resistance, which is a TGFBR-independent manner.


Assuntos
Complexo Mediador , Neoplasias , Receptor do Fator de Crescimento Transformador beta Tipo II , Resistencia a Medicamentos Antineoplásicos , Humanos , Complexo Mediador/genética , Complexo Mediador/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo
17.
Ann Transl Med ; 10(5): 260, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35402599

RESUMO

Background: Chromodomain helicase DNA-binding protein 7 (CHD7), which is associated with CHARGE (Coloboma, Heart defect, Atresia choanae, Restricted growth, Genital hypoplasia and Ear abnormality) syndrome is an important regulator in many vital developmental processes. However, its role during oocyte development remains unknown. Methods: We screened the Gene Expression Omnibus (GEO) database for expression levels of CHD7 during folliculogenesis. We generated a conditional knockout (cKO) mouse strain with oocyte-specific deletion of CHD7 (Gdf9-Cre:Chd7f/f ) using the Cre-loxP approach. Evaluation of follicle numbers and reproductive ability was then conducted. In addition, granulosa cell (GC) apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and cleaved caspase-3, using immunohistochemistry (IHC) and immunofluorescence (IF). GC proliferation was measured by Ki67 staining as evaluated by IHC. Results: In our study, we demonstrated that CHD7 has high expression throughout all developmental stages of the oocyte. We found that deletion of Chd7 in oocytes can cause infertility or sub-fertility in female mice and is associated with decreased follicle numbers at all stages. In addition, we found that GC apoptosis was significantly higher in cKO mice. Conclusions: To our knowledge, our study has been the first to show that CHD7 plays a specific role during oogenesis. Our findings provide new insights into CHD7-related infertility.

18.
Anal Chem ; 94(18): 6711-6718, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35486137

RESUMO

Alkaline phosphatase (ALP), an essential hydrolase with crucial roles in living organisms, has widely been regarded as a biomarker for various human diseases in clinical diagnoses. Herein, taking advantage of cobalt oxyhydroxide (CoOOH) nanoflakes and nonenzymatic cascade recycling amplification (CRA), a highly sensitive and label-free fluorescence biosensing strategy for the determination of ALP activity is introduced. In our design, ALP can promote the dephosphorylation of l-ascorbic acid 2-phosphate (AAP) to reduce ascorbic acid (AA), which is then able to decompose CoOOH in a nucleic acids@CoOOH nanocomplex into Co2+ cofactors. Further, enzyme-free CRA was rapidly initiated by integrating DNAzyme recycling amplification and catalytic hairpin assembly, resulting in the generation of an abundance of G-quadruplex structure-contained DNA duplexes. In the presence of thioflavin T (ThT), analytical target ALP was converted in an amplified and activatable fluorescence signal. The experimental results show that this method can be applied for the quantitative analysis of ALP activity with a low detection limit of 0.027 mU/mL. Moreover, this developed biosensing approach exhibits excellent specificity, and the evaluation of ALP activity in the complex human serum samples was successfully realized, indicating that it can afford a reliable, robust, and cost-effective nanoplatform for an ALP-based clinical diagnosis and for biomedical research.


Assuntos
Técnicas Biossensoriais , DNA Catalítico , Fosfatase Alcalina/análise , Técnicas Biossensoriais/métodos , Cobalto , Corantes Fluorescentes , Humanos , Limite de Detecção , Oxirredução , Óxidos
19.
BMJ Open ; 12(4): e049992, 2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379611

RESUMO

INTRODUCTION: The prognosis of patients with advanced metastatic colorectal adenocarcinoma (mCRC) after multiple-line therapy remains poor due to the high tumour load, high level of malignancy and strong drug resistance. The application of programmed cell death protein 1 (PD-1) blockade alone for patients with microsatellite stable/proficient mismatch repair (MSS/pMMR) mCRC is ineffective. PD-1 blockade combined with antiangiogenic therapy has synergistic effects and has initially shown therapeutic effects. The aim of this trial is to explore the efficiency and safety of tyrosine kinase inhibitors (TKIs) combined with PD-1 blockade therapy in patients with mCRC with MSS/pMMR. METHODS AND ANALYSIS: The screening phase of the trial will involve administering one cycle of TKIs (fruquintinib or regorafenib). Patients will be divided into three arms-arm A (obvious response to TKIs), arm B (general response to TKIs) and arm C (poor response to TKIs)-according to their response to TKIs, as determined by significant changes in imaging findings. Patients in arm A will then receive TKIs in combination with anti-PD-1 antibody, patients in arm C will withdraw from the study, and those in arm B will continue to take TKIs for another one further cycle. Next, patients with obvious response to TKIs will be reallocated to arm A, those with general response to TKIs will stay in arm B and will continue to take TKIs, and patients with poor response to TKIs will withdraw from the study. Administration of arm A or arm B will last until disease progression or intolerable toxicity. Anti-PD-1 antibody can be administered for up to 2 years. This trial will provide necessary data to improve the prognosis of patients with MSS/pMMR mCRC. TRIAL REGISTRATION NUMBER: NCT04483219; Pre-results.


Assuntos
Adenocarcinoma , Neoplasias Colorretais , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Anticorpos/uso terapêutico , Morte Celular , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Humanos , Repetições de Microssatélites , Inibidores de Proteínas Quinases/uso terapêutico
20.
Curr Res Transl Med ; 70(4): 103347, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35483237

RESUMO

PURPOSE: The tumor protein p53 gene (TP53) mutations are associated with poor prognosis of patients with acute myeloid leukemia (AML). This study aimed to establish TP53 mutation-based prognostic risk signatures. PATIENTS AND METHODS: The transcriptomes and clinical characteristics of AML patients were acquired from The Cancer Genome Atlas database, including 11 TP53-mutant samples and 114 TP53-wildtype samples. Differentially expressed mRNAs and long non-coding RNAs (lncRNA) in TP53-mutant samples were identified. Weighted gene correlation network analysis was performed to generate survival-associated co-expression modules. LASSO regression analysis was conducted to build mRNA- and lncRNA-based prognostic risk signatures. Kaplan-Meier curve analysis and multivariate regression analysis were carried out to assess the prognostic values of the risk signatures. Receiver operating characteristic (ROC) analysis was performed to evaluate the accuracy of the signatures. RESULTS: Based on the co-expression modules, a 5-mRNA risk signature and a 13-lncRNA risk signature were constructed to predict the overall survival for AML patients. Kaplan-Meier curves revealed that the high-risk patients had significantly shorter overall survival than the low-risk patients. ROC analysis yielded 1-, 3-, and 5-year AUCs of 0.681, 0.783, and 0.827 for mRNA signature and 0.85, 0.835, and 0.908 for lncRNA signature. Multivariate regression analysis revealed that both mRNA (HR = 1.45, P< 0.001) and lncRNA (HR = 1.19, P< 0.001) risk scores were independent prognostic factors for AML patients. CONCLUSION: We provided a potential patients stratification tool for AML prognosis prediction and management, which established by effective TP53 mutation-related gene signatures.

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