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1.
J Nanobiotechnology ; 19(1): 302, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34600560

RESUMO

BACKGROUND: Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia. METHODS: We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment. RESULTS: Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8+ T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy. CONCLUSIONS: Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment.

2.
J Clin Invest ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499619

RESUMO

The endocannabinoid system regulates appetite and energy expenditure and inhibitors of the cannabinoid receptor-1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 receptors in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 receptors in hepatocytes did not alter the development of NAFLD in mice fed a high sucrose high fat diet or high fat diet (HFD). Similarly, deletion of CB-1 deletion specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD nor did it protect mice for carbon tetrachloride (CCl4)-induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.

3.
Am J Physiol Endocrinol Metab ; 321(1): E146-E155, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34097543

RESUMO

Cannabinoid 1 receptor (CB1R) inverse agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that the deletion of CB1Rs in the VMH did not affect body weight in chow- and high-fat diet-fed male and female mice. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse agonist SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice.NEW & NOTEWORTHY Cannabinoid 1 receptors (CB1Rs) regulate metabolic homeostasis, and CB1R inverse agonists reduce body weight and improve parameters of glucose metabolism. However, the cell populations expressing CB1Rs that regulate metabolic homeostasis remain unclear. CB1Rs are highly expressed in the ventromedial hypothalamic nucleus (VMH), which is a crucial node that regulates metabolism. With CRISPR/Cas9, we generated mice lacking CB1Rs specifically in VMH neurons and found that CB1Rs in VMH neurons are essential for the regulation of glucose metabolism independent of body weight regulation.


Assuntos
Peso Corporal/fisiologia , Glucose/metabolismo , Homeostase/fisiologia , Neurônios/metabolismo , Receptor CB1 de Canabinoide/fisiologia , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Composição Corporal/fisiologia , Proteína 9 Associada à CRISPR , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Dieta Hiperlipídica , Metabolismo Energético/fisiologia , Feminino , Edição de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Receptor CB1 de Canabinoide/deficiência , Receptor CB1 de Canabinoide/genética
4.
Artigo em Inglês | MEDLINE | ID: mdl-34155585

RESUMO

Honghu Lake, the largest shallow lake in Jianghan Plain of China, is essential for maintaining ecosystem functioning in this region. However, water pollution and high disturbance are seriously threatening the ecological security of this lake. To explore the causes of water quality fluctuations in Honghu Lake, the water quality index method (CCME-WQI), multivariate statistical, and source apportionment techniques were adopted to characterize temporal trends in lake water quality (2004-2017), identify the main driving factors of water quality indicators, and quantify the contribution of various pollution sources. Besides, the water periods of the lake have been reclassified due to the seasonal variation of rainfall in the study area. The results of CCME-WQI showed that the water quality in Honghu Lake initially improved over 2004-2011, with better water quality in the wet period than in the dry periods, while the results over 2012-2017 were found to be opposite. Correlation analysis identified untreated industrial wastewater (UIW) as the main pollution source affecting CODMn concentrations in Honghu Lake, while untreated domestic sewage discharge (UDS) was identified as the main pollution source affecting BOD and F. coli concentrations. The main pollution sources affecting nutrient indicators were rainfall and enclosure aquaculture (EA). Principal component analysis (PCA) combined with absolute principal component score-multiple linear regression model (APCS-MLR) further appointed the source contribution of each pollution source to water quality indicators. The results showed that EA in 2012 was reduced by 81% compared with 2004, resulting in the contribution of EA to NH3-N, TP, and TN decreased by 0.2 mg L-1, 0.039 mg L-1, and 0.37 mg L-1, respectively. Compared with 2012, UIW was reduced by 65% in 2016, resulting in the contribution of UIW to CODMn decreased by 1.17 mg L-1. In addition, compared with 2004, UDS decreased by 85% in 2016, and the contribution of UDS to BOD and F. coli decreased by 0.7 mg L-1 and 887 cfu L-1, respectively. Based on the results of APCS-MLR, it was predicted that the concentrations of COD and TP in Honghu Lake would meet the water quality requirements after 2017. However, the rainfall non-point source pollution must be further controlled to achieve the desired level of TN concentration. This study provided an accurate method for analyzing lake water pollution, and the results can provide a valuable reference for optimizing water quality management and pollution control strategies within Honghu Lake.

5.
Support Care Cancer ; 2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34146165

RESUMO

PURPOSE: Although spiritual well-being (SWB) is gaining increasing attention within the international palliative care (PC) guidelines, a lack of insight exists into the correlates and course of SWB among cancer patients. We therefore conducted a prospective observational study to capture trend of SWB and to identify their predictors in Chinese inpatients with terminal cancer receiving short-term PC. METHODS: A prospective observational study was conducted of terminal cancer inpatients in the hospice ward, Shengjing Hospital of China Medical University. A total of 108 patients completed self-report questionnaires on Functional Assessment of Chronic Illness Therapy-Spiritual Well-being, Hospital Anxiety and Depression Scale, Numerical Rating Scales, and Life Orientation Scale-Revised anonymously at baseline; SWB, depression, anxiety, and pain were subsequently assessed at 1-week interval. Multilevel regression was used to analyze the temporal course and predictors of SWB. RESULTS: Patients' existential well-being (B = - 0.99, p = 0.008; 95%CI = - 1.72 to - 0.26) and meaning dimension (B = - 0.87, p < 0.001; 95% CI = - 1.29 to - 0.43) significantly decreased after admission to the PC unit, but peace and faith did not change over time. Increases in depression and pain were related to lower existential well-being, particularly in the meaning dimension. Optimism-pessimism moderated the linear trend of existential well-being and meaning domain, such that those with higher optimism and lower pessimism paired with a decrease in outcomes. CONCLUSIONS: Terminal cancer patients experienced worsening existential well-being, particularly in the meaning facet while hospitalized, indicating that PC should include content that targets the existential concerns of spirituality in China. These findings also supported the need for an integrated PC to address personality traits and emotional and physical distress in this population.

6.
Toxicol Appl Pharmacol ; 424: 115596, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34044072

RESUMO

Excessive iron deposition can produce toxicity. Liver, as the main storage site of iron, is more vulnerable to excessive iron than other organs. Many studies have found that Resveratrol (RES) can effectively eliminate oxygen free radicals and resist lipid peroxide damage. However, studies investigating the mechanism of how RES prevents liver injury induced by iron overload are few. This study aims to observe the protective effect of RES on liver injury induced by iron overload in mice. Mice, except for the control group, received an intraperitoneal injection of iron dextran (50 mg/kg) every morning. The L-RES and H-RES groups received intragastric administration of low- and high-concentration RES solutions (20 or 50 mg/kg). The deferoxamine (DFO) group was intraperitoneally injected with DFO (50 mg/kg), while the control and iron overload groups were intraperitoneally injected with the same amount of normal saline every afternoon. Two weeks after continuous administration, iron-overloaded mice treated with high and low doses of RES significantly improved liver injury (GOT and GPT) and decreased LDH activity and MDA content and increased SOD and GSH activities (P < 0.01). Morphological tests showed that RES treatment can reduce liver iron deposition and improve liver pathological changes in iron-overloaded mice. Furthermore, RES treatment caused a significant decrease in Ft expression (P < 0.01). In conclusion, RES can alleviate liver injury in iron-overloaded mice. The mechanism may be related to improve the antioxidant capacity and reduce excess iron in the liver.


Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Sobrecarga de Ferro/patologia , Ferro/toxicidade , Resveratrol/farmacologia , Animais , Regulação para Baixo , Ferritinas/genética , Ferritinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ferro/administração & dosagem , Peroxidação de Lipídeos , Camundongos , Estrutura Molecular , Espécies Reativas de Oxigênio , Resveratrol/química
7.
J Biochem Mol Toxicol ; 35(7): e22797, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33957017

RESUMO

Diabetic nephropathy (DN) is becoming a research hotspot in recent years because the prevalence is high and the prognosis is poor. Lipid accumulation in podocytes induced by hyperglycemia has been shown to be a driving mechanism underlying the development of DN. However, the mechanism of lipotoxicity remains unclear. Increasing evidence shows that acetyl-CoA carboxylase 2 (ACC2) plays a crucial role in the metabolism of fatty acid, but its effect in podocyte injury of DN is still unclear. In this study, we investigated whether ACC2 could be a therapeutic target of lipid deposition induced by hyperglycemia in the human podocytes. Our results showed that high glucose (HG) triggered significant lipid deposition with a reduced ß-oxidation rate. It also contributed to the downregulation of phosphorylated ACC2 (p-ACC2), which is an inactive form of ACC2. Knockdown of ACC2 by sh-RNA reduced lipid deposition induced by HG. Additionally, ACC2-shRNA restored the expression of glucose transporter 4 (GLUT4) on the cell surface, which was downregulated in HG and normalized in the insulin signaling pathway. We verified that ACC2-shRNA alleviated cell injury, apoptosis, and restored the cytoskeleton disturbed by HG. Mechanistically, SIRT1/PGC-1α is close related to the insulin metabolism pathway. ACC2-shRNA could restore the expression of SIRT1/PGC-1α, which was downregulated in HG. Rescue experiment revealed that inhibition of SIRT1 by EX-527 counteracted the effect of ACC2-shRNA. Taken together, our data suggest that podocyte injury mediated by HG-induced insulin resistance and lipotoxicity could be alleviated by ACC2 inhibition via SIRT1/PGC-1α.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Glucose/farmacologia , Resistência à Insulina , Metabolismo dos Lipídeos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Podócitos/metabolismo , Sirtuína 1/metabolismo , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/genética , Humanos , Oxirredução , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Sirtuína 1/genética
8.
J Med Chem ; 64(9): 5519-5534, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33938739

RESUMO

Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30 exhibited outstanding biochemical activity, with an IC50 of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30 significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30 showed favorable in vivo antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30 potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30 inhibited tumor growth by activating the immune microenvironment. We concluded that A30 is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.


Assuntos
Antineoplásicos/química , Antígeno B7-H1/metabolismo , Indóis/química , Receptor de Morte Celular Programada 1/metabolismo , Tiazóis/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Indóis/metabolismo , Indóis/farmacologia , Indóis/uso terapêutico , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Mapas de Interação de Proteínas/efeitos dos fármacos , Relação Estrutura-Atividade
9.
Cell Death Differ ; 28(8): 2450-2464, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33742136

RESUMO

Small nucleolar RNA SNORD50A and SNORD50B (SNORD50A/B) has been reported to be recurrently deleted and function as a putative tumor suppressor in different types of cancer by binding to and suppressing the activity of the KRAS oncoproteins. Its deletion correlates with poorer patient survival. However, in this study, we surprisingly found that SNORD50A/B loss predicted a better survival in breast cancer patients carrying wild-type p53. Functional studies showed that SNORD50A/B deletion strongly inhibited the proliferation, migration, invasion and tumorigenic potential, and induced cell cycle arrest and apoptosis in p53 wild-type breast cancer cells, while exerted the opposite effects in p53 mutated breast cancer cells. This was also supported by ectopically expressing SNORD50A/B in both p53 wild-type and mutated breast cancer cells. Mechanistically, SNORD50A/B clearly enhances the interaction between E3 ubiquitin ligase TRIM21 and its substrate GMPS by forming a complex among them, thereby promoting GMPS ubiquitination and its subsequent cytoplasmic sequestration. SNORD50A/B deletion in p53 wild-type breast cancer cells will release GMPS and induce the translocation of GMPS into the nucleus, where GMPS can recruit USP7 and form a complex with p53, thereby decreasing p53 ubiquitination, stabilizing p53 proteins, and inhibiting malignant phenotypes of cancer cells. Altogether, the present study first reports that SNORD50A/B plays an oncogenic role in p53 wild-type breast cancers by mediating TRIM21-GMPS interaction.

10.
Chemosphere ; 268: 128837, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33187652

RESUMO

In previous studies we found that bisphenol A (BPA) aggravated OVA-induced lung inflammation. The aim of this research was to determine whether BPA exposure alone also induced inflammatory response in the lungs, which mechanism was associated with TLR4/NF-κB signaling pathway and the activation of mTOR-mediated autophagy. Female C57BL/6 mice aged 4 weeks were randomly divided into three groups (10/group): control group, 0.1 and 0.2 µg mL-1 BPA groups. BPA induced the pathological changes in the lung and increased the levels of cytokines and inflammatory cells, as well as affected autophagy related proteins expression. In addition, the RAW264.7 cell culture experiment was conducted in order to confirm the role of autophagy. We found that BPA can enhance autophagy flux by enhancing autophagosome formation. It was further confirmed the details of the mechanism of action with chloroquine (CQ, a compound that inhibits the fusion of autophagosomes and lysosomes) intervention. The inhibition of autophagy led to down-regulation of expression levels associated with inflammation. This research results indicated that BPA induced inflammatory response in vitro and in vivo, and its mechanism may be related to TLR4/NF-κB signaling pathway and the activation of mTOR-mediated autophagy. After autophagy was suppressed, the inflammatory response also weakened. Our findings provide a new perspective into the mechanisms underlying inflammatory responses induced by the environmental exposure. These findings indicate that therapeutic strategies targeting autophagy may provide a new method for the treatment of inflammatory diseases.


Assuntos
Autofagia , Receptor 4 Toll-Like , Animais , Proteínas Relacionadas à Autofagia , Compostos Benzidrílicos , Feminino , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenóis , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Regulação para Cima
11.
J Food Sci Technol ; 57(10): 3913-3919, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32904034

RESUMO

This study aimed to investigate the effects of different microwave radiation power and treatment time on the antioxidant enzyme activities and radical scavenging potency in Tartary buckwheat sprouts. The results indicated that the optimal microwave irradiation conditions for superoxide dismutase, catalase, peroxidise and ascorbate peroxidise antioxidant enzymes was the power 300 W for 75 s, and their activities were all higher than those of the control and the ungerminated seeds. In addition, under the above microwave conditions, the total reducing power and the ability to scavenge DPPH, ABTS, O2- and •OH were also optimal. These results indicated that suitable microwave treatment could effectively improve the antioxidant enzyme activity in Tartary buckwheat sprouts and enhance the antioxidant capacity of sprouts.

12.
Chem Commun (Camb) ; 56(81): 12138-12141, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-32914790

RESUMO

The synthesis of strongly solubilising multibranched aliphatic side chains for π-conjugated polymers is reported. The solubilising capability of the side chains and their effect on the polymer properties are studied on the example of copolymers composed of up to six unsubstituted, 'unshielded' thiophene units per side chain-substituted naphthalene diimide unit.

13.
J Control Release ; 325: 293-303, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32653500

RESUMO

Many high-affinity peptide antagonists of MDM2 and MDMX have been reported as activators of the tumor suppressor protein p53 with therapeutic potential. Unfortunately, peptide activators of p53 generally suffer poor proteolytic stability and low membrane permeability, posing a major pharmacological challenge to anticancer peptide drug development. We previously obtained several potent dodecameric peptide antagonists of MDM2 and MDMX termed PMIs, one of which, TSFAEYWALLSP, bound to MDM2 and MDMX at respective affinities of 0.49 and 2.4 nM. Here we report the development of gold nanoparticles (Np) as a membrane-traversing delivery vehicle to carry PMI for anticancer therapy. Np-PMI was substantially more active in vitro than Nutlin-3 in killing tumor cells bearing wild-type p53, and effectively inhibited tumor growth in metastasis in a mouse homograft mode of melanoma and a patient-derived xenograft model of colon cancer with a favorable safety profile. This clinically viable drug delivery strategy can be applied not only to peptide activators of p53 for cancer therapy, but also to peptide therapeutics in general aimed at targeting intracellular protein-protein interactions for disease intervention.


Assuntos
Nanopartículas Metálicas , Proteínas Proto-Oncogênicas c-mdm2 , Sequência de Aminoácidos , Animais , Proteínas de Ciclo Celular , Ouro , Camundongos , Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
14.
Proc Natl Acad Sci U S A ; 117(28): 16616-16625, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601203

RESUMO

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensing O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.


Assuntos
Macrófagos/imunologia , N-Acetilglucosaminiltransferases/imunologia , Obesidade/imunologia , Proteínas Quinases S6 Ribossômicas 90-kDa/imunologia , Acetilglucosamina/imunologia , Tecido Adiposo/imunologia , Animais , Humanos , Ativação de Macrófagos , Macrófagos/enzimologia , Camundongos , Camundongos Knockout , N-Acetilglucosaminiltransferases/genética , Obesidade/enzimologia , Obesidade/genética , Obesidade/metabolismo , Fosforilação , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Transdução de Sinais
15.
Ann Thorac Surg ; 110(1): 236-240, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32151577

RESUMO

BACKGROUND: Our objectives are to report our outcomes and to demonstrate our evolving technique for robotic sleeve resection of the airway, with or without lobectomy, using video vignettes. METHODS: We retrospectively reviewed a single-surgeon prospective database from October 2010 to October 2019. RESULTS: Over 9 years, of 5573 operations 1951 were planned for a robotic approach. There were 755 robotic lobectomies and 306 robotic segmentectomies, and 23 consecutive patients were scheduled for elective completely portal, robotic sleeve resection. Sleeve lobectomy was performed in 18 patients: 10 right upper lobe, 6 left upper lobe, and 2 right lower lobe. Two patients had mainstem bronchus resections and 2 underwent right bronchus intermedius resections that preserved the entire lung. One patient had a robotic pneumonectomy. One operation was converted to open thoracotomy because of concern for anastomotic tension in a patient who received neoadjuvant therapy. All patients had an R0 resection. In the last 10 operations we modified our airway anastomosis, using a running self-locking absorbable suture. The median length of hospital stay was 3 days (range, 1-11), with no 30- or 90-day mortalities. Within a median follow-up of 18 months, there were no anastomotic strictures and no recurrent cancers. CONCLUSIONS: Our early and midterm results show that a completely portal robotic sleeve resection is safe and oncologically effective. Trhe technical aspects of a robotic sleeve resection of the airway are demonstrated using video vignettes.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Pneumonectomia/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
16.
Chemosphere ; 248: 126035, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32014637

RESUMO

Epidemiologic studies show that there is a link between Bisphenol A (BPA) exposure and lung inflammation. Despite this, the molecular mechanisms are not entirely known. This study sought to determine whether exposure to BPA affected the development of ovalbumin (OVA) induced lung inflammation in adolescent female mice and whether the mechanism was related to mTOR-mediated autophagy pathway. Female 4-week-old C57BL/6 mice after one week of domestication were randomly divided into five groups (8/group): control group, OVA group, 0.1 µg mL-1 BPA + OVA group, 0.2 µg mL-1 BPA + OVA group and 0.4 µg mL-1 BPA + OVA group. BPA exacerbated airway hyperresponsiveness (AHR), induced the pathological changes in the lung, which also enhanced inflammatory cells and cytokine levels. In addition, BPA exposure affected expression of autophagy associated proteins and genes. This research results indicated that BPA aggravated OVA-induced lung inflammation and induced abnormal immune function in mice, and its mechanism was related to the activation of autophagy pathway by down-regulation expression of mTOR. These findings suggest that therapeutic strategies to target autophagy may offer a new approach for severe asthma therapy.


Assuntos
Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Fenóis/toxicidade , Pneumonia/induzido quimicamente , Animais , Asma/induzido quimicamente , Autofagia , Citocinas/metabolismo , Feminino , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina , Pneumonia/patologia , Hipersensibilidade Respiratória , Serina-Treonina Quinases TOR/metabolismo , Testes de Toxicidade
17.
Nat Commun ; 11(1): 181, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924761

RESUMO

Excessive visceral fat accumulation is a primary risk factor for metabolically unhealthy obesity and related diseases. The visceral fat is highly susceptible to the availability of external nutrients. Nutrient flux into the hexosamine biosynthetic pathway leads to protein posttranslational modification by O-linked ß-N-acetylglucosamine (O-GlcNAc) moieties. O-GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Here, we report that inducible deletion of adipose OGT causes a rapid visceral fat loss by specifically promoting lipolysis in visceral fat. Mechanistically, visceral fat maintains a high level of O-GlcNAcylation during fasting. Loss of OGT decreases O-GlcNAcylation of lipid droplet-associated perilipin 1 (PLIN1), which leads to elevated PLIN1 phosphorylation and enhanced lipolysis. Moreover, adipose OGT overexpression inhibits lipolysis and promotes diet-induced obesity. These findings establish an essential role for OGT in adipose tissue homeostasis and indicate a unique potential for targeting O-GlcNAc signaling in the treatment of obesity.


Assuntos
Dieta/efeitos adversos , Gordura Intra-Abdominal/efeitos dos fármacos , Lipólise/efeitos dos fármacos , N-Acetilglucosaminiltransferases/antagonistas & inibidores , Obesidade/metabolismo , Acetilglucosamina/metabolismo , Animais , Linhagem Celular Tumoral , Jejum , Deleção de Genes , Células HEK293 , Células HeLa , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Acetilglucosaminiltransferases/genética , Perilipina-1/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Transdução de Sinais
18.
J Hazard Mater ; 384: 121325, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31586910

RESUMO

The difficulties in enriching anammox bacteria and maintaining stable partial nitrification during start-up phase limit the application of mainstream anammox process. In this study, the feasibility of starting up simultaneous partial nitrification, anammox and denitrification (SNAD) reactor treating municipal wastewater by inoculating ordinary nitrification sludge (96.2%) and a small amount of anammox sludge (3.8%) was investigated. A sequencing batch reactor with intermittent aeration was used for the SNAD process. The SNAD reactor was started up in 75 days with a nitrogen removal efficiency of 85.4% at ambient temperature. The nitrogen removal performance maintained stable despite the fluctuating inflow. Anammox bacterial activity exponentially increased although nitrite oxidizing bacteria (NOB) activity in seeding sludge was high. The enhanced ammonium oxidizing bacterial activity and partial denitrification provided sufficient nitrite for anammox bacteria. Moreover, NOB was inhibited by intermittent aeration, anammox bacteria had competitive advantage on nitrite. The improved particle size and settleability of activated sludge also favored the anammox bacterial enrichment. This study provided an improved and easily-implemented start-up strategy for mainstream anammox. The seeding sludge was easily obtained and the operation strategy was simple. These findings were meaningful to the engineering application of mainstream anammox.


Assuntos
Esgotos/microbiologia , Águas Residuárias/microbiologia , Bactérias , Reatores Biológicos , Desnitrificação , Nitrificação , Nitritos/química , Oxirredução , Tamanho da Partícula , Temperatura , Microbiologia da Água
19.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 483-488, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642223

RESUMO

OBJECTIVE: To study the application value of motion-correction phase sensitive inversion recovery (MOCO-PSIR) to evaluate myocardial fibrosis in the patients with heart failure caused by dilated cardiomyopathy (DCM). METHODS: A prospective study included 60 patients who underwent cardiac MRI enhanced scan from June 2017 to November 2018, including 38 patients who were clinically diagnosed with DCM and 22 patients in the normal control group. All patients were scanned with three late gadolinium enhancement (LGE) sequences: segmented-PSIR, single-shot-PSIR, MOCO-PSIR at the same time. The subjective quality score (level 4) and image signal-to-noise ratio (objective evaluation) of normal and abnormal myocardium were analyzed and compared in three scanning technique groups. The detection rate of myocardial fibrosis and image acquisition time of the three scanning techniques were recorded. RESULTS: In the normal control group (sinus rhythm), subjective score showed no statistical significance. Subjective scoring results in the patients with DCM: MOCO-PSIR>single-shot-PSIR> segmented-PSIR (P < 0.05). SNR results PSIR-LGE images in DCM patients as well as control group: segmented-PSIR>MOCO-PSIR> single-shot-PSIR (P < 0.05). In the whole 646 segments analysis of DCM patients, the ratio unable to judge in segmented-PSIR was up to 25.5%, but only 1.4% in MOCO-PSIR. Significant difference was found in the three groups. While in the 374 segments of control group, no statistical difference was found in comparison of incapability to judge. Acquisition time covered left ventricular: (5.6±1.7) min in segmented-PSIR, (0.4±0.2) min in single-shot-PSIR and (4.5±1.1) min in MOCO-PSIR. Pairwise comparison of acquisition time among three scanning techniques was statistically significant (P < 0.001). CONCLUSION: MOCO-PSIR-LGE has better clinical significance than conventional delayed enhanced scan sequences in the diagnosis of myocardial fibrosis in the patients with heart failure caused by dilated cardiomyopathy.


Assuntos
Cardiomiopatia Dilatada/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Imageamento por Ressonância Magnética , Miocárdio/patologia , Estudos de Casos e Controles , Meios de Contraste , Fibrose , Gadolínio , Humanos , Aumento da Imagem , Estudos Prospectivos
20.
Oncogene ; 38(35): 6241-6255, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31312026

RESUMO

Early growth response-1 (EGR1) is a transcription factor correlated with prostate cancer (PC) progression in a variety of contexts. For example, EGR1 levels increase in response to suppressed androgen receptor signaling or loss of the tumor suppressor, PTEN. EGR1 has been shown to regulate genes influencing proliferation, apoptosis, immune cell activation, and matrix degradation, among others. Despite this, the impact of EGR1 on PC metastatic colonization is unclear. We demonstrate using a PC model (DU145/RasB1) of bone and brain metastasis that EGR1 expression regulates angiogenic and osteoclastogenic properties of metastases. We have shown previously that FN14 (TNFRSF12A) and downstream NF-κB signaling is required for metastasis in this model. Here we demonstrate that FN14 ligation also leads to NF-κB-independent, MEK-dependent EGR1 expression. EGR1-depletion in DU145/RasB1 cells reduced both the number and size of metastases but did not affect primary tumor growth. Decreased EGR1 expression led to reduced blood vessel density in brain and bone metastases as well as decreased osteolytic bone lesion area and reduced numbers of osteoclasts at the bone-tumor interface. TWEAK (TNFSF12) induced several EGR1-dependent angiogenic and osteoclastogenic factors (e.g., PDGFA, TGFB1, SPP1, IL6, IL8, and TGFA, among others). Consistent with this, in clinical samples of PC, the level of several genes encoding angiogenic/osteoclastogenic pathway effectors correlated with EGR1 levels. Thus, we show here that EGR1 has a direct effect on prostate cancer metastases. EGR1 regulates angiogenic and osteoclastogenic factors, informing the underlying signaling networks that impact autonomous and microenvironmental mechanisms of cancer metastases.


Assuntos
Adenocarcinoma/patologia , Proteína 1 de Resposta de Crescimento Precoce/fisiologia , Neovascularização Patológica/genética , Osteogênese/genética , Neoplasias da Próstata/patologia , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/genética , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Proteína 1 de Resposta de Crescimento Precoce/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Metástase Neoplásica , Neovascularização Patológica/patologia , Células PC-3 , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/genética , Células RAW 264.7 , Transdução de Sinais/genética , Células Tumorais Cultivadas , Microambiente Tumoral/genética
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