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1.
Cell Death Dis ; 11(1): 39, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959745

RESUMO

Ginsenosides exhibit a large variety of biological activities in maintaining physical health; however, the molecule underpinnings underlining these biological activities remain to be defined. Here, we took a cellular condition that compound K (CK) induces autophagic cell death in HeLa cells, and setup a high-throughput genetic screening using CRISPR technology. We have identified a number of CK-resistant and CK-sensitive genes, and further validated PMAIP1 as a CK-resistant gene and WASH1 as a CK-sensitive gene. Compound K treatment reduces the expression of WASH1, which further accelerates the autophagic cell death, highlighting WASH1 as an interesting downstream mediator of CK effects. Overall, our study offers an easy-to-adopt platform to study the functional mediators of ginsenosides, and provides a candidate list of genes that are potential targets of CK.

2.
Nutr Metab (Lond) ; 16: 80, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31788012

RESUMO

Background: Cancer cachexia is a clinical manifestation in various advanced cancers that characterized by muscle atrophy and fat loss as its main features; it is frequently associated with systemic inflammatory response. However, the differences in inflammatory response and lipid metabolism of different genders remain unclear. This study explores the difference between cachexic and non-cachexic patients in different genders and cancer types and focus on the plasma inflammation factors levels and lipid metabolism parameters in different genders. Methods: We first analyzed the general characteristics in 311 cancer patients between cachexic and non-cachexic patients, with an emphasis on expression levels related to inflammatory factors and lipid metabolism parameters. We then further analyzed these characteristics in different genders and cancer types. Lastly, the correlations between plasma interleukin-6 (IL-6) and lipid metabolism parameters in cachexia patients of different genders were analyzed. Results: Among 311 patients, there were 74 cancer cachexia patients (50 males and 24 females) and 237non-cachexia patients (150 males and 87 females). Body mass index (BMI), TNM stage, plasma concentration of hemoglobin, platelet, lymphocyte count, total protein, albumin, prealbumin, total cholesterol, apolipoprotein E (ApoE), free fatty acid (FFA) and IL-6 were significantly different between cachexic and non-cachexic patients (all p < 0.05). In addition, these characteristics were different in different cancer types. When compared to male non-cachexic patients, male cachexic patients showed a significant increase in plasma levels of IL-6 and platelet, later TNM stage, with marked decrease in their plasma total protein, albumin, prealbumin, ApoE as well as their lymphocyte counts and hemoglobin levels (all p < 0.05). In comparison with female non-cachexic patients, female cachexic patients' IL-6 levels and FFA were significantly elevated with noticeable decrease in their BMI, total cholesterol, ApoE and prealbumin, as well as later TNM stage (all p < 0.05). Correlation analysis revealed that IL-6 levels in female cachexic patients had a significant positive correlation with FFA expression, but this correlation not reflected in male patients. Conclusion: This study demonstrates the different metabolic characteristics of male and female cancer cachexia patients. Future study about cancer cachexia should pay attention to different genders and cancer types.

3.
Int J Cancer ; 145(10): 2728-2739, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30977118

RESUMO

Dysregulation of calcium homeostasis endoplasmic reticulum protein (CHERP) has been implicated in several cancers, but it remains elusive how CHERP contributes to cancer cell proliferation and cancer development. Here, we observed that CHERP and its binding partner SR140 are significantly upregulated in human clinical colorectal cancer tissues (CRC). CHERP and SR140 could form a protein complex to stabilize each other. Knockdown of CHERP or SR140 triggers double-stranded DNA breaks and cell death. Furthermore, UPF3A, the RNA surveillance factor, was identified as a splicing target of CHERP and SR140, which bind specifically to the regulated exon4 and modulate UPF3A splicing. UPF3A knockdown recapitulates CHERP/SR140 depletion both in vitro and in mice. Importantly, overexpression of UPF3A significantly rescues proliferation defect of CHERP/SR140-depleted cells. These results confirmed that the effect of CHERP/SR140 in promoting tumorigenesis was partially mediated by UPF3A. Extending these results, upregulation of CHERP/SR140 observed in CRC remarkably parallels increased inclusion of UPF3A exon4. Together, our study clarifies how CHERP/SR140 exert an oncogenic role in CRC development partially through regulating expression of UPF3A variants.

4.
Cancer Med ; 8(6): 2717-2729, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30950241

RESUMO

Cyclin D2/D3 (CCND2/3) are core components of the machinery that drives cell cycle progression and therefore, are associated with tumorigenesis. Currently, there are contradictory evidences on the function of CCND2/3 in tumorigenesis. Thus, we conducted a comprehensive meta-analysis to derive a precise predictive value of CCND2/3 in various tumors. We searched PubMed, EMBASE, Web of Science for eligible studies up to October 8, 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of OS or DFS/PFS/RFS were calculated using Forest plot analysis to demonstrate their associations. A total of 14 studies were ultimately included in this meta-analysis. Our results indicated CCND2/3 played an oncogenic role in all of the cancer patients (CCND2: pooled HR = 2.21, 95% CI: 1.67-2.93; CCND3: pooled HR = 2.29, 95% CI: 1.05-5.03). In tumor subgroup, CCND2 was associated with shorter OS in patients with gastric cancer (HR = 2.20, 95% CI: 1.66-2.92), whereas it might be a tumor suppressor in NSCLC (HR = 0.28, 95% CI: 0.12-0.64). In addition, CCND3 was correlated to reduced OS in breast cancer patients (HR = 1.64, 95% CI: 1.07-2.52) and shorter DFS/PFS/RFS in bladder cancer patients (HR = 4.60, 95% CI: 1.89-12.57). Taken together, CCND2/3 could be the promising biomarkers for predicting the prognosis of patients with malignant neoplasms.

5.
Int J Cancer ; 145(7): 1809-1821, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30807648

RESUMO

Cancer-associated cachexia (CAC) is a devastating syndrome characterized by progressive losses of adipose tissue and skeletal muscle. CAC-related adipose tissue loss (CAL) occurs early and is associated with a shorter survival time. To explore potential regulatory long noncoding RNAs (lncRNAs) of CAL, RNA microarrays were used to analyze the transcriptomes of white adipose tissue from CAC mice vs. control mice. A set of differentially expressed lncRNAs was identified, and among them was CAAlnc1, which suppressed adipogenesis of C3H10 cells as demonstrated by gain-of-function and loss-of-function experiments. RNA immunoprecipitation and pull-down assays revealed Hu antigen R (HuR) was an important binding partner of CAAlnc1. The interaction between CAAlnc1 and HuR blocked the binding of HuR to adipogenic transcription factor mRNAs and further downregulated the expression of these transcription factors. This study generated a list of CAL-related lncRNAs and provided details of a functional lncRNA which may play an important role in CAL.


Assuntos
Caquexia/genética , Proteína Semelhante a ELAV 1/metabolismo , Neoplasias/complicações , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Adipogenia , Tecido Adiposo Branco/química , Animais , Caquexia/etiologia , Caquexia/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Regulação para Baixo , Proteína Semelhante a ELAV 1/genética , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos
6.
Clin Nutr ; 38(6): 2881-2888, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30630709

RESUMO

BACKGROUND & AIMS: Sarcopenia has been widely recognized as an important predictor of poor outcomes in patients with cancer after surgery, but the controversy remains, and its impact on surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer is poorly described. The aim of this study was to evaluate the prognostic impact of sarcopenia on surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer. METHODS: Six thousand four hundred and forty-seven consecutive patients who underwent abdominal surgery for digestive tract cancer in our institution were prospectively included. Sarcopenia was defined as skeletal muscle index below the lowest sex-specific quartile using computed tomography scan at L3 before surgery. The surgical and oncologic outcomes were recorded, and univariate and multivariate analyses were performed. RESULTS: Sarcopenia was present in 1638 of 6447 patients (25.4%) with digestive tract cancer before surgery based on the diagnostic cut-off values (43.13 cm2/m2 for men and 37.81 cm2/m2 for women). The incidence of postoperative total and pulmonary complications, and 30-day readmission were significantly higher in sarcopenic group than in nonsarcopenic group (37.4% vs 12.9%, P < 0.001; 3.1% vs 2.1%, P = 0.026; 1.1% vs 0.4%, P = 0.003, respectively). The postoperative hospital stay was significantly longer in sarcopenic patients (9.42 ± 3.40 vs 8.51 ± 3.17 days, P < 0.001). There were significantly more patients receiving postoperative chemotherapy or radiotherapy in sarcopenic group than in nonsarcopenic group (73.1% vs 69.2%, P = 0.003; 10.6% vs 8.8%, P = 0.038, respectively), and patients with sarcopenia had significantly more chemotherapy modifications including delay, dose reduction, or termination (48.5% vs 44.2%, P = 0.018). In addition, during the follow-up period, sarcopenic patients had significantly lower rate of overall survival and disease-free survival than nonsarcopenic patients (53.9% vs 69.3%, P = 0.002; 36.8% vs 59.7%, P = 0.000, respectively). In multivariate analysis, sarcopenia was found to be a risk factor for postoperative complications [odds ratio (OR) = 5.418, 95% confidence interval (CI) = 2.986-9.828, P < 0.001], and was an unfavorable prognostic factor for poor overall survival [hazard ratio (HR) = 0.649, 95% CI = 0.426-0.991, P = 0.045] and disease-free survival (HR = 0.514, 95% CI = 0.348-0.757, P = 0.001). CONCLUSIONS: Sarcopenia could be used as a strong and independent prognostic factor for poor surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer. Identification of preoperative sarcopenia in digestive surgery for cancer and targeted approaches may improve its negative outcomes.

7.
Zhonghua Wei Chang Wai Ke Za Zhi ; 21(11): 1285-1290, 2018 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-30506541

RESUMO

OBJECTIVE: To investigate the levels of serum inflammatory cytokines and Resolvin D1 (RvD1) and their association with pathological staging of colon cancer. METHODS: Clinical data of 50 colon cancer patients (colon cancer group) admitted to the General Surgery Department of Zhongshan Hospital of Fudan University from January to December 2016 and 5 ml of whole blood specimen were collected at admission. During the same period, 50 healthy volunteers were enrolled (healthy volunteer group). Inclusion criteria for the colon cancer group: colon cancer diagnosed by preoperative colonoscopy and pathology; no recent enteral or parenteral nutrition support treatment or use of oral nutrition preparation; age ≤85 years; no surgical contraindications by preoperative evaluation; no history of taking fish oil-related preparations; no radiotherapy or chemotherapy before surgery. Healthy volunteer group enrollment criteria: no history of malignant tumors; no organ with organic lesions detected by the healthy examination center of our hospital; detection indicators in normal reference range; no administration of fish oil-related preparations; age ≤ 85 years. Serum inflammatory factors(IL-1ß, IL-6, IL-10 and TNF-α) concentrations were detected by chemiluminescence immunoassay; serum RvD1 concentration was measured by enzyme-linked immunosorbent assay. The levels of inflammatory factors and RvD1 were compared between the two groups, and their associations with TNM staging of colon cancer patients were analyzed. RESULTS: There were no significant differences in age, gender and nutrition-related indicators between the two groups (all P>0.05). There were 31 males and 19 females in the healthy volunteer group with age of (61.8±11.6) years. There were 23 males and 27 females in the colon cancer group with age of (65.4±12.4) years. According to the 7th edition of the American Cancer Society TNM staging criteria, 10 cases were stage I, 13 cases stage II, 17 cases stage III, and 10 cases stage IV. Compared with healthy volunteer group, colon cancer group had higher serum IL-1ß [(3.89±0.24)×10 3 µg/L vs.(1.55±0.37)×10 3 µg/L, t=37.52, P<0.01], higher IL-6 [(129.14±3.07)×10 3 µg/L vs.(51.46±3.14)×10 3 µg/L, t=125.08, P<0.01], higher IL-10 [(100.59±8.69)×103 µg/L vs.(27.57±4.77)×10 3 µg/L, t=52.09, P<0.01] and higher TNF-α [(114.31±4.43)×10 3 µg/L vs.(41.04±5.27)×10 3 µg/L, t=75.25, P<0.01], while lower RvD1 [(34.19±1.93)×10 3 µg/L vs.(77.76±1.02)×10 3 µg/L, t=140.56, P<0.01], all the differences were statistically significant. Subgroup analysis revealed that concentrations of IL-6, IL-1ß, IL-10 and TNF-α gradually increased with the advancement of TNM staging (P<0.01). In stage III, concentrations of IL-6, IL-1ß, and IL-10 were the highest, TNF-α concentration was the highest in stage IV. RvD1 concentration gradually decreased with the advancement of TNM staging(P<0.01). CONCLUSIONS: Compared with healthy volunteers, the levels of serum inflammatory cytokines in colon cancer patients increase significantly while the level of RvD1 decreases significantly. Both are associated with higher TNM stage of colon cancer.


Assuntos
Neoplasias do Colo , Citocinas , Ácidos Docosa-Hexaenoicos , Idoso , Neoplasias do Colo/sangue , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Citocinas/sangue , Ácidos Docosa-Hexaenoicos/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Lipids Health Dis ; 17(1): 14, 2018 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-29338749

RESUMO

BACKGROUND: Cancer cachexia is a progressive and multi-factorial metabolic syndrome characterized by loss of adipose tissue and skeletal muscle. White adipose tissue (WAT) lipolysis and white-to-brown transdifferentiation of WAT (WAT browning) are proposed to contribute to WAT atrophy in cancer cachexia. Chronic inflammation, mediated by cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), has been reported to promote cancer cachexia. However, whether chronic inflammation promotes cancer cachexia by regulating WAT metabolism and the underlying mechanism remains unclear. METHODS: In this study, we first analyzed the association between chronic inflammation and WAT metabolism in gastric and colorectal cancer cachectic patients. In cachectic mice treated with anti-IL-6 receptor antibody, we clarified whether WAT lipolysis and browning were regulated by IL-6. RESULTS: Clinical analyses showed positive significant association between serum IL-6 and free fatty acid (FFA) both in early- and late-stage cancer cachexia. However, serum TNF-α was positively associated with serum FFA in the early- but not late-stage cachexia. WAT lipolysis was increased in early- and late-stage cachexia, while WAT browning was detected only in late-stage cachexia. Anti-IL-6 receptor antibody inhibited WAT lipolysis and browning in cachectic mice. CONCLUSIONS: Based on these findings, we conclude that chronic inflammation (especially that mediated by IL-6) might promote cancer cachexia by regulating WAT lipolysis in early-stage cachexia and browning in late-stage cachexia.


Assuntos
Tecido Adiposo Branco/metabolismo , Caquexia/metabolismo , Inflamação/complicações , Interleucina-6/fisiologia , Mobilização Lipídica , Neoplasias/complicações , Tecido Adiposo Marrom , Tecido Adiposo Branco/fisiopatologia , Idoso , Animais , Caquexia/sangue , Caquexia/etiologia , Caquexia/fisiopatologia , Transdiferenciação Celular , Neoplasias Colorretais/complicações , Feminino , Humanos , Inflamação/sangue , Inflamação/etiologia , Inflamação/fisiopatologia , Interleucina-6/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Gástricas/complicações , Fator de Necrose Tumoral alfa/sangue
9.
Zhonghua Wei Chang Wai Ke Za Zhi ; 20(10): 1117-1121, 2017 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-29130223

RESUMO

Patients with short bowel syndrome suffer from fluid and electrolyte imbalance and malabsorption due to poor nutrient processing capability of the residual intestine. Nutritional support therapy has been considered as one of the important treatments for short bowel syndrome. For patients with short bowel syndrome, a deep understanding of metabolic changes, and then rational application of nutritional support therapy and intestinal rehabilitation program can save many patients' lives, improve quality of life, and even achieve independence from parenteral nutrition, and return to a normal life.


Assuntos
Apoio Nutricional , Síndrome do Intestino Curto/metabolismo , Humanos , Nutrição Parenteral , Nutrição Parenteral Total , Qualidade de Vida , Síndrome do Intestino Curto/complicações
10.
Asia Pac J Clin Nutr ; 26(4): 591-597, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28582806

RESUMO

BACKGROUND AND OBJECTIVES: Short bowel syndrome (SBS) is a complicated and challenging disease where home parenteral nutrition (HPN) is widely used. The complications of long-term HPN-dependent in adult patients with SBS are poorly documented. This study was mainly aimed to assess the prevalence and risk factors of HPNassociated complications in adult patients with SBS, especially the catheter-related sepsis and HPN-associated liver/biliary disorders. METHODS AND STUDY DESIGN: 47 non-malignant adult patients with SBS who received HPN for more than 2 years in our clinical nutrition center were included. Patients were divided into two groups according to whether HPN-associated complications were present or not. Student's t-test and χ2 test were applied to compare the differences between the two groups. RESULTS: The mean frequency of catheter-related sepsis was 0.31±0.05 per catheter year of HPN. An higher incidence of catheter-related infections (p<0.001) and shorter delay between HPN onset and first infection (p<0.001) were identified as risk factors for catheter-related sepsis. A total of 25 patients (53.2%) developed HPN-associated liver/biliary diseases. The identified risk factors for HPNassociated liver/biliary disorders were higher rate of catheter-related infections (p=0.009), shorter delay between HPN onset and first infection (p=0.017), higher energy content of HPN (p=0.014), higher glucose rate of HPN (p=0.009), and lower lipid rate of HPN (p=0.022). CONCLUSION: Our study revealed that adult patients with SBS receiving long-term HPN treatment developed a low prevalence of catheter-related sepsis but a rather high prevalence of HPN-associated liver/biliary disorders. We also identified several risk factors for HPN-associated complications which should be taken notice of in clinical practice.


Assuntos
Nutrição Parenteral no Domicílio/efeitos adversos , Síndrome do Intestino Curto/dietoterapia , Adulto , Doenças Biliares/induzido quimicamente , Cateteres/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
11.
Nutr Clin Pract ; 32(4): 545-551, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28537849

RESUMO

BACKGROUND: Parenteral nutrition (PN) covering the need for carbohydrates, amino acids, and lipids can either be compounded from single nutrients or purchased as an industrially manufactured ready-to-use regimen. This study compares a commercially available 3-chamber bag (study group) with a conventionally compounded monobag regarding nutrition efficacy, safety, and regimen preparation time. MATERIALS AND METHODS: This prospective, randomized, single-blind study was conducted at 5 Chinese hospitals from October 2010-October 2011. Postsurgical patients requiring PN for at least 6 days were randomly assigned to receive the study or control regimen. Plasma concentrations of prealbumin and C-reactive protein (CRP), regimen preparation time, length of hospital stay (LOS), 30-day mortality, safety laboratory parameters, and adverse events (AEs) were recorded. RESULTS: In total, 240 patients (121 vs 119 in study and control groups) participated in this study. Changes in prealbumin concentrations during nutrition support (ΔPrealb(StudyGroup) = 2.65 mg/dL, P < .001 vs ΔPrealb(ControlGroup) = 0.27 mg/dL, P = .606) and CRP values were comparable. Regimen preparation time was significantly reduced in the study group by the use of 3-chamber bags (t(StudyGroup) = 4.90 ± 4.41 minutes vs t(ControlGroup) = 12.13 ± 5.62 minutes, P < .001). No differences were detected for LOS, 30-day mortality, safety laboratory parameters, and postoperative AEs (37 vs 38 in study and control groups). CONCLUSION: The PN regimen provided by the 3-chamber bag was comparable to the compounded regimen and safe in use. Time savings during regimen preparation indicates that use of 3-chamber bags simplifies the process of regimen preparation.


Assuntos
Composição de Medicamentos , Soluções de Nutrição Parenteral/química , Soluções de Nutrição Parenteral/farmacologia , Nutrição Parenteral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Feminino , Seguimentos , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Período Pós-Operatório , Pré-Albumina/metabolismo , Estudos Prospectivos , Método Simples-Cego , Adulto Jovem
12.
Cancer Biomark ; 18(3): 249-256, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27983531

RESUMO

OBJECTIVE: Gastric cancer is one of the most common cancers worldwide, and the prognosis is still very poor due to the lack of specific and sensitive biomarkers. Aerobic glycolysis is one of the critical hallmarks of gastric cancer cells, and several glycolytic enzymes are highly expressed in gastric cancer patients. However, the expression and clinical significances of phosphofructokinase-2/fructose-2,6-bisphosphatase3 (PFKFB3, one of the glycolytic enzymes) in a large sample of gastric cancer patients remain unclear. METHODS: The expression of PFKFB3 was detected in 134 gastric cancer patients by qRT-PCR, immunohistochemistry, and western blot analyses. The correlation between PFKFB3 expression and clinicopathological factors was analyzed by χ 2 test. In addition, we also analyzed whether the knockdown of PFKFB3 by siRNAs could inhibit the ability of gastric cancer cells (MGC-803 and AGS) to proliferate and migrate by MTT analysis and transwell analyses. RESULTS: PFKFB3 was highly expressed in 81.3% (109/134) of gastric cancer patients. The overexpression of PFKFB3 was associated with lymph node metastasis (P = 0.045) and TNM stage (P = 0.033). Knockdown of PFKFB3 by siRNAs significantly inhibited the proliferation and migration abilities of gastric cancer cells. CONCLUSION: Our data suggest that PFKFB3 might be a potential biomarker for gastric cancer and anti-neoplastic targeting gene.


Assuntos
Expressão Gênica , Fosfofrutoquinase-2/genética , Neoplasias Gástricas/genética , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Fosfofrutoquinase-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo
14.
Oncol Lett ; 12(5): 4013-4020, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27895764

RESUMO

Cancer cachexia remains a leading cause of morbidity and mortality worldwide, despite extensive research and clinical trials. The prominent clinical feature of cancer cachexia is the continuous loss of skeletal muscle that cannot be fully reversed by conventional nutritional support, and that leads to progressive functional impairment. The mechanism underlying muscle loss in patients with cachexia is poorly understood. The present study analyzed 21 cancer patients with or without cachexia, and demonstrated that mitofusin-2 (Mfn2) was downregulated in the rectus abdominis of patients with cachexia, which was associated with body weight loss. In vitro cell experiments indicated that loss of Mfn2 was associated with atrophy of the C2C12 mouse myoblast cell line. Furthermore, in vivo animal experiments demonstrated that cachexia decreased gastrocnemius muscle mass and Mfn2 expression, and overexpression of Mfn2 in gastrocnemius muscle was able to partially attenuate cachexia-induced gastrocnemius muscle loss. The results of the present study suggested that Mfn2 is involved in cachexia-induced muscle loss and may serve as a potential target for therapy of cachexia.

15.
Transl Oncol ; 9(6): 512-520, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27816688

RESUMO

Succinate dehydrogenase (SDH) is a heterotetrameric complex, among which the catalytic core SDHB loss-of-function mutations lead to mitochondrial enzyme SDH dysfunction and are associated with cancer formation. However, the impact of SDHB loss on colorectal carcinoma and the underlying mechanisms are largely unknown. In this study, we found a coherent decreased SDHB expression both in human colorectal cancer (CRC) samples and CRC cell lines. Combined clinical analysis in a cohort of 43 CRC patients demonstrated a correlation between reduced SDHB activity and a more advanced clinical phenotype regarding lymphatic and distant metastasis. Applying genetic interference and cellular function approaches, we found that knocking down SDHB promoted cell migration and invasion through enabling epithelial-mesenchymal transition (EMT), and inverse results of SDHB overexpression further confirmed our theory. Mechanical exploration revealed that SDHB knockdown could activate TGFß signaling pathway, more precisely through up-regulation of a tight-junction transcriptional repression complex SNAIL1-SMAD3/SMAD4, thus contributed to the increase in metastasis. In conclusion by identifying SNAIL1-SMAD3/SMAD4 as essential for the TGFß-mediated tumorigenic capacity in SDHB-deficient CRC cells, this study revealed a critical mechanical vulnerability for potential future therapeutic target of SDHB-associated CRC.

16.
Int J Surg ; 33 Pt A: 124-32, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27504848

RESUMO

INTRODUCTION: The role of laparoscopic surgery in the repair for peptic ulcer disease is unclear. The present study aimed to compare the safety and efficacy of laparoscopic versus open repair for peptic ulcer disease. METHODS: Randomized controlled trials (RCTs) comparing laparoscopic versus open repair for peptic ulcer disease were identified from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and references of identified articles and relevant reviews. Primary outcomes were postoperative complications, mortality, and reoperation. Secondary outcomes were operative time, postoperative pain, postoperative hospital stay, nasogastric tube duration, and time to resume diet. Statistical analysis was carried out by Review Manage software. RESULTS: Five RCTs investigating a total of 549 patients, of whom, 279 received laparoscopic repair and 270 received open repair, were included in the final analysis. There were no significant differences between these two procedures in some primary outcomes including overal postoperative complication rate, mortality, and reoperation rate. Subcategory analysis of postoperative complications showed that laparoscopic repair had also similar rates of repair site leakage, intra-abdominal abscess, postoperative ileus, pneumonia, and urinary tract infection as open surgery, except of the lower surgical site infection rate (P < 0.05). In addition, there were also no significant differences between these two procedures in some second outcomes including operative time, postoperative hospital stay, and time to resume diet, but laparoscopic repair had shorter nasogastric tube duration (P < 0.05) and less postoperative pain (P < 0.05) than open surgery. CONCLUSIONS: Laparoscopic surgery is comparable with open surgery in the setting of repair for perforated peptic ulcer. The obvious advantages of laparoscopic surgery are the lower surgical site infection rate, shorter nasogastric tube duration and less postoperative pain. However, more higher quality studies should be undertaken to further assess the safety and efficacy of laparoscopic repair for peptic ulcer disease.


Assuntos
Laparoscopia/efeitos adversos , Úlcera Péptica Perfurada/cirurgia , Complicações Pós-Operatórias/epidemiologia , Humanos , Tempo de Internação , Duração da Cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto , Reoperação , Resultado do Tratamento
17.
Am J Transl Res ; 8(2): 405-18, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27158335

RESUMO

DCAF4L2 is a member of WD-repeat proteins, which commonly serve as mediators of protein-protein interplay. In this study, we reported that elevated DCAF4L2 expression in human colorectal cancer (CRC) significantly correlated with a more advanced clinical stage as in lymphatic and distant metastasis. More importantly, elevated DCAF4L2 expression is an independent prognosis factor for survival. Genetic perturbations demonstrated that DCAF4L2 overexpression in CRC cells promoted cell migration and invasion, whereas knockdown of which had opposing effects. Moreover we discovered that DCAF4L2 overexpression could promote epithelial-mesenchymal-transition (EMT) through activating NFκB signal pathway. Mass spectrometry analysis showed that DCAF4L2 could form an E3 ligase complex with Cul4A and DDB1 thus mediated degradation of PPM1B, which has been reported to negatively regulate NFκB signaling. We identified PPM1B as a substrate of Cul4A-DDB1-DCAF4L2 E3 ligase complex, as knockdown of PPM1B abrogated shDCAF4L2 mediated inhibition of cell invasion in CRC cells. For further verification, DCAF4L2 expression inversely correlated with PPM1B expression in a cohort of 87 CRC patients. These findings may provide insight into the understanding of DCAF4L2 as a novel critical factor and a candidate target for CRC treatment.

18.
Cancer Med ; 5(7): 1599-606, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27139420

RESUMO

Fatty acid synthase (Fasn) is the key metabolic enzyme that accounts for the terminal catalytic step in fatty acid synthesis, which is hyperactivated in various tumors. In this study, we depicted that Fasn expression was elevated in human colorectal cancer (CRC), which accordingly led to lymphatic and distant metastasis and a more advanced clinical phenotype. Genetic perturbations demonstrated that knocking down Fasn inhibited cell migration and invasion both in SW480 and HT29 CRC cell lines. Further mechanical exploration revealed that Fasn knockdown could attenuate Wnt signaling pathway via downregulating distinctive genes, namely Wnt5a, Wnt5b, Fzd2, which at least partly contributed to the decrease in metastasis. Clinical evidence verified a positive correlation between Fasn expression and Wnt signal marker gene expression in a cohort of 43 CRC patients. In conclusion, we shed light on metabolic switches took place during CRC carcinogenesis, among which Fasn is a critical factor and a potential therapeutic target.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ácido Graxo Sintases/metabolismo , Via de Sinalização Wnt , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Ácido Graxo Sintases/genética , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico
19.
J Surg Res ; 202(1): 77-86, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27083951

RESUMO

BACKGROUND: Peritoneal air exposure is needed in open abdominal surgery, but long-time exposure could induce intestinal mucosal barrier dysfunction followed by many postoperative complications. High-fat enteral nutrition can ameliorate intestinal injury and improve intestinal function in many gastrointestinal diseases. In the present study, we investigated the effect of high-fat enteral nutrition on intestinal mucosal barrier after peritoneal air exposure and the underlying mechanism. METHODS: Male adult rats were administrated saline, low-fat or high-fat enteral nutrition via gavage before and after peritoneal air exposure for 3 h. Rats undergoing anesthesia without laparotomy received saline as control. Twenty four hours after surgery, samples were collected to assess intestinal mucosal barrier changes in serum D-lactate levels, intestinal permeability, intestinal tight junction protein ZO-1 and occludin levels, and intestinal histopathology. The levels of malondialdehyde and the activity of superoxide dismutase in the ileum tissue were also measured to assess the status of intestinal oxidative stress. RESULTS: High-fat enteral nutrition significantly decreased the serum D-lactate level and increased the intestinal tight junction protein ZO-1 level when compared to the group treated with low-fat enteral nutrition (P < 0.05). Meanwhile, histopathologic findings showed that the intestinal mucosal injury assessed by the Chiu's score and the intestinal epithelial tight junction were also improved much more in the high-fat enteral nutrition-treated group (P < 0.05). In addition, the intestinal malondialdehyde level was lower, and the intestinal superoxide dismutase activity was higher in the high-fat enteral nutrition-treated group than that in the low-fat enteral nutrition-treated group (P < 0.05). CONCLUSIONS: These results suggest that high-fat enteral nutrition could reduce intestinal mucosal barrier damage after peritoneal air exposure, and the underlying mechanism may be associated with its antioxidative action. Perioperative administration of high-fat enteral nutrition may be a promising intervention to preserve intestinal mucosal barrier function in open abdominal surgery.


Assuntos
Ar , Dieta Hiperlipídica , Nutrição Enteral/métodos , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Laparotomia/efeitos adversos , Peritônio , Animais , Biomarcadores/metabolismo , Íleo/patologia , Mucosa Intestinal/patologia , Masculino , Assistência Perioperatória/métodos , Permeabilidade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Distribuição Aleatória , Ratos , Junções Íntimas/metabolismo
20.
J Surg Res ; 201(2): 408-15, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27020826

RESUMO

BACKGROUND: Peritoneal air exposure is a common phenomenon in abdominal surgery, but long-term exposure could induce intestinal inflammatory responses, resulting in delayed recovery of gastrointestinal motility after surgery. High-fat enteral nutrition has been reported to ameliorate inflammation in many diseases. In the present study, we investigated whether high-fat enteral nutrition could control intestinal inflammation and improve intestinal motility after peritoneal air exposure. METHODS: Male adult rats were administrated saline, low-fat enteral nutrition, or high-fat enteral nutrition via gavage before and after peritoneal air exposure for 3 h. Control rats underwent anesthesia without laparotomy and received saline. Intestinal motility was assessed 24 h after surgery by charcoal transport assay; systemic inflammation was assessed by analyzing serum levels of tumor necrosis factor α, interleukin (IL)-1ß, IL-6, and IL-10; and intestinal inflammation was assessed by analyzing myeloperoxidase activity and concentrations and gene expression of tumor necrosis factor α, IL-1ß, IL-6, and IL-10 in the intestinal tissue. RESULTS: Peritoneal air exposure decreased intestinal motility significantly compared with the control group (P < 0.05). The systemic and intestinal inflammatory parameters were also much higher in the peritoneal air exposure groups than in the control group. Both low-fat and high-fat enteral nutrition increased intestinal motility and reduced systemic and intestinal inflammatory parameter levels to different degrees. However, high-fat enteral nutrition significantly improved the negative alterations in these biochemical parameters compared with low-fat enteral nutrition (P < 0.05). CONCLUSIONS: These results suggest that high-fat enteral nutrition might be able to control intestinal inflammation and improve intestinal motility after peritoneal air exposure. Thus, the perioperative administration of high-fat enteral nutrition may be a promising treatment to enhance the recovery of intestinal motility after surgery.


Assuntos
Gorduras na Dieta/uso terapêutico , Nutrição Enteral , Enterite/prevenção & controle , Motilidade Gastrointestinal , Complicações Pós-Operatórias/prevenção & controle , Animais , Citocinas/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Peroxidase/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley
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