Publications by authors named "Bin Ke"

53 Publications

Protective effects of calorie restriction on insulin resistance and islet function in STZ-induced type 2 diabetes rats.

Nutr Metab (Lond) 2021 May 5;18(1):48. Epub 2021 May 5.

Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China.

Background: Caloric restriction (CR) has become increasingly attractive in the treatment of type 2 diabetes mellitus (T2DM) because of the increasingly common high-calorie diet and sedentary lifestyle. This study aimed to evaluate the role of CR in T2DM treatment and further explore its potential molecular mechanisms.

Methods: Sixty male Sprague-Dawley rats were used in this study. The diabetes model was induced by 8 weeks of high-fat diet (HFD) followed by a single dose of streptozotocin injection (30 mg/kg). Subsequently, the diabetic rats were fed HFD at 28 g/day (diabetic control) or 20 g/day (30% CR regimen) for 20 weeks. Meanwhile, normal rats fed a free standard chow diet served as the vehicle control. Body mass, plasma glucose levels, and lipid profiles were monitored. After diabetes-related functional tests were performed, the rats were sacrificed at 10 and 20 weeks, and glucose uptake in fresh muscle was determined. In addition, western blotting and immunofluorescence were used to detect alterations in AKT/AS160/GLUT4 signaling.

Results: We found that 30% CR significantly attenuated hyperglycemia and dyslipidemia, leading to alleviation of glucolipotoxicity and thus protection of islet function. Insulin resistance was also markedly ameliorated, as indicated by notably improved insulin tolerance and homeostatic model assessment for insulin resistance (HOMA-IR). However, the improvement in glucose uptake in skeletal muscle was not significant. The upregulation of AKT/AS160/GLUT4 signaling in muscle induced by 30% CR also attenuated gradually over time. Interestingly, the consecutive decrease in AKT/AS160/GLUT4 signaling in white adipose tissue was significantly reversed by 30% CR.

Conclusion: CR (30%) could protect islet function from hyperglycemia and dyslipidemia, and improve insulin resistance. The mechanism by which these effects occurred is likely related to the upregulation of AKT/AS160/GLUT4 signaling.
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http://dx.doi.org/10.1186/s12986-021-00575-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097947PMC
May 2021

Dynamic monitoring of serum liver function indexes in patients with COVID-19.

World J Clin Cases 2021 Mar;9(7):1554-1562

Department of Pediatrics, Shantou Central Hospital, Shantou 515000, Guangdong Province, China.

Background: Some patients with the novel 2019 coronavirus disease (COVID-19) display elevated liver enzymes. Some antiviral drugs that can be used against COVID-19 are associated with a risk of hepatotoxicity.

Aim: To analyze the clinical significance of the dynamic monitoring of the liver function of patients with COVID-19.

Methods: This was a retrospective study of patients diagnosed with COVID-19 in January and February 2020 at the Department of Infection, Shantou Central Hospital. The exclusion criteria for all patients were: (1) History of chronic liver disease; (2) History of kidney disease; (3) History of coronary heart disease; (4) History of malignancy; or (5) History of diabetes. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase, and total bilirubin of patients with COVID-19 were measured on days 1, 3, 7 and 14 after admission, and compared to non-COVID-19 patents.

Results: Twelve patients with COVID-19 (seven men and five women) and twelve controls (eight men and four women) were included. There were one, two, and nine patients with severe, mild, and moderate COVID-19, respectively. There were no differences in age and sex between the two groups (both > 0.05). No significant differences were found in albumin, ALT, AST, γ-glutamyltransferase, or total bilirubin between the controls and the patients with COVID-19 on day 1 of hospitalization (all > 0.05). Serum albumin showed a decreasing trend from days 0 to 7 of hospitalization, reaching the lowest level on day 7. Total bilirubin was higher on day 3 than on day 7. ALT, AST, and γ-glutamyltransferase did not change significantly over time. The severe patient was observed to have ALT levels of 67 U/L and AST levels of 75 U/L on day 7, ALT of 71 U/L and AST of 35 U/L on day 14, and ALT of 210 U/L and AST of 123 U/L on day 21.

Conclusion: Changes in serum liver function indicators are not obvious in the early stage of COVID-19, but clinically significant changes might be observed in severe COVID-19.
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http://dx.doi.org/10.12998/wjcc.v9.i7.1554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942056PMC
March 2021

Parthenolide Augments the Chemosensitivity of Non-small-Cell Lung Cancer to Cisplatin the PI3K/AKT Signaling Pathway.

Front Cell Dev Biol 2020 5;8:610097. Epub 2021 Feb 5.

Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, China.

The mortality rate of non-small-cell lung cancer (NSCLC) remains high worldwide. Although cisplatin-based chemotherapy may greatly enhance patient prognosis, chemotherapy resistance remains an obstacle to curing patients with NSCLC. Therefore, overcoming drug resistance is the main route to successful treatment, and combinatorial strategies may have considerable clinical value in this effort. In this study, we observed that both parthenolide (PTL) and cisplatin (DDP) inhibited the growth of NSCLC cells in a dose- and time-dependent manner. The combination of PTL and DDP presented a synergistic inhibitory effect on NSCLC at a ratio of 50:1. The combination of PTL and DDP synergistically inhibited cell migration and invasion, inhibited cell cycle progression, and induced apoptosis of A549 and PC9 cells. Bioinformatics and network pharmacology analysis indicated that PTL may primarily affect the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway. After treatment with PTL and DDP either alone or in combination, Western blot analysis revealed that the proteins levels of Bax and cleaved Caspase-3 were upregulated, while p-PI3K, p-Akt, Caspase-3, and Bcl-2 proteins were downregulated. Among these alterations, the combination of PTL and DDP was found to exhibit the most significant effects. PTL might therefore be considered as a new option for combination therapy of NSCLC.
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http://dx.doi.org/10.3389/fcell.2020.610097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892899PMC
February 2021

Modified Linggui Zhugan Decoction () Ameliorates Glycolipid Metabolism and Inflammation via PI3K-Akt/mTOR-S6K1/AMPK-PGC-1 α Signaling Pathways in Obese Type 2 Diabetic Rats.

Chin J Integr Med 2020 Nov 19. Epub 2020 Nov 19.

Department of VIP Ward, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.

Objective: To investigate the protective effects of modified Linggui Zhugan Decoction (, MLZD), a traditional Chinese medicine formula, on obese type 2 diabetes mellitus (T2DM) rats.

Methods: Fifty Sprague-Dawley rats were randomly divided into 5 groups by a random number table, including normal, obese T2DM (ob-T2DM), MLZD low-dose [MLDZ-L, 4.625 g/(kg·d)], MLZD middle-dose [MLD-M, 9.25 g/(kg·d) ] and MLZD high-dose [MLD-H, 18.5 g/(kg·d)] groups, 10 rats in each group. After 4-week intervention, blood samples and liver, pancreas, muscle tissues were collected to assess the insulin resistance (IR), blood lipid, adipokines and inflammation cytokines. The alteration of phosphatidylinositol 3 kinase (PI3K)-protein kinase B (PKB or Akt)/the mammalian target of rapamycin (mTOR)-ribosome protein subunit 6 kinase 1 (S6K1 )/AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 α) pathways were also studied.

Results: MLZD dose-dependently reduced fasting blood glucose, fasting insulin, homeostasis model of assessment for IR index and increased insulin sensitive index compared with ob-T2DM rats (P<0.05). Similarly, total cholesterol, triglyceride, low-density lipoprotein cholesterol and free fatty acids were also decreased compared with ob-T2DM rats after 4-week treatment (P<0.05 or P<0.01). Improvements in adipokines and inflammatory cytokines were observed with a raised level of adiponectin and a reduced level of leptin, resistin, tumor necrosis factor-α and interleukin-6 (P<0.05 or P<0.01). MLZD regulated the PI3K-Akt/mTOR-S6K1/AMPK-PGC-1 α pathways and restored the tissue structure of liver and pancreas (P<0.05 or P<0.01).

Conclusions: MLZD ameliorated glycolipid metabolism and inflammation, which may be attributed to the regulation of PI3K-Akt/mTOR-S6K1/AMPK-PGC-1 α pathways.
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http://dx.doi.org/10.1007/s11655-020-3285-2DOI Listing
November 2020

Fasting Therapy Contributes to the Improvement of Endothelial Function and Decline in Vascular Injury-Related Markers in Overweight and Obese Individuals via Activating Autophagy of Endothelial Progenitor Cells.

Evid Based Complement Alternat Med 2020 27;2020:3576030. Epub 2020 Jul 27.

Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.

Background: High body mass index- (BMI-) related vascular injury contributes to the pathogenesis of the atherosclerotic cardiovascular disease (ASCVD). Rigorous calorie restriction is one of the major lifestyle interventions to reduce vascular risk in overweight or obese individuals. However, the effects of fasting therapy (FT) on vascular function and the mechanism are still unclear. This study was aimed to investigate the impacts of FT on endothelial function, arterial stiffness, and circulating arterial damage parameters in overweight and obese individuals and possible mechanism.

Methods: Overweight and obese individuals participated in FT intervention (7-day very low calorie diet). Arterial function including brachial arterial flow-mediated dilation (FMD), brachial-ankle pulse wave velocity (baPWV), vascular injury-related markers including trimethylamine N-oxide (TMAO), and leptin and endothelial microparticles (EMPs) were assessed. Endothelial progenitor cells (EPCs) of these participants were isolated and cultured to investigate EPCs function. mRFP-GFP-LC3 confocal microscopy scanning and western blot were carried out to determine autophagy.

Results: After FT, body weight and BMI significantly decreased (81.76 ± 12.04 vs. 77.51 ± 12.06 kg, < 0.01; 29.93 ± 2.82 vs. 28.47 ± 2.83 kg/m, < 0.01). FT remarkably improved FMD (5.26 ± 1.34 vs. 6.25 ± 1.60%, =0.01) while baPWV kept unchanged. TMAO and leptin levels decreased (3.96 ± 1.85 vs. 2.73 ± 1.33 mol/L, =0.044; 6814 ± 2639 vs. 3563 ± 2668 mol/L, < 0.01). EMPs showed a decreased tendency. EPCs function was significantly improved, autophagy fluorescence intensity was enhanced, and the level of Beclin1, Atg5, LC3 II/I also increased after starvation in vitro, and the effects were blocked by autophagy inhibitor.

Conclusions: Our present study demonstrated for the first time that FT markedly improves endothelial function and reduces the levels of arterial injury markers through improving EPCs function via activating autophagy. These findings provide a novel insight into FT as a lifestyle intervention strategy to promote the maintenance of vascular homeostasis in overweight or obese individuals. The trial was registered with ChiCTR1900024290.
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http://dx.doi.org/10.1155/2020/3576030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403908PMC
July 2020

Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer.

J Cancer 2020 6;11(13):3932-3943. Epub 2020 Apr 6.

Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin, 300060, P.R. China.

: The aberrant activation of the Sonic hedgehog (Shh) signaling pathway is involved in progression of several types of cancer, including gastric cancer (GC). However, it remains uncertain whether it also plays a critical role in promoting cancer initiation and progression by inducing epithelial-to-mesenchymal transition (EMT) in GC. Thus, the aim of the present study was to determine whether the Shh pathway is involved in GC, and to investigate the function of the Shh pathway in the induction of EMT in GC. : The expression levels of Shh pathway members and EMT markers were examined in GC tissues by immunohistochemistry. The association between these factors and patient clinicopathological characteristics was analyzed. In addition, Gli-antagonist 61 (GANT61) was used to block Shh/Gli1 pathway activity, and recombinant Shh proteins (N-Shh) were used to activate the Shh pathway in GC cells. Wound healing and Transwell invasion and migration assays were performed to assess the effects of the Shh pathway on the migration and invasion of GC cells . Furthermore, western blot analysis was used to examine the changes in protein expression. : The results demonstrated that these Shh/Gli1 pathway members were upregulated in GC tissues, and that Gli1 upregulation was associated with tumor progression and a poor prognosis. Gli1 expression was negatively associated with E-cadherin (E-Cad) expression, and positively with Vimentin (VIM) expression in GC specimens. Further analysis revealed that when the Shh/Gli1 pathway was activated, the migratory and invasive abilities of GC cells were enhanced, and the expression levels of Gli1 and VIM were increased, while E-Cad expression was decreased. Opposite results were observed when the Shh/Gli1 pathway was blocked by GANT61. : The present study indicated that the Shh/Gli1 pathway exhibits an abnormal activation pattern in GC with possible predictive and prognostic significance. The Shh/Gli1 pathway may promote the migratory and invasive potential of GC cells by inducing EMT. The Shh/Gli1 pathway can thus be considered as a potential therapeutic target for GC.
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http://dx.doi.org/10.7150/jca.42900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171499PMC
April 2020

A Preliminary Study on the Establishment of the PDTX Model.

Cancer Manag Res 2020 17;12:1969-1979. Epub 2020 Mar 17.

Department of Gastroenterology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, People's Republic of China.

Objective: The current study aims to explore the establishment of the patient-derived tumor xenograft (PDTX) model.

Materials And Methods: Twenty patients with gastric cancer, 10 males and 10 females, were enrolled in the current study. Firstly, the volume, invasion and metastasis of the xenografts were observed. Subsequently, the correlation between tumor tissues of the PDTX mouse model and the patients' primary tumor tissues was evaluated by pathological H&E staining and immunohistochemistry.

Results: The results showed that the PDTX models corresponding to 15 of the 20 patients were successfully established, and the success rate of PDTX model establishment was 75%. Furthermore, the PDTX models maintained the differentiation degree, morphological characteristics and structural characteristics of tumor cells.

Conclusion: A PDTX model can be used as a substitute for cancer patients in clinical practice and may be suitable for clinical pharmacodynamic screening and new drug development.
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http://dx.doi.org/10.2147/CMAR.S230668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096243PMC
March 2020

Interleukin-7 Resensitizes Non-Small-Cell Lung Cancer to Cisplatin via Inhibition of ABCG2.

Mediators Inflamm 2019 14;2019:7241418. Epub 2019 Dec 14.

Department of Traditional Chinese Medicine, Zhujiang Hospital of Southern Medical University, China.

Treatment with cisplatin (DDP) is one of the standard therapies used to treat non-small-cell lung cancer (NSCLC) and fundamentally causes resistance in cancer cells, which eventually poses as an obstacle to the efficacy of chemotherapy in NSCLC. Efforts are on all over the world to explore a sensitizer of NSCLC to DDP. Here, we studied the effect of IL-7 on the resistance of NSCLC to chemotherapy. We observed that IL-7 treatment significantly enhanced DDP-induced effects in A549 and A549/DDP cells (DDP-resistant cells), including decreased cell viability and proliferation, as well as increased cell apoptosis and S arrest, indicating that IL-7 treatment resensitized DDP-resistant NSCLC cells to DDP. Subsequently, IL-7 enhanced the sensitivity of PI3K/AKT signaling and expressions of ABCG2 to DDP. By inhibiting IL-7 signaling via IL-7R knockdown or activating PI3K/AKT signaling via PI3K activation, the resensitization to DDP by IL-7 was abrogated, and the expression levels of ABCG2, p-PI3K, and p-AKT were found to be significantly higher. In vivo results also confirmed that IL-7 only in combination with DDP could remarkably induce tumor regression with reduced levels of ABCG2 in tumorous tissues. These findings indicate that IL-7, apart from its adjuvant effect, could overcome multidrug resistance of DDP to restore its chemotherapy sensitivity.
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http://dx.doi.org/10.1155/2019/7241418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931030PMC
July 2020

IL-7-Mediated IL-7R-JAK3/STAT5 signalling pathway contributes to chemotherapeutic sensitivity in non-small-cell lung cancer.

Cell Prolif 2019 Nov 10;52(6):e12699. Epub 2019 Oct 10.

Department of Traditional Chinese Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Objectives: The chemotherapy drug resistance is a major challenge for non-small-cell lung cancer (NSCLC) treatment. Combination of immunotherapy and chemotherapy has shown promise for cancer. The goal of this study was to evaluate the anti-tumour efficacy of interleukin-7 (IL-7) combining cisplatin against NSCLC.

Materials And Methods: Cell proliferation was analysed using CCK-8 assay, EdU proliferation assay and colony-forming assay. Cell apoptosis was evaluated using HOECHST 33342 assay and flow cytometry. The protein expression levels were analysed by Western blot. The blocking antibody against the IL-7 receptor and the inhibitors of STAT5 and JAK3 were used to investigate the pathway involved. A xenograft model was established to assess the anti-tumour efficacy of IL-7 combining cisplatin in vivo.

Results: Here we found IL-7R was increased in A549/DDP cells compared with A549 cells. The block of IL-7R reversed the inhibitory effects of IL-7 combined with cisplatin and decreased the numbers of apoptosis cells induced by treatment of IL-7 combined with cisplatin. The JAK3 inhibitor and STAT5 inhibitor were used to identify the pathway involved. The results showed that JAK3/STAT5 pathway was involved in enhancing role of cisplatin sensitivity of NSCLC cells by IL-7. In vivo, cisplatin significantly inhibited tumour growth and IL-7 combined with cisplatin achieved the best therapeutic effect.

Conclusion: Together, IL-7 promoted the sensitivity of NSCLC cells to cisplatin via IL-7R-JAK3/STAT5 signalling pathway.
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http://dx.doi.org/10.1111/cpr.12699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6869130PMC
November 2019

Yi-qi-yang-yin-tian-sui-fang enhances cisplatin-induced tumor eradication and inhibits interleukin-7 reduction in non-small cell lung cancer.

Biosci Rep 2019 06 28;39(6). Epub 2019 Jun 28.

Department of Traditional Chinese Medicine, Zhujiang Hospital of Southern Medical University, 253 Industrial Road, Guangzhou, Guangdong 510280, People's Republic of China

Traditional Chinese Medicine (TCM) has been recognized to be conducive to enhancing the efficiency and reducing the side effects in the whole course of cancer treatment. The mechanisms of TCM/chemotherapy combination involved with interleukin-7 (IL-7) potentially enhance immune responses against tumor. In the present study, we emphasized on a herbal formulation Yi-qi-yang-yin-tian-sui-fang or TCM for short, and investigated its roles in chemotherapy in non-small cell lung cancer (NSCLC). The mice bared with tumor were treated with cisplatin (DDP) and simultaneously administrated with/without low, medium and high doses of TCMs (effective content: 0.5, 2.0 and 8.0 g/per mice) via oral gavage. The results indicated that combination of TCM further elevated the therapy efficiency of DDP in a dose-dependent manner. The growth of tumor cells was estimated by Ki-67 stain and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay. The addition of TCM to the DDP treatment could significantly decrease the expression of Ki-67 and promote the apoptosis of tumor cells. In addition, the serum IL-7 level was down-regulated by DDP but restored by the treatment of TCM. The expression of IL-7 and its receptor IL-7R in tumor tissues was also recovered by TCM. Furthermore, the side effect from bone marrow suppression (myelosuppression) induced by DDP were assessed. TCM could abrogate DDP-induced apoptosis of bone marrow and also remarkably induced the expressions of IL-7 and hematopoietic growth factors including G-CSF, GM-CSF, SCF, and SDF-1 in bone marrow. These data indicated that this TCM combined with DDP showed superior anti-tumor effects with reduced myelosuppression via up-regulating IL-7.
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http://dx.doi.org/10.1042/BSR20190052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597844PMC
June 2019

L-carnitine ameliorated weight loss in fasting therapy: A propensity score-matched study.

Complement Ther Med 2019 Jun 4;44:162-165. Epub 2019 Apr 4.

Department of Traditional Chinese Medicine, the Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China. Electronic address:

l-carnitine infusion has been proven to reduce fasting-induced fatigue and hunger in patients with metabolic syndrome in our former study. However, the association between l-carnitine and clinical outcomes of fasting therapy is yet to be investigated. In this study, data from 192 patients who finished fasting therapy from September 2008 to July 2018 were reviewed, among which 142 patients received l-carnitine infusion in fasting regimen. Propensity matching was used to overcome retrospective bias. Patients' anthropometric measurements and metabolic markers were evaluated. After propensity matching, 40 patients were included in each group. Weight (-4.05 ± 1.65 kg vs -3.25 ± 1.68 kg, P = 0.031) and BMI (-1.51±0.61 kg/m vs -1.20 ± 0.62 kg/m, P = 0.036) decreased in both groups, but significantly more in l-carnitine group, while diastolic blood pressure (-1.67±9.82 mmHg vs -6.21±8.83 mmHg, P = 0.043) and triglycerides (-0.18±0.63 mmol/L vs -1.05±1.70 mmol/L, P = 0.007) decreased significantly more in non-l-carnitine group compared between groups, blood glucose did not differ significantly between groups. l-carnitine can boost the positive effects of fasting therapy on weight loss and maintain the stability of blood pressure.
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http://dx.doi.org/10.1016/j.ctim.2019.03.020DOI Listing
June 2019

Inhibition of MAPKs Signaling Pathways Prevents Acrolein-Induced Neurotoxicity in HT22 Mouse Hippocampal Cells.

Biol Pharm Bull 2019 Apr 29;42(4):617-622. Epub 2019 Jan 29.

Department of Traditional Chinese Medicine, the First Affiliated Hospital, Sun Yat-sen University.

Activation of mitogen-activated protein kinases (MAPKs) in neurons may underlie the pathogenesis of Alzheimer's disease (AD). Acrolein, a ubiquitous pollutant, has been reported to implicate in the etiology of AD. Our previous data showed that acrolein changed the levels of key AD-associated proteins, including advanced glycation end products (RAGE), A-disintegrin and metalloprotease (ADAM-10), and beta-site amyloid-beta peptide cleaving enzyme 1 (BACE-1). In this study, we investigated whether acrolein-induced alterations of AD-associated proteins are relevant to MAPKs activation, and strategies to inhibit MAPKs activation yield benefits to acrolein-induced neurotoxicity in HT22 mouse hippocampal cells. We found that acrolein activated MAPKs signaling pathways to mediate cells apoptosis, and then altered the levels of AD-associated proteins ADAM-10, BACE-1 and RAGE. Inhibitors of MAPKs signaling pathways attenuated the cells death and restored the proteins levels of ADAM-10, BACE-1 and RAGE in varying degrees induced by acrolein. Taken together, activated MAPKs signaling pathways should be underlying the pathology of acrolein-induced neuronal disorders. Inhibitors of MAPKs pathways might be promising agents for acrolein-related diseases, such as AD.
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http://dx.doi.org/10.1248/bpb.b18-00715DOI Listing
April 2019

Clinical significance of Stathmin1 expression and epithelial-mesenchymal transition in curatively resected gastric cancer.

Mol Clin Oncol 2019 Feb 26;10(2):214-222. Epub 2018 Nov 26.

Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, P.R. China.

In our previous study, it was demonstrated that the Stathmin1 (STMN1) is overexpressed in gastric cancer (GC) and that its high expression level is associated with tumor invasion and metastasis. Epithelial-mesenchymal transition (EMT) has also been shown to be critically involved in GC invasion and metastasis. Certain studies have indicated that STMN1 may serve an important role in the EMT process. However, the association between STMN1 expression and EMT-associated markers, as well as clinicopathological characteristics of patients with GC, remains unclear. The aim of the present study was to investigate the clinicopathological significance and prognostic value of STMN1 and EMT-associated markers in GC. The expression of STMN1 and the EMT-associated proteins E-cadherin (E-Cad) and vimentin (VIM) were analyzed by immunohistochemistry in GC and adjacent non-tumorous tissues. Associations between the expression of these markers and clinicopathological parameters were analyzed. The association between STMN1 expression and EMT-associated markers was investigated in the GC cell lines BGC-803 and SGC-7901. The results revealed that STMN1 was expressed in 63.5% of the 167 GC tissues, which was significantly higher than the percentage observed in the adjacent non-tumorous tissues (P=0.003). The STMN1 expression was demonstrated to be positively associated with the VIM levels (P=0.001) and negatively associated with the E-Cad levels (P=0.022) in GC tissues. The STMN1 expression was associated with Lauren's Classification, invasion depth, lymph node metastasis and pathological Tumor-Node-Metastasis (pTNM) stage (P<0.05). In the univariate analyses, the high E-Cad expression was a positive prognostic indicator for overall survival, whereas the high STMN1 and VIM expression was a negative indicator. COX multiple regression analysis demonstrated that the pTNM stage [hazard ratio (HR) 1.912, 95% confidence interval (CI): 1.282-2.851, P=0.001] and E-Cad expression (HR 0.403, 95% CI: 0.249-0.650, P=0.000) were independent prognostic factors. It was also revealed that the expression level of E-Cad decreased, while the expression level of VIM increased by depleting STMN1 levels in GC cells. The present results suggest that the aberrant expression of STMN1 may promote tumor progression through EMT in GC.
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http://dx.doi.org/10.3892/mco.2018.1774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327211PMC
February 2019

Prognostic value of inflammation-based scores in patients receiving radical resection for colorectal cancer.

BMC Cancer 2018 Nov 12;18(1):1102. Epub 2018 Nov 12.

Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651, Dongfengdong Road, Guangzhou, 510060, China.

Background: The modified Glasgow Prognostic Score (mGPS) and the neutrophil-to-lymphocyte ratio (NLR) are conventional inflammation-based scores for colorectal cancer (CRC). The systemic inflammation score (SIS) has been shown to be more informative than the mGPS in CRC. The albumin-NLR, composed of albumin and the NLR, can also be a candidate for a valuable inflammation score. However, about the utility of the mGPS, SIS, and albumin-NLR for CRC patients who have received radical resections remains unclear.

Methods: This study enrolled 877 CRC patients, who underwent radical surgical resection between January 1, 2007 and December 31, 2014. The prognostic values of the mGPS, SIS, and albumin-NLR were compared by the Kaplan-Meier survival analysis, multivariate Cox regression modelling, and the time-dependent receiver operating characteristic curve analysis (ROC).

Results: In the Kaplan-Meier analysis, all three inflammation scores were significantly associated with overall survival (OS) in the group including all the patients (mGPS, p = 0.016; SIS, p < 0.001; albumin-NLR, p = 0.007) and in the left-sided colon tumour subgroup (mGPS, p = 0.029; SIS p = 0.0013; albumin-NLR, p = 0.001). In the right-sided colon tumour subgroup, only the albumin-NLR was associated with OS (p = 0.048). The albumin-NLR was the only independent prognostic factor of the three scores for OS in the multivariate survival analysis.

Conclusions: The albumin-NLR outperformed both the SIS and mGPS in predicting OS in CRC patients undergoing radical resection.
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http://dx.doi.org/10.1186/s12885-018-4842-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233268PMC
November 2018

Flavored Guilu Erxian decoction inhibits the injury of human bone marrow mesenchymal stem cells induced by cisplatin.

Cell Mol Biol (Noisy-le-grand) 2018 May 15;64(6):58-64. Epub 2018 May 15.

Department of Traditional Chinese Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou, China.

To examine the exact role of flavored Guilu Erxian decoction, a Traditional Chinese Medicine (TCM) in the treatment of cisplatin-induced side-effects in bone marrow mesenchymal stem cells (BM-MSCs). BM-MSCs were isolated from bone marrow collected from SD rats and identified by flow cytometry. Cells were cultivated in MEM alpha medium containing 5% (TCM-L), 10% (TCM-M) and 20% (TCM-H) dosages of flavored Guilu Erxian decoction with or without cisplatin. Cell viability was determined through CCK-8 and thymidine analog 5-ethynyl-2'-deoxyuridine (EdU) staining assay. Flow cytometry was used to determine cell cycle and apoptosis. The expression of p21 and cleaved-caspase-3 were examined using Western blot assay. The PI3K-AKT-mTOR pathway associated proteins, including p-PI3K, p-AKT and p-mTOR, were also examined by Western blot assay. CCK-8 and EdU staining assay demonstrated that cisplatin could inhibit cell proliferation in BM-MSCs in a dose and time dependent manner. Further, cisplatin could induce apoptosis through increasing G0/G1 cell cycle arrest, p21 and cleaved-caspase-3 expression. However, these phenomena would be significantly alleviated when adding the serum containing flavored Guilu Erxian decoction. Furthermore, the PI3K-AKT-mTOR pathway activation could be inhibited by cisplatin in BM-MSCs, while flavored Guilu Erxian decoction treatment successfully abrogated this effect. Combination of flavored Guilu Erxian decoction and cisplatin could reduce the damage to BM-MSCs. This indicates that the flavored Guilu Erxian decoction can enhance the possibility of BM-MSCs repairing and rehabilitating the normal function of injured tissues induced by cisplatin, which could provide a new direction for therapeutic applications.
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May 2018

Caloric restriction ameliorates acrolein-induced neurotoxicity in rats.

Neurotoxicology 2018 03 31;65:44-51. Epub 2018 Jan 31.

Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China. Electronic address:

Objective: Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and oxidative damage induced by acrolein is hypothesized to involve in the etiology of Alzheimer's disease (AD). Calorie restriction (CR) is the only non-genetic intervention that has consistently been verified to retard aging by ameliorating oxidative stress. Therefore, we investigated the effects of CR on acrolein-induced neurotoxicity in Sprague-Dawley (SD) rats.

Methods: A total of 45 weaned and specific-pathogen-free SD rats (male, weighing 180-220 g) were gavage-fed with acrolein (2.5 mg/kg/day) and fed ab libitum of 10 g/day or 7 g/day (representing 30% CR regimen), or gavage-fed with same volume of tap water and fed al libitum as vehicle control for 12 weeks. After behavioral test conducted by Morris Water Maze, SD rats were sacrificed and brain tissues were prepared for histochemical evaluation and Western blotting to detect alterations in oxidative stress, BDNF/TrkB pathway and key enzymes involved in amyloid precursor protein (APP) metabolism.

Results: Treatment with 30% CR in SD rats significantly attenuated acrolein-induced cognitive impairment. Oxidative damage including deletion of glutathione and superoxide dismutase and sharp rise in malondialdehyde were notably improved by 30% CR. Further study suggested that 30% CR showed protective effects against acrolein by modulating BDNF/TrkB signaling pathways. Moreover, 30% CR restored acrolein-induced changes of APP, β-secretase, α-secretase and receptor for advanced glycation end products.

Conclusion: These findings suggest that CR may provide a promising approach for the treatment of AD, targeting acrolein.
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http://dx.doi.org/10.1016/j.neuro.2018.01.003DOI Listing
March 2018

Fucoidan elevates surface organic cation transporter 2 expression via upregulation of protein kinase A in uric acid nephropathy.

Exp Ther Med 2017 Nov 30;14(5):4153-4159. Epub 2017 Aug 30.

Department of Traditional Chinese Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.

Uric acid nephropathy (UAN) is caused by excessive uric acid, and is a key risk factor for uric acid nephrolithiasis, gouty arthritis, renal diseases and cardiovascular diseases. The present study aimed to evaluate the protective effect of fucoidan, a sulfated polysaccharide component of brown algae, on UAN and to elucidate the underlying molecular mechanism. A rat model of UAN was induced by adenine treatment, and rats were then randomly assigned to control, model or fucoidan treatment groups. Hematoxylin and eosin staining of the kidney tissues of rats with UAN was subjected to conventional morphological evaluation. Cellular infiltrate in the tubules, atrophic glomeruli, tubular ectasia, granuloma hyperplasia focal fibrosis and accumulated urate crystals in the tubules of UAN rat renal tissues were observed. These symptoms of kidney damage were reduced in the fucoidan treatment group. Periodic acid methenamine silver-Masson staining was performed and the results indicated that renal interstitial fibrosis was reduced among renal tissues from the fucoidan treatment group compared with the model group. Terminal deoxynucleotidyl-transferase-mediated dUTP nick end labelling staining revealed a lower proportion of apoptotic nuclei in the kidneys of the fucoidan treatment group compared with the model group. Protein kinase A (PKA) 2β and phosphorylated PKA 2β protein levels were significantly elevated in renal tissues of the fucoidan treatment group compared with the model group (P<0.05 and P<0.01, respectively), suggesting that PKA expression was upregulated by fucoidan. Immunohistochemistry staining of PKA in rat renal tissues demonstrated increased expression of PKA. The surface organic cation transporter 2 (OCT2) level was significantly increased by fucoidan treatment compared with the model group (P<0.01), with no significant change in total OCT2 level. COS-7 cells ectopically expressing OCT2 were established. It was indicated that fucoidan was able to activate PKA and upregulate surface OCT2 in OCT2-expressing COS-7 cells. This further demonstrated that upregulation of surface OCT2 expression in OCT2-expressing cells was induced by PKA upregulation. In conclusion, fucoidan upregulated surface OCT2 expression in renal tissues to alleviate the symptoms of UAN via upregulated expression of PKA.
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http://dx.doi.org/10.3892/etm.2017.5077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658688PMC
November 2017

[Analysis of lymph node metastasis pattern in gastric cancer patients at stage pN1].

Zhonghua Wei Chang Wai Ke Za Zhi 2017 Jul;20(7):782-786

Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.

Objective: To investigate the lymph node metastasis pattern in pN1 stage gastric cancer patients and to analyze its risk factors.

Methods: Clinicopathological data of 219 patients who underwent radical gastrectomy and were confirmed as pN1 stage gastric cancer between January 2013 and March 2016 were reviewed. All the patients underwent D2 or extended D2(D2+) lymphadenectomy. The overall metastatic rate was calculated. The risk factors associated with lymph node metastasis were analyzed. The pattern of skip lymph node metastasis and clinicopathological factors related to skip metastasis were analyzed.

Results: Among 219 patients, 119 patients had only one metastatic lymph node, and 100 patients had two metastatic lymph nodes. The relatively higher sites of lymph node metastasis were station No.3[29.2%(64/219)], No.6[18.3%(40/219)] and No.4[11.4%(25/219)]. Compared to patients with tumor diameter ≤5 cm, metastatic rates of station No.3[39.4% (39/99) vs. 20.8%(25/120), P=0.003], No.4[16.2%(16/99) vs. 7.5%(9/120), P=0.045] and No.8[16.2%(16/99) vs. 6.7%(8/120), P=0.025] were significantly higher in those with tumor diameter >5 cm. Skip lymph node metastasis was detected in 56 cases(25.6%) and skip lymph node metastatic rate was significantly higher in patients with tumor diameter >5 cm [34.3%(34/99) vs. 18.3%(22/120), P=0.007]. Logistic regression analysis showed that the tumor size was an independent risk factor for the skip lymph node metastasis in pN1 stage gastric cancer (OR=1.982, 95%CI: 0.978 to 3.921, P=0.033).

Conclusions: The perigastric station No1 lymph node is the main site of early lymph node metastasis of pN1 stage gastric cancer. General pattern of lymph node metastasis is from proximus to distance, while quite a lot of skip lymph node metastases are observed. Tumor size is an important factor affecting the lymph node metastasis and bigger tumor may result in skip lymph node metastasis easily.
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July 2017

Additive effects of atorvastatin combined with sitagliptin on rats with myocardial infarction: a pilot study.

Arch Med Sci 2017 Jun 12;13(4):956-961. Epub 2017 Jun 12.

Department of Cardiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Introduction: Atorvastatin and sitagliptin are able to exert cardio-protective effects. However, whether atorvastatin plus sitagliptin could confer additive benefits for rats with myocardial infarction (MI) is unknown.

Material And Methods: Forty rats with MI were produced and 37 surviving rats were randomly divided into atorvastatin (10 mg/kg daily, = 9), sitagliptin (10 mg/kg daily, = 9), combined (10 mg/kg daily atorvastatin plus 10 mg/kg daily sitagliptin, = 9), and control groups (3 ml normal saline daily, = 10). Fourteen days later, cardiac function was detected and fasting venous blood was sampled for lipid profiles and glucose evaluation. Cardiac tissues were used for hematoxylin-eosin staining, for interleukin-6 (IL-6) and tumor necrotic factor-α (TNF-α) evaluation, and for rho-associated kinase 2 (ROCK2) assessment.

Results: Fourteen days after MI, the inflammatory reaction regarding the degree of leukocyte infiltration and IL-6 and TNF-α expression in cardiac tissues was ameliorated in atorvastatin and sitagliptin groups compared to the control group ( < 0.05). In addition, ROCK2 was attenuated by either atorvastatin or sitagliptin ( < 0.05). Echocardiography showed that cardiac function was significantly improved with atorvastatin and sitagliptin therapy ( < 0.05). Overall, all these benefits were further enhanced by combined therapy, suggesting that atorvastatin combined with sitagliptin therapy has additive effects on reducing cardiac inflammation and improving cardiac function. No significant changes in lipid profiles or glucose were observed, suggesting that the benefits derived from atorvastatin and sitagliptin therapy might not depend on cholesterol and glucose modulation.

Conclusions: In rats with MI, atorvastatin plus sitagliptin therapy provides additive effects for cardio-protection, and mechanisms operating in these processes may be due to ROCK2 diminishment.
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http://dx.doi.org/10.5114/aoms.2017.68143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510516PMC
June 2017

Astragalus polysaccharides attenuates TNF-α-induced insulin resistance via suppression of miR-721 and activation of PPAR-γ and PI3K/AKT in 3T3-L1 adipocytes.

Am J Transl Res 2017 15;9(5):2195-2206. Epub 2017 May 15.

Department of Traditional Chinese Medicine, Zhujiang Hospital, Southern Medical UniversityGuangzhou 510280, Guangdong, China.

Insulin resistance is associated with obesity and type 2 diabetes. The aim of this study was to explore the mechanism of how Astragalus Polysaccharides (APS) improves insulin resistance in 3T3-L1 adipocytes. A cell culture model of insulin resistance was established in mature 3T3-L1 adipocytes by treating them with TNF-α, high glucose and insulin. Glucose uptake levels were detected in each group. To determine the mechanism by which APS improves insulin resistance in 3T3-L1 adipocytes, qRT-PCR was used to detect the expression of miR-721, and Western blots were used to detect the expression or activity of PPAR-γ, PAKT, PI3K, AKT, and GLUT4. Immunostaining was used to detect the expression of GLUT4. We successfully madea model of insulin resistance in mature 3T3-L1 adipocytes. APS increased glucose uptake levels in insulin-resistant adipocytes in a dose- and time-dependent manner, and also increased insulin sensitivity. APS suppressed miR-721 with its target gene PPAR-γ in a dose-dependent manner. miR-721 or PPAR inhibitor T0070907 inhibited the expressions of PPAR-γ, pAKT, and GLUT4 and also reduced glucose accumulation. APS attenuated these miR-721- and PPAR-γ-induced changes. APS increased insulin sensitivity by attenuating the effects of miR-721. The PI3K inhibitor wortmannin reduced the APS-increased pAKT, glucose uptake, and GLUT4 levels, and also reduced those levels in the presence of insulin with or without APS. Taken together, our findings suggest that APS promotes glucose uptake and increases insulin sensitivity in 3T3-L1 adipocytes and may involve the miR-721-PPAR-γ-PI3K/AKT-GLUT4 signaling pathway. These might be new therapeutic targets for treating insulin resistance in obesity and diabetes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446503PMC
May 2017

[Analysis of clinicopathological characteristics and prognosis on 42 patients with primary gastric adenosquamous cell carcinoma].

Zhonghua Wei Chang Wai Ke Za Zhi 2017 Feb;20(2):207-212

Department of Gastric Cancer Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.

Objective: To investigate the clinicopathological characteristics, diagnosis, treatment and prognosis of patients with primary gastric adenosquamous cell carcinoma.

Methods: A total of 5 562 patients with gastric neoplasm were admitted in Tianjin Medical University Cancer Institute and Hospital from January 2001 to January 2011. Among them 42 patients were diagnosed as primary gastric adenosquamous cell carcinoma, accounting for 0.76% of all the patients. The clinicopathological and follow-up data of these 42 patients with primary gastric adenosquamous cell carcinoma were retrospectively analyzed, and Cox proportional hazard model was used to analyze the prognostic factors of gastric adenocarcinoma squamous cell carcinoma.

Results: Among above 42 patients, 32 were male and 10 were female, with a male-to-female ratio of 3.2/1.0 and the average age was 63 years (range: 46 to 77 years). Five patients (11.9%) were confirmed as adenosquamous cell carcinoma by preoperative pathological examination, while other 37 patients were diagnosed as adenocarcinoma preoperatively. According to the 7th edition AJCC TNM classification system for gastric adenocarcinoma, 5 patients (11.9%) were in stage II(, 30 patients (71.4%) in stage III( and 7 patients (16.7%) in stage IIII(. The maximum tumor diameter was > 5 cm in 18 patients (42.9%). Borrmann type III(-IIII( was found in 29 patients (69.0%), and poorly differentiated (or undifferentiated) tumor was found in 32 patients (76.2%). Radical operations were performed in 31 patients (73.8%), the reasons of non radical operations included infiltration of pancreas in 3 patients, infiltration of radices mesocili transvers in 1 patient and classification of stage IIII( in 7 patients. Lymph node dissection was performed in 37 patients, 83.8% of them (31/37) was found with lymphatic metastases. Twenty-five patients received adjuvant chemotherapy except for 7 patients in stage IIII( and 10 patients who refused adjuvant chemotherapy. All the patients had an average survival time of 36.4 months and median survival time of 28.0 months, and the overall 1-, 3- and 5-year survival rates were 82.2%, 42.3% and 18.2% respectively. Univariate analysis revealed that tumor size (χ=4.039, P=0.044), Borrmann type (χ=18.728, P=0.000), tumor differentiation (χ=19.612, P=0.000), radical gastectomy (χ=41.452, P=0.000), lymph node metastasis (χ=9.689, P=0.002) and clinical stage (χ=26.277, P=0.000) were associated with postoperative survival. Multivariate analysis revealed that tumor differentiation (HR=10.560, 95%CI:2.263-49.281, P=0.003), radical gastrectomy (HR=4.309, 95%CI:1.311-14.168, P=0.016) and clinical stage (HR=2.392, 95%CI:1.022-5.600, P=0.044) were independent prognosis factors.

Conclusions: Primary gastric adenosquamous cell carcinoma is rare with poor prognosis. Radical gastrectomy is recommended. Tumor differentiation, radical gastrectomy and clinical stage are important indicators to evaluate prognosis of primary gastric adenosquamous cell carcinoma.
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February 2017

Up-regulation of miR-146a increases the sensitivity of non-small cell lung cancer to DDP by downregulating cyclin J.

BMC Cancer 2017 02 15;17(1):138. Epub 2017 Feb 15.

Department of Traditional Chinese Medicine, The First Affiliated Hospital of Sun Yet-sen University, 58 Second Zhongshan Road, Guangzhou, Guangdong, 510080, People's Republic of China.

Background: Cisplatin (DDP)-based chemotherapy is the common first-line therapy for lung cancer. However, their efficacy is often limited by primary drug resistance and/or acquired drug resistance. The aim of this study was to investigate the function of miRNA-146a (miR-146a) in DDP-resistant non-small cell lung cancer (NSCLC), as well as the underlying mechanisms.

Methods: The effect of overexpression of miR-146a and/or knockdown of cyclin J (CCNJ) in A549/DDP and SPC-A1/DDP cells were investigated as follows. The cellular sensitivity to DDP, cell apoptosis, cell cycle and cell mobility were detected by CCK-8, flow cytometry, hoechst staining and cell invasion/migration assay, respectively. The effects of miR-146a overexpression in NSCLC resistant cells were further analyzed in a nude mouse xenograft model.

Results: Overexpression of miR-146a and/or knockdown of CCNJ significantly increased the sensitivity to DDP in A549/DDP and SPC-A1/DDP cells compared to NC group via arresting cell cycle, enhancing cell apoptosis, inhibiting cell viability and motility in vitro and in vivo. Furthermore, miR-146a could specially degrade the mRNA of CCNJ, as examined by dual luciferase report assay.

Conclusion: The study indicates a crucial role of miR-146a in the development of acquired drug resistance to DDP in NSCLC cells. Further understanding of miR-146a mediated crosstalk networks may promote the clinical use of miR-146a analogue in NSCLC therapy.
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http://dx.doi.org/10.1186/s12885-017-3132-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312565PMC
February 2017

Neuronal-derived Ccl7 drives neuropathic pain by promoting astrocyte proliferation.

Neuroreport 2016 08;27(11):849-57

aInstitute of Anesthesiology & pain (IAP), PET-CT and Department of Anesthesiology Departments of bNephrology cNeuroscience, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, China.

Recent studies suggest that peripheral nerve injury converts resting spinal cord astroglial cells into an activated state, which is required for the development and maintenance of neuropathic pain. However, the underlying mechanisms of how resting astrocytes are activated after nerve injury remain largely unknown. Astroglial cell proliferation and activation could be affected by endogenous factors including chemokines, growth factors, and neurotropic factor. Chemokine (C-C motif) ligand 7 (Ccl7) is essential in facilitating the development of neuropathic pain; however, the mechanism is unknown. In the present study, we found that Ccl7 promoted astrocyte proliferation and thus contributed toward neuropathic pain. Spinal nerve ligation increased the expression in the spinal cord of neuronal Ccl7. Behavioral analyses showed that knockdown of Ccl7 alleviated spinal nerve ligation-induced neuropathic pain. Further in-vitro study showed that neuronal-derived Ccl7 was sufficient for the proliferation and activation of astroglial cells. We found a novel mechanism of Ccl7 stimulating the proliferation and activation of spinal cord astrocytes that contributes toward neuropathic pain.
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http://dx.doi.org/10.1097/WNR.0000000000000625DOI Listing
August 2016

[Analysis of risk factors for No.11p lymph node metastasis in advanced gastric cancer].

Zhonghua Wei Chang Wai Ke Za Zhi 2016 Feb;19(2):186-9

Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.

Objective: To investigate the risk factors for No.11p lymph node metastasis in advanced gastric cancer.

Methods: A retrospective analysis was executed of the clinical data of 204 patients who were subject to advanced gastric cancer and accepted radical gastrectomy in Tianjin Cancer Hospital from January 2007 to December of 2011. All of the patients were diagnosed as gastric adenocarcinoma and received No.11p lymph node dissection. The general information of the patients and the number of dissected and positive lymph nodes were recorded in detail. Univariate and multivariate analysis of clinicopathological factors influencing No.11p lymph metastasis were performed by chi-square test and binary Logistiic Discussion, respectively.

Results: The No.11p lymph node metastasis rate is 14.3%(29/204) in the 204 patients. The univariate analysis showed that No.11p lymph metastasis was correlated with diameter of tumor, depth of invasion (T stage), lymph node metastasis (N stage) and TNM stage (χ(2)=5.106, χ(2)=5.368, χ(2)=25.911, P<0.05). The association between the metastasis of the regional lymph nodes No.1, No. 3, No. 4sb, No. 5, No. 7, No. 9 and No.11p was significant (χ(2)=4.228, χ(2)=10.655, χ(2)=17.954, χ(2)=11.087, χ(2)=15.142, χ(2)=16.727, all P<0.05). Multivariate analysis confirmed that lymph node N3 stage(OR=4.791, 95% CI:2.056-11.167), No.4sb(OR=3.498, 95% CI:1.157-10.578) and No.9(OR=4.006, 95% CI:1.359-11.805) were three independent risk factors of No.11p lymph node metastasis(all P<0.05).

Conclusion: The No.11p lymph node dissection in radical gastrectomy conventionally is reasonable and necessary. Lymph node N3 stage and the metastasis of regional lymph No.4sb and No.9 are independent risk factors of the metastasis of No.11p lymph node.
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February 2016

Uric acid crystal could inhibit Numb-induced URAT1 lysosome degradation in uric acid nephropathy.

J Physiol Biochem 2015 Jun 17;71(2):217-26. Epub 2015 Mar 17.

Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Second Zhongshan Road, Guangzhou, 510080, China,

To investigate whether uric acid could regulate urate transporter 1 (URAT1) protein and activity level, we established uric acid nephropathy (UAN) rat model and detected their serum uric acid and URAT1 level with or without the treatment of allopurinol. Results here showed that allopurinol could reduce serum uric acid level in UAN rat model. We further found that in UAN rats, the total and surface URAT1 expression level were both increased while this increase could be blocked by allopurinol treatment. By treating URAT1 stable expressed HEK cell with monosodium urate (MSU) crystals, we found that URAT1 level showed an increase in both total and cell surface level, and it would colocalize more with Rab11 instead of Rab7. Consistently, we also found that the total URAT1 protein level will show an increase in the presence of lysosome inhibitors but not ubiquitin-proteasome inhibitors. Furthermore, we also found that MSU crystal could drive Numb, a clathrin-coated adaptor protein which performs a key function in cell division, out of cell surface and disassociated it from URAT1. Finally, we found that Numb short hairpin RNA (shRNA)-transfected showed a phenocopy as MSU treatment, while Numb-2A mutation over-expression could resist crystal-induced phenotypes. These findings indicated that uric acid crystal could increase URAT1 membrane distribution through inhibiting Numb-induced URAT1 lysosome degradation.
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http://dx.doi.org/10.1007/s13105-015-0399-7DOI Listing
June 2015

Effect of alternate-day fasting therapy combined with Linggui Zhugan Decoction () on hepatic oxidative stress in hyperlipidemic rat.

Chin J Integr Med 2015 Jan 14. Epub 2015 Jan 14.

Department of Traditional Chinese Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.

Objective: To observe the effect of alternate-day fasting (ADF) therapy combined with Linggui Zhugan Decoction (, LZD) on hepatic oxidative stress and blood lipids in hyperlipidemic rats.

Methods: Fifty-two Wistar rats were randomly assigned to two groups: the high-fat-diet (HF) group and the normal-diet (ND) group. Hyperlipidemia was induced by feeding rats with high-cholesterol-diet for 5 weeks. Then the HF group was randomized to the model-control (MC) group, the alternate-day-fasting (ADF) group, and the ADF combined with LZD (AL) group. The ND group was regarded as the negative control (NC) group. The AL and ADF groups were put on fast for 24 h on alternate days for 4 weeks. The AL group was administrated with LZD on the fast days. Body weight and food intake were measured once a week. After 4-week ADF, blood sample was collected for determination of plasma total cholesterol (TC), triglyceride (TG), low-density-lipoprotein cholesterol (LDL-C) and high-density-lipoprotein cholesterol (HDL-C). Liver oxidative stress parameters including total superoxide dismutase (T-SOD) activity, malondialdehyde (MDA) level and glutathione (GSH) content were also tested.

Results: Body weight in the HF group decreased significantly (P<0.01). TC, TG, HDL-C, and LDL-C concentrations in the HF group were higher than those in the NC group (P<0.01), respectively. T-SOD in the HF group was clearly lower than that in the NC group (P<0.05). After 4-week intervention, body weight, TC and TG concentrations in the ADF and AL groups declined significantly, respectively, compared to MC group (P<0.05). GSH in the ADF and AL groups were much higher than those in the MC group (P<0.01). MDA level was also greatly higher in the ADF group as compared with the NC group (P<0.05).

Conclusion: ADF therapy combined with LZD may be used as an effective combination approach for treatment of hyperlipidemia and oxidative stress damage.
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http://dx.doi.org/10.1007/s11655-014-1999-8DOI Listing
January 2015

L-carnitine ameliorated fasting-induced fatigue, hunger, and metabolic abnormalities in patients with metabolic syndrome: a randomized controlled study.

Nutr J 2014 Nov 26;13:110. Epub 2014 Nov 26.

Department of Traditional Chinese Medicine, First Affiliated Hospital of Sun Yat-Sen University, No, 58 Zhongshan 2nd Road, Guangzhou 510080, China.

Background: The present study aimed to determine that whether L-carnitine infusion could ameliorate fasting-induced adverse effects and improve outcomes.

Method: In this 7-day, randomized, single-blind, placebo-controlled, pilot study, 15 metabolic syndrome (MetS) patients (11/4 F/M; age 46.9 ± 9.14 years; body mass index [BMI] 28.2 ± 1.8 kg/m2) were in the L-carnitine group (LC) and 15 (10/5 F/M; age 46.8 ± 10.9 years; BMI 27.1 ± 2.3 kg/m2) were in the control group (CT). All participants underwent a 5-day modified fasting therapy introduced with 2-day moderate calorie restriction. Patients in the LC group received 4 g/day of intravenous L-carnitine, while patients in the CT group were injected with saline. Blood pressure (BP), anthropometric characteristics, markers of liver function, metabolic indices (plasma glucose, lipid profiles, uric acid, free fatty acid and insulin) and hypersensitivity C-reactive protein were measured. Perceived hunger was recorded daily by self-rating visual analogue scales. Fatigue was evaluated by Wessely and Powell scores.

Results: In contrast to the CT group, total cholesterol, alanine aminotransferase, systolic and diastolic BP did not change significantly in the LC group after prolonged fasting. There were significant differences in weight loss (LC -4.6 ± 0.9 vs. CT -3.2 ± 1.1 kg, P = 0.03), and waist circumference (LC -5.0 ± 2.2 vs. CT -1.7 ± 1.16 cm, P < 0.001), waist hip ratio (LC -0.023 ± 0.017 vs. CT 0.012 ± 0.01, P < 0.001), insulin concentration (LC -9.9 ± 3.58 vs. CT -6.32 ± 3.44 µU/mL, P = 0.046), and γ-glutamyltransferase concentration (LC -7.07 ± 6.82 vs. CT -2.07 ± 4.18, P = 0.024). Perceived hunger scores were significantly increased (P < 0.05) in the CT group during starvation, which was alleviated with L-carnitine administration in the LC group. Physical fatigue (LC -3.2 ± 3.17 vs. CT 1.8 ± 2.04, P < 0.001) and fatigue severity (LC -11.6 ± 8.38 vs. CT 8.18 ± 7.32, P < 0.001) were significantly reduced in the LC group but were aggravated in the CT group.

Conclusion: Intravenous L-carnitine can ameliorate fasting-induced hunger, fatigue, cholesterol abnormalities and hepatic metabolic changes and facilitate fasting-induced weight loss in MetS patients.

Trial Registration: ChiCTR-TNRC-12002835.
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http://dx.doi.org/10.1186/1475-2891-13-110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258024PMC
November 2014

Prognostic value analysis of mutational and clinicopathological factors in non-small cell lung cancer.

PLoS One 2014 8;9(9):e107276. Epub 2014 Sep 8.

Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin Lung Cancer Center, Tianjin, China.

Introduction: Targeting activating oncogenic driver mutations in lung adenocarcinoma has led to prolonged survival in patients harboring these specific genetic alterations. The prognostic value of these mutations has not yet been elucidated. The prevalence of recently uncovered non-coding somatic mutation in promoter region of TERT gene is also to be validated in lung cancer. The purpose of this study is to show the prevalence, association with clinicalpathological features and prognostic value of these factors.

Methods: In a cohort of patients with non-small cell lung cancer (NSCLC) (n = 174, including 107 lung adenocarcinoma and 67 lung squamous cell carcinoma), EGFR, KRAS, HER2 and BRAF were directly sequenced in lung adeoncarcinoma, ALK fusions were screened using FISH (Fluorescence in situ Hybridization).TERT promoter region was sequenced in all of the 174 NSCLC samples. Associations of these somatic mutations and clinicopathological features, as well as prognostic factors were evaluated.

Results: EGFR, KRAS, HER2, BRAF mutation and ALK fusion were mutated in 25.2%, 6.5%, 1.9%, 0.9% and 3.7% of lung adenocarcinomas. No TERT promoter mutation was validated by reverse-sided sequencing. Lung adenocarcinoma with EGFR and KRAS mutations showed no significant difference in Disease-free Survival (DFS) and Overall Survival (OS). Cox Multi-variate analysis revealed that only N stage and HER2 mutation were independent predictors of worse overall survival (HR = 1.653, 95% CI 1.219-2.241, P = 0.001; HR = 12.344, 95% CI 2.615-58.275, P = 0.002).

Conclusions: We have further confirmed that TERT promoter mutation may only exist in a very small fraction of NSCLCs. These results indicate that dividing lung adenocarcinoma into molecular subtypes according to oncogenic driver mutations doesn't predict survival difference of the disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107276PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157862PMC
December 2015

Prognostic nutritional index predicts postoperative complications and long-term outcomes of gastric cancer.

World J Gastroenterol 2014 Aug;20(30):10537-44

Nan Jiang, Jing-Yu Deng, Xue-Wei Ding, Bin Ke, Ning Liu, Ru-Peng Zhang, Han Liang, Key Laboratory of Cancer Prevention and Therapy, Department of Gastrointestinal Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.

Aim: To investigate the impact of prognostic nutritional index (PNI) on the postoperative complications and long-term outcomes in gastric cancer patients undergoing total gastrectomy.

Methods: The data for 386 patients with gastric cancer were extracted and analyzed between January 2003 and December 2008 in our center. The patients were divided into two groups according to the cutoff value of the PNI: those with a PNI ≥ 46 and those with a PNI < 46. Clinicopathological features were compared between the two groups and potential prognostic factors were analyzed. The relationship between postoperative complications and PNI was analyzed by logistic regression. The univariate and multivariate hazard ratios were calculated using the Cox proportional hazard model.

Results: The optimal cutoff value of the PNI was set at 46, and patients with a PNI ≥ 46 and those with a PNI < 46 were classified into PNI-high and PNI-low groups, respectively. Patients in the PNI-low group were more likely to have advanced tumor (T), node (N), and TNM stages than patients in the PNI-high group. The low PNI is an independent risk factor for the incidence of postoperative complications (OR = 2.223). The 5-year overall survival (OS) rates were 54.1% and 21.1% for patients with a PNI ≥ 46 and those with a PNI < 46, respectively. The OS rates were significantly lower in the PNI-low group than in the PNI-high group among patients with stages II (P = 0.001) and III (P < 0.001) disease.

Conclusion: The PNI is a simple and useful marker not only to identify patients at increased risk for postoperative complications, but also to predict long-term survival after total gastrectomy. The PNI should be included in the routine assessment of advanced gastric cancer patients.
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http://dx.doi.org/10.3748/wjg.v20.i30.10537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130864PMC
August 2014

Effects of modified lingguizhugan decoction combined with weekend fasting on metabolic syndrome.

J Tradit Chin Med 2014 Feb;34(1):48-51

Objective: To assess the therapeutic effect of weekend fasting and administration of a modified Lingguizhugan decoction on metabolic syndrome (MetS).

Methods: Twenty-one patients with MetS were recruited from the First Affiliated Hospital of Sun Yat-Sen University. Fasting plasma glucose (FPG), 30-min and 2-h post-prandial blood glucose (PG), fasting serum insulin (FINS), blood pressure (BP), body mass index (BMI), waist circumference (WC), homeostasis model assessment for insulin resistance index (HOMA-IR), and levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were tested. Patients were allowed to drink only water and a Chinese herbal decoction during weekends. All samples were tested again after 12 weeks of treatment.

Results: FPG, 30-min PG, 2-h PG, FINIS, LDL-C, systolic BP, diastolic BP, BMI, WC, and HOMA-IR decreased significantly (P < 0.05) compared with before treatment. Levels of TG, TC, and HDL-C did not change significantly.

Conclusion: Weekend fasting improved glucose metabolism, lowered BP, reduced LDL-C levels, BMI, and WC. These data suggest that weekend fasting may be an effective therapy for MetS by protection against coronary atherosclerosis.
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http://dx.doi.org/10.1016/s0254-6272(14)60053-4DOI Listing
February 2014