Diet high in branched-chain amino acid promotes PDAC development by USP1-mediated BCAT2 stabilization.

BCAT2-mediated branched-chain amino acid (BCAA) catabolism is critical for pancreatic ductal adenocarcinoma (PDAC) development, especially at an early stage. However, whether a high-BCAA diet promotes PDAC development in vivo, and the underlying mechanism of BCAT2 upregulation, remain undefined. Here, we find that a high-BCAA diet promotes pancreatic intraepithelial neoplasia (PanIN) progression in LSL-KrasG12D/+ ; Pdx1-Cre (KC) mice. Moreover, we screened with an available deubiquitylase library which contains 31 members of USP family and identified that USP1 deubiquitylates BCAT2 at the K229 site. Furthermore, BCAA increases USP1 protein at the translational level via the GCN2-eIF2α pathway both in vitro and in vivo. More importantly, USP1 inhibition recedes cell proliferation and clone formation in PDAC cells and attenuates pancreas tumor growth in an orthotopic transplanted mice model. Consistently, a positive correlation between USP1 and BCAT2 is found in KC; LSL-KrasG12D/+ ; p53flox/+ ; Pdx1-Cre mice and clinical samples. Thus, a therapeutic targeting USP1-BCAT2-BCAA metabolic axis could be considered as a rational strategy for treatment of PDAC and precisive dietary intervention of BCAA has potentially translational significance.

BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma.

Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)1-4. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC3,4. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.

Mechanism of Non-receptor Tyrosine Kinase Src Regulating Neuroinflammation Through Phosphatase and Tensin Homology Protein in Microglia / 中国医学科学院学报

Objective To investigate the mechanism of non-receptor tyrosine kinase Src regulating neuroinflammation through phosphatase and tensin homology protein(PTEN)in microglia. Methods BV2 cells were incubated with PTEN inhibitor bpv(HOpic)for 2 hours,and then added with lipopolysaccharide(LPS)to induce neuroinflammation,Western blot was performed to determine the expression of phosphorylated protein kinase B(Akt)to investigate the activity of PTEN. Enzyme-linked immunosorben assay(ELISA)was used to determine the release of tumor necrosis factor α(TNF-α)to assess neuroinflammation.After PTEN inhibitor or Src specific small interfering RNA was added,the change of neuroinflammation was evaluated to study the mechanism of Src regulating neuroinflammation. Results LPS induced significant neuroinflammation in BV2 cells,as indicated by significantly increased expression of p-Akt and release of TNF-α(P<0.001).The PTEN inhibitor signficantly increased Akt phosphorylation(P<0.05)and TNF-α release(P<0.001)in LPS-induced BV2 cells compared to simply LPS-induced cells.The Src small interfering RNA significantly decreased the release of TNF-α(P<0.001)and inhibited PTEN(P<0.001)and Akt(P<0.001)phosphorylation. Conclusion Src kinase may regulate neuroinflammtion response in BV2 cells by regulating the phosphorylation of PTEN.

Relationship between disease progression of primary gastric cancer and preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio / 中国现代普通外科进展

Objective:To investigate The relationship between the disease progression of primary gastric cancer and preoperative neutrophil-to-lymphocyte ratio、platelet-to-lymphocyte ratio.Methods:A retrospective analysis of the clinical data of 188 cases treated in our hospital from April 2015 to February 2015 with primary gastric cancer.according to the peripheral venous blood NLR、PLR,analyze the relationship of NLR、PLR with different tumor infiltration depth、lymph node staging and TNM staging with statistical methods.Results:There is statistically significance of NLR、PLR between different groups (P＜0.01);tumor infiltration depth,lymph node staging and TNM stage of high NLR、PLR group in patients with gastric cancer were higher than low NLR、PLR group,the difference is statistically significant (P＜0.01);NLR is significantly positive correlated to PLR (r=0.379,P＜0.001);Multiple linear regression analysis shows the above factors had significant effects on preoperative NLR,PLR (P＜0.05).Conclusions:Preoperative peripheral blood NLR and PLR levels may be value in predicting the progression of gastric cancer,High preoperative NLR indicates later disease progression and worse prognosis.

Relationship between disease progression of primary gastric cancer and preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio / 中国现代普通外科进展

Objective:To investigate The relationship between the disease progression of primary gastric cancer and preoperative neutrophil-to-lymphocyte ratio、platelet-to-lymphocyte ratio.Methods:A retrospective analysis of the clinical data of 188 cases treated in our hospital from April 2015 to February 2015 with primary gastric cancer.according to the peripheral venous blood NLR、PLR,analyze the relationship of NLR、PLR with different tumor infiltration depth、lymph node staging and TNM staging with statistical methods.Results:There is statistically significance of NLR、PLR between different groups (P＜0.01);tumor infiltration depth,lymph node staging and TNM stage of high NLR、PLR group in patients with gastric cancer were higher than low NLR、PLR group,the difference is statistically significant (P＜0.01);NLR is significantly positive correlated to PLR (r=0.379,P＜0.001);Multiple linear regression analysis shows the above factors had significant effects on preoperative NLR,PLR (P＜0.05).Conclusions:Preoperative peripheral blood NLR and PLR levels may be value in predicting the progression of gastric cancer,High preoperative NLR indicates later disease progression and worse prognosis.

Protective effect of Danxuetong injection against testicular injury after testis torsion/detorsion in rats / 中华男科学杂志

<p><b>OBJECTIVE</b>To investigate the protective effect of Danxuetong injection (DXT, a combination of Danshen and Xueshuantong injections) against testicular ischemia-reperfusion injury following testis torsion/detorsion in rats.</p><p><b>METHODS</b>Thirty-two 4-week-old healthy male SD rats were randomly divided into four groups of equal number: sham operation, normal saline, single DXT injection, and successive DXT injection. The rat models of testicular ischemia-reperfusion injury were established by 2-hour 720-degree torsion/detorsion of the unilateral testis. At 6 weeks after modeling, the rats were killed and their testes were harvested for measure- ment of testicular coefficients, sperm counts, sperm motility, and the levels of total anti-oxidative capacity (T-AOC) , superoxide dismutase (SOD) , nitric oxide synthase (NOS) , and malondialdehyde ( MDA) in the testis tissue.</p><p><b>RESULTS</b>Compared with the rats of the normal saline group, those of the single DXT injection and successive DXT injection groups showed significant increases in the testicular coefficient (0.11 ± 0.03 vs 0.35 ± 0.04 and 0.40 ± 0.06, P < 0.05), sperm count ([0.46 ± 0.10] vs [1.44 ± 0.50] and [3.00 ± 1.28] x10(9)/ml, P < 0.05), sperm motility ([13.63 ± 14.04] vs [39.63 ± 5.04] and [76.31 ± 3.67]%, P < 0.05), the activity of SOD (72.76 ± 5.58 vs 116.25 ± 8.83 and 133.20 ± 13.84, P < 0.05), and the level of T-AOC (5.58 ± 1.07 vs 13.34 ± 5.81 and 19.21 ± 5.69, P < 0.05), but a remarkable decrease in the content of MDA (42.38 ± 8.94 vs 20.94 ± 5.65 and 15.02 ± 1.03, P < 0. 05) in the injured testes.</p><p><b>CONCLUSION</b>DXT can effectively rid the testis tissue of oxygen free radicals, improve sperm count and motility by antioxidation, and protect the testis tissue of prepubertal rats against testicular ischemia-reperfusion injury after testis torsion/detorsion. It also has a protective effect on the contralateral testis, and successive injection has a better effect than single injection of DXT.</p>

Comparison of effect between early and delayed in primary intramedullary nailing combined with locked plate fixation for the treatment of multi-segments tibial fractures of type / 中国骨伤

<p><b>OBJECTIVE</b>To compare the clinical results of early and delayed intramedullary nailing and locked plating for the treatment of multi-segments tibial fractures of type AO/ASIF-42C2.</p><p><b>METHODS</b>Between January 2010 and January 2013,45 patients with multi-segments closed tibial fractures of AO/ASIF-42C2 were treated by early primary intramedullary nailing and locked plating in 20 cases as early group and delayed in 25 cases as delayed group. In early group,20 cases included 13 males and 7 females with an average age of (37.9±14.3) years old ranging from 20 to 56 years;according to soft tissue injury Tscherne classification, 8 fractures were frade I,12 were grade II. In delayed group, 25 cases included 17 males and 8 females with an average age of (38.7±17.2) years old ranging from 24 to 55 years,4 fractures were grade I ,19 were grade II ,2 were grade III. The operative time, blood loss, hospital stay,fracture healing time and complications were recorded. At final follow-up, the Johner-Wruhs score were used to evaluate functional efficacy, and the posterior-anterior and lateral X-ray to evaluate fracture reduction and alignment.</p><p><b>RESULTS</b>All the patients were followed up for (12.5±2.5) months in early group and (13.2±2.8) months in delayed group (P>0.05). No wounds infections were happened. At the last follow-up, the mean range of knee joint was 10°-0°-120°. According to Johner-Wruhs scoring,there were 15 cases in excellent,3 in good,fair in 2 in early group; 21 in excellent,2 in good,2 in fair. The average operative time,blood loss had no significant differences between two groups (P>0.05), but hospital stay in early group was significantly shorter than those in delayed group(P<0.05). Average fracture healing time of early group and delayed group were (5.3±2.6) months and (6.0±2.9) months, respectively (P>0.05).</p><p><b>CONCLUSION</b>For multi-segments tibial fractures of type AO/ASIF-42C2 with preoperative minor soft tissue injuries lighter of Tscherne grade I or II, early primary intramedullary nailing and locked plating does not significantly increase the postoperative incidence of soft tissue complications for patients. The early and delayed primary intramedullary nailing and locked plating for treatment of AO/ASIF-42C2 proximal third tibial fractures can get similar curative effect.</p>

The role of heat shock protein 70 in regulating neuroinflammation / 药学学报

Neurodegenerative disease is characterized by progressive loss of neurons in specific brain regions that results in neuronal dysfunction of the central nervous system. Although the pathological mechanism is not fully established, the activation of glial cells mediated neuroinflammation appears to be involved. Heat shock protein 70 (HSP70) is originally described as intracellular chaperone, which plays an important role in protein quality control in cells. However, recent study showed that up-regulation of HSP70 had anti-inflammatory effects in the brain. HSP70 protected neurons from damage and improved neurological function by decreasing inflammatory response as indicated by inactivation of glial cells and inhibition of pro-inflammatory cytokine release. So it is of great significance to find new compounds targeting at HSP70 as neuroprotective agents to delay the progress of neurodegenerative disease. This review will focus on the role of HSP70 in neuroinflammation and the recent advances in using HSP70 as a target for the treatment of neurodegenerative disease.