High dose isoleucine stabilizes nuclear PTEN to suppress the proliferation of lung cancer.

PURPOSE: Cancer cells require a supply of amino acids, particularly essential amino acids such as branched-chain amino acids (BCAAs, i.e., valine, leucine, and isoleucine), to meet the increased nutrient demands of malignant tumors. The cell-autonomous and non-autonomous roles of altered BCAA supply have been implicated in cancer progression. The critical proteins involved in BCAA uptake, transport, metabolism, etc. serve as potential therapeutic biomarkers in human cancers. Here, we summarize the potential anti-tumor mechanism of BCAA by exploring the chain reaction triggered by increased BCAA supply in the tumor. METHOD: A system-wide strategy was employed to provide a generic solution to establish the links between BCAA and cancer based on comprehensive omics, molecular experimentation, and data analysis. RESULTS: BCAA over-supplementation (900 mg/kg) significantly inhibited tumor growth and reduced tumor burden, with isoleucine having the most pronounced effect. Surprisingly, isoleucine inhibited tumor growth independently of mTORC1 activation, a classical amino acid sensor. Exploratory transcriptome analysis revealed that Phosphatase and tensin homolog (PTEN) is the critical factor in the anti-tumor effect of isoleucine. By inhibiting PTEN ubiquitination, isoleucine can promote PTEN nuclear import and maintain PTEN nuclear stability. Interestingly, this process was regulated by isoleucine-tRNA ligase, cytoplasmic (IARS), a direct target of isoleucine. We demonstrated the enhanced interaction between IARS and PTEN in the presence of excess isoleucine. At the same time, IARS knockout leads to loss of isoleucine tumor suppressor ability. CONCLUSION: Overall, our results provide insights into the regulation of the IARS-PTEN anti-tumor axis by isoleucine and reveal a unique therapeutic approach based on enhancing cellular isoleucine supply.

[Differentially expressed proteins of severe acute pancreatitis intervened by Qingyi granule].

OBJECTIVE: To observe the effects of Qingyi Granule (QYG) on the changes of total protein expressions in the pancreatic tissue of rats with severe acute pancreatitis (SAP) induced by sodium taurocholate (STC). METHODS: SAP was induced by retrograded injecting 5% STC from the gut-pancreatic duct in 36 Sprague-Dawley (SD)rats. Then they were randomly divided into the SAP group and the QYG treatment group (abbreviated as the QYG group), 18 in each group. After successful modeling, rats in the QYG group were administered with QYG water solution (W: W = 1:1) once with an interval of 12 h (1 mL/100 g), while rats in the SAP group were administered with normal saline. The medication was performed four times. The total proteins were extracted from the pancreatic tissue of all rats to perform two-dimensional electrophoresis, fluorescent staining, and atlas analysis. The protein dots with differential expressions more than four times between each other in 48 h gel pictures were chosen and used for MALDI-TOF/TOF mass chromatographic analysis and biological information analysis. RESULTS: The 5% STC induced SAP model rats had typical pathological changes in the pancreatic tissue. The proteomics changes of the pancreatic tissue were analyzed by gel image manipulation software. Twenty two disparate points were detected between two groups at 48 h, 5 points of the protein were up-regulated and 17 points were down-regulated of the total after QYG intervention. Nine protein spots expressed differently more than 4 times and stably at 48 h, 7 kinds of proteins have been identified by mass chromatographic analysis and Data Base Retrieval, and they were Serpinb1a 39 kDa protein, Serpinb1a 43 kDa protein, Prdx4 Prx IV, Clps, gamma-actin (Actg1), Eprs and Hadhsc. Those proteins were involved in signal transmit during the process of SAP pancreas--pathological injury analyzed from their functions. CONCLUSIONS: Proteomics can well reflect the effects of QYG on differential expression proteins in the pancreatic tissue of rats with SAP. Studying differential expression proteins may provide a new theoretical basis and molecule target for QYG treating SAP.

[Activation of nuclear factor-kappa B and its modulalorg effects on intercellular adhesion molecule-1 expression in mice with dextran sulphate sodium-induced rat colitis].

OBJECTIVE: To investigate the changes in the activity of nuclear factor-kappaB (NF-kappa B) in mice with dextran sulphate sodium (DSS)-induced rat colitis and its modulalorg effect on intercellular adhesion molecule-1 (ICAM-1) expression. METHODS: Twenty normal male mice were randomized into DSS group and normal saline (NS) control group according to a matched-pair design. From days 1 to 7, the mice in DSS group were subjected to oral administration of 5%DSS solution, and from days 8 to 20, NS was given instead, for a total of 3 cycles. In the control group, only NS was administered. The colonic pathology was observed using HE staining and the mucosa 1 damage was scored for each mouse. The DNA-binding activity of NF-kappa B was tested by electrophoretic mobility shift assay, and the expressions of ICAM-1 and NF-kappa B p65 were detected using immunohistochemistry. RESULTS: The DNA-binding activity of NF-kappa B was significantly increased in DSS group as compared with NS group. ICAM-1 and p65 expressions were detected in the nuclei of the vascular endothelial and inflammatory cells, especially in the mucosa and submucosa, but such positive cells were seldom observed in NS group. A positive correlation was found between the DNA-binding activity of NF-kappa B and ICAM-1 expression. CONCLUSION: NF-kappa B activation is an important event in the development of DSS-induced colitis in that activated NF-kappa B upregulates ICAM-1 expression during colonic inflammation.

A case-control study on children with Guillain-Barre syndrome in North China.

OBJECTIVE: To explore the risk factors for Guillain-Barre syndrome. METHODS: Case-control study design was used in 51 cases of Guillain-Barre syndrome, and 51 matched controls. All of the 51 cases in this study had been examined by electrophysiology. Serum IgG antibodies specific for C. jejuni were determined in all the subjects by ELISA. Each case and control were interviewed using an ad hoc questionnaire, including his/her demographic information, onset of the illness, their personal hygiene and so on. RESULTS: The study showed that Guillain-Barre syndrome was associated with a few factors, such as polio vaccine immunization before onset of illness (OR=7.27), no hand washing after defecation and before meals (OR=6.15). Infection of C. jejuni was strongly associated with the illness (OR=9.5, P<0.001). CONCLUSION: It is suggested that occurrence of Guillain-Barre syndrome may correlate to infection of C. jejuni and poor personal hygiene in children.