Structural and Functional Insights into PpgL, a Metal-Independent ß-Propeller Gluconolactonase That Contributes to Pseudomonas aeruginosa Virulence.

Biofilm formation is a critical determinant in the pathopoiesis of Pseudomonas aeruginosa It could significantly increase bacterial resistance to drugs and host defense. Thus, inhibition of biofilm matrix production could be regarded as a promising attempt to prevent colonization of P. aeruginosa and the subsequent infection. PpgL, a periplasmic gluconolactonase, has been reported to be involved in P. aeruginosa quorum-sensing (QS) system regulation. However, the detailed function and catalysis mechanism remain elusive. Here, the crystal structure of PpgL is described in the current study, along with biochemical analysis, revealing that PpgL is a typical ß-propeller enzyme with unique metal-independent lactone hydrolysis activity. Consequently, comparative analysis of seven-bladed propeller lactone-catalyzing enzymes and mutagenesis studies identify the critical sites which contribute to the diverse catalytic and substrate recognition functions. In addition, the reduced biofilm formation and attenuated invasion phenotype resulting from deletion of ppgL confirm the importance of PpgL in P. aeruginosa pathogenesis. These results suggest that PpgL is a potential target for developing new agents against the diseases caused by P. aeruginosa.

Mechanistic insights into the allosteric regulation of Pseudomonas aeruginosa aspartate kinase.

In plants and microorganisms, aspartate kinase (AK) catalyzes an initial commitment step of the aspartate family amino acid biosynthesis. Owing to various structural organizations, AKs from different species show tremendous diversity and complex allosteric controls. We report the crystal structure of AK from Pseudomonas aeruginosa (PaAK), a typical α2ß2 hetero-tetrameric enzyme, in complex with inhibitory effectors. Distinctive features of PaAK are revealed by structural and biochemical analyses. Essentially, the open conformation of Lys-/Thr-bound PaAK structure clarifies the inhibitory mechanism of α2ß2-type AK. Moreover, the various inhibitory effectors of PaAK have been identified and a general amino acid effector motif of AK family is described.

[Research progress of mitochondrial fission and fusion related proteins].

Mitochondria are an essential component of multicellular life and play important roles in the health of the cells and the body. Mitochondria can produce energy by oxidative phosphorylation, mediate calcium and reactive oxygen signal transduction, and regulate cell apoptosis. Recent studies indicate that mitochondria continually change their shapes and distribution by fission and fusion, which are collectively termed mitochondrial dynamics. Mitochondrial dynamics play critical roles in maintaining mitochondrial function. This review focuses on the structure and biological functions of mitochondrial fission and fusion related proteins in mammal cells.

Multi-omics characterization of the unsaturated fatty acid biosynthesis pathway in colon cancer.

The biosynthesis of unsaturated fatty acids is involved in the initiation and progression of colon adenocarcinoma (COAD). In this study, we aimed to investigate the multi-omics characteristics of unsaturated fatty acid biosynthesis-related genes and explore their prognostic value in colon cancer by analyzing the data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. An unsaturated fatty acid biosynthesis pathway related-genes enrichment score (BUFAS) was constructed utilizing the single sample gene set enrichment analysis (ssGSEA). We discovered that a high BUFAS was associated with longer overall survival (OS) in both the training and the validation sets. Multivariable analysis including the clinical characteristics further verified the independent prognostic value of the BUFAS in both the TCGA-COAD and the GSE39582 datasets. In addition, GSEA analysis revealed that BUFAS was positively associated with several signaling pathways, including MTORC1, peroxisome, and pathways related to fatty acid metabolism, while was negatively associated with other signaling pathways, such as hedgehog, NOTCH, and Wnt/beta-catenin pathway. Furthermore, in the COAD cell lines of the Genomics of Drug Sensitivity in Cancer (GDSC) database, we found that BUFAS was positively correlated with the drug sensitivities of cisplatin, gemcitabine, camptothecin, lapatinib, and afatinib, while was negatively correlated with that of ponatinib. Moreover, in the COAD single-cell transcriptomic dataset (GSE146771), the BUFAS varied among different cell types and was enriched in mast cells and fibroblasts. Taken together, the BUFAS we constructed could be used as an independent prognostic signature in predicting the OS and drug resistance of colon cancer. Unsaturated fatty acid biosynthesis pathway might serve as potential therapeutic targets for cancer treatment.

The P275A Polymorphism in the Macrophage Scavenger Receptor 1 Gene and Prostate Cancer Risk: a Meta-Analysis.

BACKGROUND: Published data regarding associations between the P275A polymorphism in the macrophage scavenger receptor 1 (MSR1) gene and prostate cancer (PCa) risk are inconclusive. The aim of this study was to comprehensively evaluate the genetic risk of P275A polymorphism in MSR1 gene for PCa. MATERIALS AND METHODS: A systematic literature search was carried out in Pubmed, Medline (Ovid), Embase, CBM, CNKI, Weipu, and Wanfang databases, covering all available publications (last search was performed on Apr 27, 2015). Statistical analysis was performed using Revman 5.2 and STATA 10.1 software. RESULTS: A total of 5,017 cases and 4,869 controls in 12 case-control studies were included in this meta-analysis. When all groups were pooled, there was no evidence that the P275A polymorphism had a significant association with PCa under dominant (OR=0.93, 95%CI=0.81-1.06, and p=0.28), co-dominant (homogeneous OR=0.97, 95%CI=0.56-1.68, and p=0.92; heterogeneous OR=0.93, 95%CI=0.74-1.15, and p=0.49), recessive (OR=1.10, 95%CI=0.65-1.87, and p=0.73), over-dominant (OR=0.93, 95%CI=0.75-1.15, and p=0.50), and allelic (OR=0.95, 95%CI=0.77-1.16, and p=0.61) genetic models. For stratified analyses by ethnicity and study design, no significant associations were found in the white race, the yellow race, the black race and mixed ethnicity, and the population-based case-control (PCC) and hospital-based case-control (HCC) studies under all genetic models. CONCLUSIONS: Based on our meta-analysis, the P275A polymorphism in the MSR1 gene is unlikely to be a risk factor for PCa.

Effects of triterpenic acid from Prunella vulgaris L. on glycemia and pancreas in rat model of streptozotozin diabetes.

BACKGROUND: The effects of triterpenic acid from Prunella vulgaris L. (TAP) on diabetes and its mechanism are uncertain. The aim of this study was to investigate the effects of TAP on antihyperglycemic, antioxidant, and pancreas-protective in streptozotozin (STZ)-diabetic rats. METHODS: The diabetic model was produced by injection of 60 mg/kg STZ. Blood was drawn from the tail vein of rats after 72 hours. Rats with blood glucose ≥ 16.7 mmol/L were considered diabetic. Diabetic rats were randomly divided into four groups: (1) Diabetes rat (STZ), (2) Diabetic rats treated with 50 mg/kg of triterpenic acid from Prunella vulgaris L (STZ + TAP50), (3) Diabetic rats treated with 100 mg/kg TAP (STZ + TAP100), and (4) Diabetic rats treated with 200 mg/kg TAP (STZ + TAP200). Normal rats (n = 10) acted as the control group (NC). TAP was administered by the intragastric route once each day for six weeks. Body weight and the concentration of blood glucose (BG) were measured after three and six weeks. Fructosamine (FMN), malondialdehyde (MDA), and nitric oxide (NO), and the activities of nitric oxide synthase (NOS) and superoxide dismutase (SOD) in serum were determined after six weeks using commercially available kits following the manufacturer's instructions. Pathologic changes in pancreatic ß-cells were also investigated by microscopic examination after hematoxylin-eosin (HE) staining. The level of SOD mRNA in pancreatic ß-cells was measured by polymerase chain reaction (PCR). RESULTS: The levels of BG, FMN, NO, and MDA and the activities of NOS in serum in the four diabetes groups were significantly increased compared with the control group (P < 0.01). The activity of SOD in serum and the body weight was significantly decreased compared with the control group (P < 0.01). After administration of TAP to diabetic rats for six weeks, the body weight and the levels of BG, FMN, MDA, NO and the activity of NOS in serum decreased significantly compared with the STZ group in a dose-dependent manner. The activity of SOD in serum and body weight increased significantly compared with the STZ group in a dose-dependent manner. In addition, diabetic rats showed a significant decrease in SOD mRNA expression in pancreatic ß cells. However, these changes were reversed by TAP. Histopathological examination also showed the protective effect of TAP on pancreatic ß cells. CONCLUSIONS: Triterpenic acid from Prunella vulgaris L. has an anti-diabetic effect, by controlling blood glucose and antioxidants, and has a protective effect on the pancreas.