gamma-Glutamyl transpeptidase (GGT) is the only enzyme known that can cleave the gamma-peptide bond between glutamate and cysteine in glutathione, and is therefore a key step in glutathione degradation. There are three functional GGT genes in Arabidopsis, two of which are considered here. GGT1 and GGT2 are apoplastic, associated with the plasma membrane and/or cell wall. RNA blots and analysis of enzyme activity in knockout mutants suggest that GGT1 is expressed most strongly in leaves but is found throughout the plant. A GGT1::GUS fusion construct showed expression only in vascular tissue, specifically the phloem of the mid-rib and minor veins of leaves, roots and flowers. This localization was confirmed in leaves by laser microdissection. GGT2 expression is limited to embryo, endosperm, outer integument, and a small portion of the funiculus in developing siliques. The ggt2 mutants had no detectable phenotype, while the ggt1 knockouts were smaller and flowered sooner than wild-type. In ggt1 plants, the cotyledons and older leaves yellowed early, and GSSG, the oxidized form of glutathione, accumulated in the apoplastic space. These observations suggest that GGT1 is important in preventing oxidative stress by metabolizing extracellular GSSG, while GGT2 might be important in transporting glutathione into developing seeds.

The degradation pathway of glutathione (GSH) in plants is not well understood. In mammals, GSH is predominantly metabolized through the g-glutamyl cycle, where GSH is degraded by the sequential reaction of g-glutamyl transpeptidase (GGT), g-glutamyl cyclotransferase, and 5-oxoprolinase to yield glutamate (Glu) and dipeptides that are subject to peptidase action. In this study, we examined if GSH is degraded through the same pathway in Arabidopsis (Arabidopsis thaliana) as occurs in mammals. In Arabidopsis, the oxoprolinase knockout mutants (oxp1-1 and oxp1-2) accumulate more 5-oxoproline (5OP) and less Glu than wild-type plants, suggesting substantial metabolite flux though 5OP and that 5OP is a major contributor to Glu steady-state levels. In the ggt1-1/ggt4-1/oxp1-1 triple mutant with no GGT activity in any organs except young siliques, the 5OP concentration in leaves was not different from that in oxp1-1, suggesting that GGTs are not major contributors to 5OP production in Arabidopsis. 5OP formation strongly tracked the level of GSH in Arabidopsis plants, suggesting that GSH is the precursor of 5OP in a GGT-independent reaction. Kinetics analysis suggests that g-glutamyl cyclotransferase is the major source of GSH degradation and 5OP formation in Arabidopsis. This discovery led us to propose a new pathway for GSH turnover in plants where GSH is converted to 5OP and then to Glu by the combined action of g-glutamyl cyclotransferase and 5-oxoprolinase in the cytoplasm.

In 2012, the National Central Cancer Registry (NCCR) of China collected cancer registration information for the year 2009 from local cancer registries and analyzed it to describe the incidences and mortalities of cancers in China. Based on the data quality criteria from NCCR, data from 104 registries covering 85,470,522 people (57,489,009 in urban areas and 27,981,513 in rural areas) were checked and evaluated. The data from 72 registries were qualified and accepted for the cancer registry annual report in 2012. The total cancer incident cases and cancer deaths were 244,366 and 154,310, respectively. The morphologically verified cases accounted for 67.23%, and 3.14% of the incident cases only had information from death certifications. The crude incidence in the Chinese cancer registration areas was 285.91/100,000 (317.97/100,000 in males and 253.09/100,000 in females). The age-standardized rates for incidences based on the Chinese standard population (ASRIC) and the world standard population (ASRIW) were 146.87/100,000 and 191.72/100,000, respectively, with a cumulative incidence of 22.08%. The cancer mortality in the Chinese cancer registration areas was 180.54/100,000 (224.20/100,000 in males and 135.85/100,000 in females). The age-standardized rates for mortalities based on the Chinese standard population (ASRMC) and the world standard population (ASRMW) were 85.06/100,000 and 115.65/100,000, respectively, and the cumulative mortality was 12.94%. Lung cancer, gastric cancer, colorectal cancer, liver cancer, esophageal cancer, pancreatic cancer, encephaloma, lymphoma, female breast cancer, and cervical cancer were the most common cancers, accounting for 75% of all cancer cases. Lung cancer, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, pancreatic cancer, breast cancer, encephaloma, leukemia, and lymphoma accounted for 80% of all cancer deaths. The cancer registration's population coverage has been increasing, and its data quality is improving. As the basis of the cancer control program, the cancer registry plays an important role in directing anticancer strategies in the medium and long term. Because cancer burdens are different in urban and rural areas in China, prevention and control efforts should be based on practical situations.

Pancreatic cancer has the lowest survival rate among human cancers, and there are no effective markers for its screening and early diagnosis. To identify genetic susceptibility markers for this cancer, we carried out a genome-wide association study on 981 individuals with pancreatic cancer (cases) and 1,991 cancer-free controls of Chinese descent using 666,141 autosomal SNPs. Promising associations were replicated in an additional 2,603 pancreatic cancer cases and 2,877 controls recruited from 25 hospitals in 16 provinces or cities in China. We identified five new susceptibility loci at chromosomes 21q21.3, 5p13.1, 21q22.3, 22q13.32 and 10q26.11 (P = 2.24 × 10(-13) to P = 4.18 × 10(-10)) in addition to 13q22.1 previously reported in populations of European ancestry. These results advance our understanding of the development of pancreatic cancer and highlight potential targets for the prevention or treatment of this cancer.

Summary c-Glutamyl transpeptidase (GGT) is the enzyme responsible for breaking the c-glutamyl bond between Glu and Cys in glutathione (GSH). We are using this gene family to study GSH degradation in plants. There are four putative GGT genes in Arabidopsis, and one of them, GGT3 (At4g29210), is analyzed in this study. GGT3 is localized to the vacuole based on organelle-targeting programs, subcellular distribution of GFP fusion proteins during transient expression in onion (Allium cepa) epidermal tissues, and its ability to metabolize vacuolar substrates in Arabidopsis plants. While Northern blots and promoter:GUS expression patterns have suggested that GGT3 is transcribed at relatively high levels in all parts of the plant, a comparison of enzyme activities in different organs of wild-type and a ggt3 knockout mutant showed that GGT3 was a major contributor to total GGT activity in roots, but a relatively minor contributor in other tissues. Wild-type Arabidopsis plants treated with monobromobimane (mBB) form a fluorescent GSH-mBB conjugate that is moved into the vacuole and then metabolized to Cys-Gly-mBB and Cys-mBB in that order. The first step is catalyzed by GGT3, and GSHmBB metabolism is completely blocked in the roots of ggt3 knockout plants. In ggt3 leaves, some GSH-mBB metabolism still proceeds using the apoplastic GGT1. This identifies GGT3 as catalyzing the obligate initial step in GSH conjugate metabolism, and suggests that it has an important role in protecting plants from some xenobiotic chemicals.

AIM:To investigate the expression of annexin I in pancreatic cancer and its relationship with the clinicopathologic factors, and to evaluate its potential clinical significance.

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Isoflurane preconditioning induces neuroprotection in neonatal rats. This neuroprotection is inducible nitric oxide synthase-dependent.