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Advanced glycoxidation end products (AGEs) are implicated in delayed diabetic wound healing. To test the role of diet-derived AGE on the rate of wound healing, we placed female db/db (؉/؉) (n ‫؍‬ 55, 12 weeks old) and age-matched control db/db (؉/؊) mice (n ‫؍‬ 45) on two diets that differed only in AGE content (high [H-AGE] versus low [L-AGE] ratio, 5:1) for 3 months. Full-thickness skin wounds (1 cm) were examined histologically and for wound closure. Serum 24-h urine and skin samples were monitored for N ⑀ -carboxymethyl-lysine and methylglyoxal derivatives by enzyme-linked immunosorbent assays. L-AGE-fed mice displayed more rapid wound closure at days 7 and 14 (P < 0.005) and were closed completely by day 21 compared with H-AGE nonhealed wounds. Serum AGE levels increased by 53% in H-AGE mice and decreased by 7.8% in L-AGE mice (P < 0.04) from baseline. L-AGE mice wounds exhibited lower skin AGE deposits, increased epithelialization, angiogenesis, inflammation, granulation tissue deposition, and enhanced collagen organization up to day 21, compared with H-AGE mice. Reepithelialization was the dominant mode of wound closure in H-AGE mice compared with wound contraction that prevailed in L-AGE mice. Thus, increased diet-derived AGE intake may be a significant retardant of wound closure in diabetic mice; dietary AGE restriction may improve impaired diabetic wound healing. Diabetes 52:2805-2813, 2003 W ound healing is impaired in diabetes and constitutes a major cause for increased morbidity and mortality in patients with diabetes (1). The majority of nonhealing wounds often lead to amputation. The percentage of amputees increases with age as do the direct costs of their care, rehabilitation, and lost productivity (2) The exact cellular and molecular mechanisms underlying the pathogenesis of this complication are not fully elucidated (3,4). However, a number of hyperglycemiadependent factors have been identified, including the progressive accumulation of advanced glycation end products (AGEs) (5).Two well characterized compounds, N ⑀ -carboxymethyllysine (CML) and methylglyoxal (MG), derivatives of glucoseprotein or glucose-lipid interactions, serve as markers for AGE in a wide range of disorders related to diabetes, renal failure, and aging (6 -8). According to recent observations, AGEs can be introduced in the body by exogenous sources such as diet and possibly in amounts that exceed those caused by hyperglycemia alone. A direct correlation is shown between the amount of AGEs consumed and that found in the circulation (9,10). In vitro data show that food-derived AGEs, which include CML and MG derivatives, can mimic the actions of endogenously formed AGEs and can induce intracellular oxidative stress and inflammatory cell activation, in a manner reversible by antioxidants or anti-AGE agents (11). Animal studies have revealed a significant contribution to the total AGE pool and related pro-oxidant or proinflammatory processes by dietary AGE intake, including tissue damage; this seems to be preventable by restric...

In today’s global economy, manufacturing enterprises must be viewed in the context of their contribution to the total value chain. Extended or virtual enterprises, consisting of tele‐computing mediated chains of suppliers, manufacturers, assemblers, distributors and customers, compete to supply quasi‐customised products to discerning markets. This paper reviews the thinking behind the extended enterprise and virtual enterprise models of manufacturing systems, identifies the characteristics of each and the similarities and differences between them.

MaR1 is a therapeutic target for RA, likely operating through effects on the imbalanced Treg/Th17 ratio found in the disease.

Metabolic reprogramming is critical for the polarization and function of tumor-associated macrophages (TAM) and hepatocarcinogenesis, but how this reprogramming occurs is unknown. Here, we showed that receptor-interacting protein kinase 3 (RIPK3), a central factor in necroptosis, is downregulated in hepatocellular carcinoma (HCC)-associated macrophages, which correlated with tumorigenesis and enhanced the accumulation and polarization of M2 TAMs. Mechanistically, RIPK3 deficiency in TAMs reduced reactive oxygen species and significantly inhibited caspase1-mediated cleavage of PPAR. These effects enabled PPAR activation and facilitated fatty acid metabolism, including fatty acid oxidation (FAO), and induced M2 polarization in the tumor microenvironment. RIPK3 upregulation or FAO blockade reversed the immunosuppressive activity of TAMs and dampened HCC tumorigenesis. Our findings provide molecular basis for the regulation of RIPK3-mediated, lipid metabolic reprogramming of TAMs, thus highlighting a potential strategy for targeting the immunometabolism of HCC.

Receptor-interacting protein kinase 3 (RIPK3) is essential for mucosal repair in inflammatory bowel diseases (IBD) and colorectal cancer. However, its role in tumor immunity is unknown. Here, we report that decreased RIPK3 in colorectal cancer correlates with the accumulation of myeloid-derived suppressor cells (MDSC). Deficiency of RIPK3 boosted tumorigenesis via accumulation and immunosuppressive activity of MDSCs. Reduction of RIPK3 in MDSC and colorectal cancer cells elicited NFκB-transcribed COX-2, which catalyzed the synthesis of prostaglandin E (PGE). PGE exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE suppressed RIPK3 expression while enhancing expression of NFκB and COX-2 in MDSCs and colorectal cancer cells. Inhibition of COX-2 or PGE receptors reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. Patient databases also delineated the correlation of RIPK3 and COX-2 expression with colorectal cancer survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE regulate tumor immunity, providing potential ideas for immunotherapy against colorectal cancer. A novel signaling circuit involving RIPK3 and PGE enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in anticancer immunotherapy. http://cancerres.aacrjournals.org/content/canres/78/19/5586/F1.large.jpg .