No abstract

Pancreatic carcinoma, a leading cause of cancer death, is thought to develop out of pancreatic intraepithelial neoplasia (PanIN). PanIN lesions have not yet attained the fully malignant phenotype, but show increased proliferation and dysplasia, and frequently bear an oncogenic KRAS mutation. Pancreatic cancer development is associated with increased activity of the transcription factor NF-κB. NEMO (IKKγ) is a subunit of the IKK complex essential for the activation of canonical NF-κB signaling and has been ascribed both oncogenic and tumor-suppressive roles in gastrointestinal tumors. Here, we wanted to address the function of NEMO in pancreatic tumorigenesis. We therefore conditionally ablated NEMO in a mouse model for pancreatic carcinoma based on the expression of oncogenic KRAS in pancreatic precursor cells. Mice were analyzed for PanIN lesions and for the activation of associated signaling pathways. NEMO ablation in the pancreas, while in itself not causing any overt pathology, led to a drastic (>93%) decrease in the prevalence of both low-grade and high-grade PanIN in 10-month-old mice expressing oncogenic KRAS. Also, the inflammatory and fibrotic response associated with KRAS action in the pancreas was virtually abolished, including expression of inflammatory cytokines and activation of the interleukin-6/STAT3 axis. Moreover, the activation of MAPK signaling, Notch and KLF4 signaling normally observed in KRAS-induced PanIN was strongly reduced or absent when NEMO was ablated. Our study suggests that NEMO, an IKK subunit necessary for canonical NF-κB activation, is dispensable for normal pancreatic development and function, but essential for the propagation of KRAS-induced PanIN lesions.

A novel series of thiazole-based heterocycles was synthesized using 1,3-dipolar cycloaddition reactions in the presence of chitosan-grafted-poly(vinylpyridine) as an eco-friendly biopolymeric basic catalyst. The molecular structure of the synthesized compounds was illustrated by spectroscopic and elemental analysis. Various in vitro biological assays were performed to explore the potential antitumor, antimicrobial and hepatoprotective activities of the newly synthesized compounds. The cytotoxic activities were assessed against human hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116) and breast cancer (MCF-7) cell lines and results revealed that all compounds displayed antitumor activities with the chlorine-containing derivatives, 11c and 6g, being the most potent. The majority of the tested thiazole derivatives exhibited satisfactory antibacterial activity towards the used gram positive and gram-negative bacterial species. Moreover, many derivatives showed weak hepatoprotective activity against CCl4-induced hepatotoxicity.

Type 1 diabetes is a multifactorial inflammatory disease in genetically susceptible individuals characterized by progressive autoimmune destruction of pancreatic b-cells initiated by yet unknown factors. Although animal models of type 1 diabetes have substantially increased our understanding of disease pathogenesis, heterogeneity seen in human patients cannot be reflected by a single model and calls for additional models covering different aspects of human pathophysiology. Inhibitor of kB kinase (IKK)/nuclear factor-kB (NF-kB) signaling is a master regulator of inflammation; however, its role in diabetes pathogenesis is controversially discussed by studies using different inhibition approaches. To investigate the potential diabetogenic effects of NF-kB in b-cells, we generated a gain-of-function model allowing conditional IKK2/NF-kB activation in b-cells. A transgenic mouse model that expresses a constitutively active mutant of human IKK2 dependent on Pdx-1 promoter activity (IKK2-CA Pdx-1 ) spontaneously develops full-blown immunemediated diabetes with insulitis, hyperglycemia, and hypoinsulinemia. Disease development involves a gene expression program mimicking virus-induced diabetes and allergic inflammatory responses as well as increased major histocompatibility complex class I/II expression by b-cells that could collectively promote diabetes development. Potential novel diabetes candidate genes were also identified. Interestingly, animals successfully recovered from diabetes upon transgene inactivation. Our data give the first direct evidence that b-cell-specific IKK2/NF-kB activation is a potential trigger of immune-mediated diabetes. Moreover, IKK2-CA Pdx-1 mice provide a novel tool for studying critical checkpoints in diabetes pathogenesis and mechanisms governing b-cell degeneration/ regeneration. Diabetes 2014;63:960-975 | DOI: 10.233763:960-975 | DOI: 10. /db13-1037 Type 1 diabetes is an autoimmune disease in genetically predisposed individuals and presumably triggered and/or accelerated by environmental factors (1). Analyses of animal models of type 1 diabetes have greatly improved our knowledge about disease pathophysiology and genetic contribution. However, there is still an unmet need to understand islet cell pathology and ongoing inflammatory processes within the islets of Langerhans.

New ecofriendly Biginelli reaction procedures have been adapted to prepare new dihydropyrimidines (DHPMs) using a multicomponent one-pot reaction. All the synthesized compounds were evaluated for their anticancer activity against 59 human cancer cell lines and evaluated for their antimicrobial activities against representatives of both Gram-positive and Gram-negative bacteria. Compound 4 showed marked wide spectrum anticancer activity towards most of the tested cancer cell lines with a percentage of growth inhibition of 29.04-71.68% against leukemia cell line (K-562 and SR), lung cancer cell line (NCI-H522), five colon cancer cell lines (HCT-116, HCT-15, HT29, KM12 and SW-620), CNS cancer cell line (SF-295 and SNB-75), melanoma cell lines (MALME-3M and M14), renal cancer cell line (CAKI-1) and breast cancer cell lines (MCF7 and MDA-MB-468). The highest observed anticancer activity was against leukemia cell lines K-562 and SR with inhibition percentages of 64.97 and 71.68%, respectively. The renal cancer cell line (UO-31) was particularly sensitive towards all the evaluated compounds. Compounds including 2b and 5c exhibited antibacterial activity against S. aureus while 2a and 5b exhibited antifungal activity against C. albicans. The results also showed that compounds 2c and 5e exhibited both antibacterial and antifungal activity against S. aureus and C. albicans respectively.

Diabetes is a major health problem that is associated with high risk of various complications. Medicinal plants hold great promise against diabetes. The traditional use of Cleome droserifolia as an antidiabetic agent was correlated to its flavonol glycosides content. In the current study, five major flavonol glycosides appeared on the RP-HPLC chromatogram of the aqueous extract namely; quercetin-3-O-β-d-glucosyl-7-O-α-rhamnoside (1), isorhamnetin-7-O-β-neohesperidoside (2), isorhamnetin-3-O-β-d-glucoside (3) kaempferol-4′-methoxy-3,7-O-α-dirhamnoside (4), and isorhamnetin-3-O-α-(4″-acetylrhamnoside)-7-O-α-rhamnoside (5). The inhibitory activities of these compounds were tested in vitro against several enzymes involved in diabetes management. Only the relatively less polar methoxylated flavonol glycosides (4, 5) showed mild to moderate α-amylase and α-glucosidase inhibitory activities. Compounds 1–4 displayed remarkable inhibition of dipeptidyl peptidase IV (DPPIV) enzyme (IC50 0.194 ± 0.06, 0.573 ± 0.03, 0.345 ± 0.02 and 0.281 ± 0.05 µg/mL, respectively) comparable to vildagliptin (IC50 0.154 ± 0.02 µg/mL). Moreover, these compounds showed high potential in preventing diabetes complications through inhibiting aldose reductase enzyme and combating oxidative stress. Both isorhamnetin glycoside derivatives (2, 3) exhibited the highest activities in aldose reductase inhibition and compound 2 (IC50 5.45 ± 0.26 µg/mL) was even more potent than standard quercetin (IC50 7.77 ± 0.43 µg/mL). Additionally, these flavonols exerted excellent antioxidant capacities through 2, 2-diphenyl-1-picrylhydrazil (DPPH) and ferric reducing antioxidant (FRAP) assays.

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Maturity-onset diabetes of the young (MODY) is a group of monogenetic forms of diabetes mellitus caused by mutations in genes regulating β-cell development and function. MODY represents a heterogeneous group of non-insulin-dependent diabetes arising in childhood or adult life. Interestingly, clinical heterogeneity in MODY patients like variable disease onset and severity is observed even among individual family members sharing the same mutation, an issue that is not well understood. As high blood glucose levels are a well-known factor promoting β-cell stress and ultimately leading to cell death, we asked whether additional β-cell stress might account for the occurrence of disease heterogeneity in mice carrying a MODY4 mutation. In order to challenge β-cells, we established a MODY4 animal model based on Pdx1 (pancreatic and duodenal homeobox 1) haploinsufficiency, which allows conditional modulation of cell stress by genetic inhibition of the stress-responsive IKK/NF-κB signalling pathway. While Pdx1+/− mice were found glucose intolerant without progressing to diabetes, additional challenge of β-cell function by IKK/NF-κB inhibition promoted rapid diabetes development showing hyperglycaemia, hypoinsulinemia and loss of β-cell mass. Disease pathogenesis was characterized by deregulation of genes controlling β-cell homeostasis and function. Importantly, restoration of normal IKK/NF-κB signalling reverted the diabetic phenotype including normalization of glycaemia and β-cell mass. Our findings implicate that the avoidance of additional β-cell stress can delay a detrimental disease progression in MODY4 diabetes. Remarkably, an already present diabetic phenotype can be reversed when β-cell stress is normalized.