Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion.

Solid cancers like pancreatic ductal adenocarcinoma (PDAC), a type of pancreatic cancer, frequently exploit nerves for rapid dissemination. This neural invasion (NI) is an independent prognostic factor in PDAC, but insufficiently modeled in genetically engineered mouse models (GEMM) of PDAC. Here, we systematically screened for human-like NI in Europe's largest repository of GEMM of PDAC, comprising 295 different genotypes. This phenotype screen uncovered 2 GEMMs of PDAC with human-like NI, which are both characterized by pancreas-specific overexpression of transforming growth factor α (TGF-α) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGF-α upregulated CCL2 secretion from sensory neurons, which induced hyperphosphorylation of the cytoskeletal protein paxillin via CCR4 on cancer cells. This activated the cancer migration machinery and filopodia formation toward neurons. Disrupting CCR4 or paxillin activity limited NI and dampened tumor size and tumor innervation. In human PDAC, phospho-paxillin and TGF-α-expression constituted strong prognostic factors. Therefore, we believe that the TGF-α-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC.

Effects of moderate aerobic exercise, low-level laser therapy, or their combination on muscles pathology, oxidative stress and irisin levels in the mdx mouse model of Duchenne muscular dystrophy.

This study aimed to investigate how the combined use of low-level laser therapy (LLLT) and exercise, to reduce the possible side effects and/or increase the benefits of exercise, would affect oxidative stress, utrophin, irisin peptide, and skeletal, diaphragmatic, and cardiac muscle pathologies. In our study, 20 mdx mice were divided into four groups. Groups; sedentary and placebo LLLT (SC), sedentary and LLLT (SL), 30-min swimming exercise (Ex), and 30-min swimming exercise and LLLT (ExL). After 8 weeks of swimming exercise, muscle tests, biochemically; oxidative stress index (OSI), utrophin and irisin levels were measured. Skeletal, diaphragmatic and cardiac muscle histopathological scores, skeletal and cardiac muscle myocyte diameters were determined under the light and electron microscope. While only irisin levels were increased in group SL compared to SC, it was determined that OSI, heart muscle histopathological scores decreased and irisin levels increased in both exercise groups (p < 0.05). In addition, in the ExL group, an increase in rotarod and utrophin levels, and a decrease in muscle and diaphragm muscle histopathological scores were observed (p < 0.05). It was determined that the application of swimming exercise in the mdx mouse model increased the irisin level in the skeletal muscle, while reducing the OSI, degeneration in the heart muscle, inflammation and cardiopathy. When LLLT was applied in addition to exercise, muscle strength, skeletal muscle utrophin levels increased, and skeletal and diaphragmatic muscle degeneration and inflammation decreased. In addition, it was determined that only LLLT application increased the level of skeletal muscle irisin.

Caffeic acid attenuates gastric mucosal damage induced by ethanol in rats via nitric oxide modulation.

Anti-oxidant and anti-inflammatory properties of caffeic acid (CA) have been reported recently. In this study, the therapeutic effects of CA on ethanol-induced ulcer and the roles of nitric oxide and cholinergic pathways in these effects were investigated. Ulcer was induced by ethanol via oral gavage. Ulcer induced rats were treated with either vehicle (ulcer group) or CA (100, 250 or 500 mg/kg, per oral gavage). Macroscopic evaluation showed that 250 mg/kg CA was the effective dose. To elucidate the action mechanism of CA, 10 mg/kg l-NAME or 1 mg/kg atropine sulfate was administered to 250 mg/kg CA treated groups. All rats were decapitated 1 h after ulcer induction and gastric samples were scored macroscopically and microscopically, and analyzed for myeloperoxidase (MPO), malondialdehyde (MDA), and glutathione (GSH) levels. ANOVA test was used for statistical analyses. Macroscopic and microscopic damage scores, MDA levels and MPO activity were increased while GSH levels were decreased in ulcer group. Treatment with 250 mg/kg and 500 mg/kg CA reduced macroscopic and microscopic damage scores, decreased MPO activity and MDA levels, and preserved the depleted glutathione significantly. l-NAME administration before CA treatment elevated MDA levels, MPO activity and depleted glutathione. However, atropine sulfate had no effect on biochemical parameters. We conclude that CA ameliorates ethanol-induced gastric mucosal damage, and NO pathway contributes to this effect. On the other hand, there is a lack of evidence for the contribution of the muscarinic cholinergic system.

Uridine treatment prevents REM sleep deprivation-induced learning and memory impairment.

Previous studies have shown that sleep plays an important role in cognitive functions and sleep deprivation impairs learning and memory. Uridine is the main pyrimidine nucleoside found in human blood circulation and has beneficial effects on cognitive functions. The aim of the present study was to investigate the effects of uridine administration on learning and memory impairment in sleep-deprived rats. Flower pot method was used to induce REM sleep deprivation. Uridine-treated groups received 1 mmol/kg uridine and control groups received 1 ml/kg saline (0.9% NaCl) twice a day for four days and once a day on the 5th day intraperitoneally. Learning and memory performances were measured using Morris water maze (MWM) test. We also measured the ratios of total calcium-calmodulin dependent kinase II (tCaMKII)/ß-tubulin and phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB)/ß-tubulin, long-term potentiation (LTP) related molecules, using western blot analysis on the hippocampus. The results showed that REM sleep deprivation impaired learning and memory and also decreased the ratios of tCaMKII and pCREB. Uridine treatment enhanced learning and memory parameters in REM sleep-deprived rats. Additionally, decreases in tCaMKII and pCREB were prevented by uridine treatment. These data suggest that administration of uridine for five consecutive days prevents REM sleep deprivation-induced deficits in learning and memory associated with enhanced tCaMKII and pCREB ratios in the hippocampus.

Effects of different aerobic exercise frequencies on streptozotocin-nicotinamide-induced type 2 diabetic rats: Continuous versus short bouts and weekend warrior exercises.

BACKGROUND: Exercise training is known to have multiple beneficial effects on type 2 diabetes mellitus (T2DM). The aim of this study was to explore the effects of aerobic exercise frequency on diabetic parameters, the histopathological structure of skeletal muscle, diabetic myopathy, and mitochondrial enzyme activity in an experimental model of T2DM. METHODS: Sprague-Dawley rats (n = 35) were rendered diabetic by injection of nicotinamide (110 mg/kg) and streptozotocin (65 mg/kg). Rats with blood glucose concentrations between 7 and 17 mmol/L were used. Diabetic rats were randomly allocated to one of the following groups: (i) control sedentary; (ii) diabetic sedentary; (iii) diabetic with continuous exercise (30 min/day, 5 days/week); (iv) diabetic with short bouts of exercise (3 × 10 min/day, 5 days/week); and (v) diabetic rats as "weekend warriors" (35 + 40 min/day, 2 days/week). After 6 weeks swimming exercise (total duration 150 min/week), biochemical tests were performed to measure insulin, glucose, cytokines, serum and muscle myeloperoxidase (MPO), and malondialdehyde (MDA) levels. Histologic analysis (histomorphometric and mitochondrial enzyme analysis) was also performed. RESULTS: Compared with diabetic sedentary rats, significant improvements were observed in all exercise groups in terms of glucose levels, weight loss, tissue MPO and MDA levels, muscular connective tissue, muscle atrophy, mitochondrial enzyme, and all histomorphometric analyses. CONCLUSIONS: The results of the study emphasize the effects of training on inflammation, increased oxidative stress, myopathy, and mitochondrial damage in a rat model of T2DM, and demonstrate that there is no major difference between exercise modalities provided that the total duration of exercise remains the same.