Cell Type-Specific p38δ Targeting Reveals a Context-, Stage-, and Sex-Dependent Regulation of Skin Carcinogenesis.

Activation and/or upregulated expression of p38δ are demonstrated in human skin malignancies including cutaneous squamous cell carcinoma, suggesting a role for p38δ in skin carcinogenesis. We previously reported that mice with germline deletion of the p38δ gene are significantly protected from chemical skin carcinogenesis. Here, we investigated the effects of cell-selective targeted ablation of p38δ in keratinocytes and in immune (myeloid) cells on skin tumor development in a two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) chemical mouse skin carcinogenesis model. Conditional keratinocyte-specific p38δ ablation (p38δ-cKO∆K) did not influence the latency, incidence, or multiplicity of chemically-induced skin tumors, but led to increased tumor volume in females during the TPA promotion stage, and reduced malignant progression in males and females relative to their wild-type counterparts. In contrast, conditional myeloid cell-specific p38δ deletion (p38δ-cKO∆M) inhibited DMBA/TPA-induced skin tumorigenesis in male but not female mice. Thus, tumor onset was delayed, and tumor incidence, multiplicity, and volume were reduced in p38δ-cKO∆M males compared with control wild-type males. Moreover, the percentage of male mice with malignant tumors was decreased in the p38δ-cKO∆M group relative to their wild-type counterparts. Collectively, these results reveal that cell-specific p38δ targeting modifies susceptibility to chemical skin carcinogenesis in a context-, stage-, and sex-specific manner.

Does L-arginine induce intestinal adaptation by epithelial growth factor?

BACKGROUND: To evaluate whether L-Arginine has an effect on endogenous epidermal growth factor secretion and intestinal adaptation in massive small bowel resection an experimental study was performed. METHODS: Fourteen albino Wistar rats weighing 250-300 g were used for the study. After performing 50% small bowel resection and anastomosis the rats were randomly divided into two groups. The first group received 500 mg/kg/day of L-Arginine intraperitoneally for 14 days just after the surgical procedure. The control group received isotonic saline instead. Body weight measurement was preformed daily. At the end of the second postoperative week all rats underwent relaparotomy. Small bowel was resected for histopathological examination. Levels of epidermal growth factor were measured by enzyme-linked immunosorbent assay in serum, saliva, and urine at the end of second postoperative week in both groups. RESULTS: The weight gain was higher in the L-Arginine treated group (P < 0.05). Serum, saliva and urinary epidermal growth factor levels were significantly higher at the end of the second week compared to the control group (P < 0.05). The villus height was higher on histopathological examination in L-Arginine treated group compared to the control group (P < 0.05). CONCLUSION: L-Arginine resulted in a better intestinal adaptation after massive bowel resection. The high levels of epidermal growth factor in body fluids of L-Arginine treated rats could be the explanation for this effect.

The effect on the intestines of continuous release of methylene blue from a drug delivery system: an experimental study in a chick embryo gastroschisis model.

Increased small bowel nitric oxide synthase (NOS) activity has been suspected as a cause of postnatal intestinal dysmotility in gastroschisis. The effect of continuous delivery of methylene blue loaded polymer (MBLP) hydroxy-propyl methyl cellulose-ethyl cellulose (HPEC-MC) and daily injection of methylene blue (MB) on the intestinal damage (ID) was evaluated using a chick embryo gastroschisis model. Fourteen-day-old fertilized chick eggs were divided into five groups. In the control (C) group, no intervention was performed. In the sham (S) group, the allantoic and amniotic membranes were opened to create a common cavity that resembles the amniotic cavity in human. In the gastroschisis only (GO) group, a defect in the abdominal wall of the embryo was made, and intestinal loops were exteriorized following connection of amniotic and allantoic cavities. In the gastroschisis plus methylene blue (G+MB) group, gastroschisis was created and MB administered into the amnioallantoic cavity (AAC) by daily injections for 5 days. In the gastroschisis plus methylene blue loaded polymer (G+MBLP) group, MBLP was placed into AAC after gastroschisis was created. At the end of the 19th day of incubation, intestinal morphological changes were investigated macroscopically and microscopically. Although the survival rates were decreased in the chick embryos with creation of gastroschisis compared with C and S groups ( p<0.001), the survival rates were increased in G+MBLP group (76.92%) when compared with the GO group (41%) ( p<0.001). Because of multiple intervention of embryos, higher mortality was observed in the G-MB group (75.61%). Macroscopic and microscopic scores of ID and mean intestinal wall thickness were significantly higher in the GO group when compared with C, S, G+MB, and G+MBLP groups ( p<0.001). The mean score of intestinal ganglia morphology was significantly increased and the total number of ganglion cells was significantly decreased in the GO group when compared with C, S, G+MB, and G+MBLP groups ( p<0.001). It is possible to decrease intrauterine intestinal morphological changes in gastroschisis by inhibiting NOS. As a first preliminary study, we believe that use of MBLP may be an alternative for fetal treatment by eliminating the harmful effects of multiple interventions or amniotic fluid exchanges.

The effects of piroxicam to the muscosal barrier of the bladder after overdistension--an experimental study in rabbits.

UNLABELLED: The effects of piroxicam on the duration and severity of damage to the mucosal barrier of the urinary bladder after overdistension was investigated. Overdistension of the bladder was induced for 3 h in 16 New Zealand male rabbits by giving Ringer's lactate infusion (40 mL/kg/h) and furosemide (1 mg/kg) to the peritoneal cavity. Insertion of 8 Fr Foley catheter was used for obstruction of the bladder neck. In both control (C) and piroxicam (P) groups, 20 mL of 2% solution of Trypan blue in 0.9% NaCl solution was instilled into the bladder for 1 hr at 0, 24, 48 h and 7 days after overdistension. In group P daily intramuscular injection of 5 mg/kg piroxicam, and isotonic saline in group C was administrated for 7 days. Full-thickness samples were taken from the bladder at 0, 24, 48 h and 7 days after overdistension. The bladder wall was deep blue throughout in both groups at 0, 24, and 48 h. The severity and duration of inflammatory reaction was lower and nearly normalized on the 7th post procedure day in piroxicam group. CONCLUSION: Inflammatory reaction can be prevented by administration of anti-inflammatory drugs such as piroxicam but the prevention of increased permeability is unclear after overdistension of the bladder.

The effect of nitric oxide in testicular ischemia-reperfusion injury.

UNLABELLED: This experiment was carried out to investigate the effect of endogenous nitric oxide (NO) on the ischemia-reperfusion injury of testis. Testicular ischemia was achieved by twisting the right testis and spermatic cord 1080 counter-clockwise for 30 minutes and reperfusion was allowed for 30 minutes after detorsion of 33 rats. Animals were treated with normal saline in controls just before detorsion, NG-nitro-L-arginine methyl ester (L-NAME), and L-arginine (L-arg) in others. The tissue damage was evaluated with light microscopy, malondialdehyde (MDA) level in tissue, and the blood flow measurement using 133xenon (Xe) clearence technique. MDA indicator of reperfusion injury increased 25% after detorsion when only normal saline was given, L-NAME further increased MDA, L-arginin decreased MDA to control level. CONCLUSION: L-arginin infusion during the detorsion reduced the reperfusion injury of testis and improved the testicular blood flow after the detorsion.