From suntan to skin cancers: molecular pathways and prevention strategies

The incidence of skin cancer is rising, and significantly linked to carcinogenic effects of ultraviolet radiation. While clashes in lifestyle and cancer risk have undoubtedly contributed to this health crisis, it is equally clear that certain human populations have a notably lower risk of skin cancer. This apparent natural protection, typically afforded by darker skin pigmentation or an easy ability to tan, has begun to reveal mechanistic insights of great relevance to skin cancer risk. An understanding of the genes that participate in pigmentation and the sun-tanning response has permitted greater understanding of the intracellular and intercellular signaling events that culminate in human skin pigmentation. Moreover the same observations have also suggested novel targeted approaches to mimic the pigmentary response using agents that spare the cell from carcinogenic effects of ultraviolet radiation. The application of such strategies is not yet at hand, but potentially promises to provide a complementary approach to prevention of cutaneous cancer.     

Lipid peroxidation and mucin secretagogue activity in bile of gallstone patients

Background Chronic inflammation of the gallbladder wall and mucin hypersecretion are considered to be important factors in the pathogenesis of cholesterol gallstone disease. The aim of the study was to compare mucin concentration and mucin secretagogue activity with lipid peroxidation in gallbladder bile of patients with cholesterol or pigment stones. Material and methods We studied mucin concentration and, as a marker of lipid peroxidation, malondialdehyde concentration in 11 rapid (1 to 3 days) and eight non‐nucleating (> 21 days) gallbladder biles of patients with cholesterol or pigment stones. Furthermore, the mucin secretagogue activity of rapid and non‐nucleating gallbladder biles, as well as 1–5 µmol L⁻¹ malondialdehyde on cultured gallbladder epithelial cells, was determined. Results Our data show an increased malondialdehyde (7·2 ± 1·8 vs. 3·8 ± 0·5 µmol L⁻¹, P = 0·01) and mucin concentration (0·9 ± 0·09 vs. 0·41 ± 0·03 mg mL⁻¹, P = 0·01) and an increased mucin secretagogue activity (2·0 ± 0·5 vs. 1·1 ± 0·3 mucin secretion/control, P = 0·04) and cholesterol saturation index (1·2 ± 0·1 vs. 08 ± 0·1, P = 0·04) in rapid as compared to non‐nucleating gallbladder biles. Malondialdehyde stimulated mucin secretion of cultured gallbladder epithelial cells in a concentration dependent manner. Conclusions Our results support a promoting effect of gallbladder mucin hypersecretion by lipid peroxidation leading to rapid formation of cholesterol crystals in gallbladder bile. These findings suggest that besides hypersecretion of cholesterol in bile, chronic inflammation of the gallbladder wall is implicated in the pathogenesis of cholesterol gallstone disease.     

The evaluation of gallbladder function by quantitative radionuclide cholescintigraphy before and after ESWL for gallstones: Preliminary report

We assessed changes of gallbladder function including concentration and contraction in patients with gallstones after extracorporeal shock-wave lithotripsy (ESWL). The abilities of concentration and contraction were expressed as filling fraction (FF) at 90 min and ejection fraction (EF) at 30 min after a fatty diet by Tc-99m DISIDA Cholescintigraphy. A total of 12 patients who had symptomatic gallstones without cholecystitis were included in our study. ESWL failed in three cases: FF decreased in two of three cases and increased in one of three cases, whereas EF decreased in two of three cases and increased in one of three cases. In another nine cases, ESWL was successful and the gallstones were fragmented. One month after ESWL, in three of these nine cases, the gallstones had completely disappeared. In the three cases at 1 month after ESWL, FF decreased in two of three cases and increased in one of three cases, whereas EF decreased in one of three cases and increased in two of three cases. In the remaining six cases after ESWL, there were still some residual stone fragments in the gallbladder. In these six cases after 6 months, no fragments were found in the gallbladders, the third Tc-99m DISIDA Cholescintigraphy was performed. In these six cases, the changes of FF and EF, before ESWL, 1 month after ESWL, and 6 months after ESWL, were irregular and fluctuant. However, no significant improvement of gallbladder function was demonstrated even when ESWL was successful. In our preliminary results, we found that not only the residual stone fragments but also the procedure of ESWL may impair gallbladder function by evidence of a noninvasive and quantitative Tc-99m DISIDA Cholescintigraphy.     

Floating stones in a nonopacified gallbladder: Ultrasonographic sign of gas-containing gallstones

Floating stones were noted in the nonopacified gallbladder at ultrasound examination. Gas-containing fissures in these stones could be demonstrated pre- and postoperatively (Mercedes Benz sign).     

Glucuronidation of bilirubin and the occurrence of pigment gallstones in patients with chronic haemolytic diseases

A group of thirty-seven patients with increased haem catabolism has been studied to gain insight in their bilirubin conjugating capacity. Bilirubin UDP-glucuronyl transferase activity (GlcATa) in the liver and bilirubin monoconjugates in bile were measured and the hepatic bilirubin clearance was calculated from the radio-chromium-survival data. In the present group, 41% of the patients clearly had a deficiency in bilirubin conjugation similar to what is classically found in Gilbert's syndrome. The association may facilitate detection of these patients as serum bilirubin levels were higher (65.8 microM +/- 19) (m +/- 1 SD) in the fifteen patients with associated Gilbert's syndrome versus thirteen having only haemolysis (43.6 microM +/- 15). A fair correlation was found between the percentage of monoconjugates in bile and the GlcATa levels in the liver as well as with the calculated hepatic bilirubin clearance, although some discrepancies exist. Using these determinations, a clearcut separation from normal values was not obtained, suggesting at least in the present group of patients that Gilbert' syndrome represents only one end of a continuum of bilirubin conjugation rates and not a separate entity. Pigment stones in the gall-bladder were documented in 51% of the patients and usually at an early age. There was no relationship towards sex, serum bilirubin, GlcATa in liver, total bilirubin or monoconjugates in bile. Age played some role as well as the type of haemolysis as all patients with congenital dyserythropoiesis (n = 4) or acquired haemolysis (n = 3) had lithiasis. Moderate chronic cholecystitis was present, whereas an accumulation of iron and bile pigment was evident in the liver.     

Apolipoprotein E polymorphism and lithogenic factors in gallbladder bile

BACKGROUND: Associations between the polymorphism of apolipoprotein E, which plays an important role in cholesterol metabolism and cholesterol gallstone formation, have been reported recently. Patients with the apo E4 isoform showed increased numbers and cholesterol contents of their stones, a higher frequency of cholesterol crystals in bile, increased susceptibility to gallstone fragmentation by extracorporeal shock-wave lithotripsy and an increase in recurrence rate after dissolution. A recent study, however, showed that fast cholesterol crystallization in bile is associated with multiple stones but not with apo E4. Therefore the mechanism for an increased risk of gallstone formation in patients with the apo E4 isoform still remains under debate. DESIGN: To clarify this issue we investigated 37 patients with gallstones (10 with the apo E4 allele and 27 without the allele). Gallbladder biles were examined for total cholesterol and other lipids, cholesterol saturation index, crystal observation time, crystal mass, total protein and mucin. Moreover, number of gallstones and cholesterol in gallstones was compared in both groups. RESULTS: The crystal observation time (2.5 vs. 2.0 days, median) and the cholesterol saturation index (1.34 +/- 0.45 vs. 1.43 +/- 0.74) did not differ significantly between the apo E4 and the non apo E4 group. Total biliary lipids (11.6 +/- 3.8 vs. 9.3 +/- 3.9 g 100 mL-1, P = 0.126) and total biliary cholesterol (21.8 +/- 9.7 vs. 15.7 +/- 7 mmol L-1, P = 0.067) tended to be elevated in the apo E4 group. Crystal mass (3.60 +/- 4.10 vs. 2.38 +/- 2.70 mmol L-1), biliary total protein (8.6 +/- 3.5 vs. 8.3 +/- 6.6 mg mL-1) and mucin (0.55 +/- 0.38 vs. 0.66 +/- 0.67 mg mL-1), number (solitary/multiple) of gallstones and cholesterol in gallstones were not different in both groups of patients. CONCLUSIONS: In comparison to the non apo E4 patients the apo E4 group showed a trend to elevated biliary cholesterol whereas crystal observation time, cholesterol saturation index, crystal mass, number of gallstones, cholesterol content of gallstones and total protein and mucin were not different. These findings do not suggest an association of the apo E isoform and the formation of cholesterol gallstones     

Enterohepatic cycling of bilirubin as a cause of 'black' pigment gallstones in adult life

In contrast to bile salts, which undergo a highly efficient enterohepatic circulation with multiple regulatory and physiologic functions, glucuronic acid conjugates of bilirubin are biliary excretory molecules that in health do not have a continuing biologic life. Intestinal absorptive cells are devoid of recapture transporters for bilirubin conjugates, and their large size and polarity prevent absorption by passive diffusion. However, unconjugated bilirubin, the beta-glucuronidase hydrolysis product of bilirubin glucuronides can be absorbed passively from any part of the small and large intestines. This can occur only if unconjugated bilirubin is kept in solution and does not undergo rapid bacterial reduction to form urobilinoids. Here we collect, and in some cases reinterpret, experimental and clinical evidence to show that in addition to the well-known occurrence in newborns, enterohepatic cycling of unconjugated bilirubin can reappear in adult life. This happens as a result of several common conditions, particularly associated with bile salt leakage from the small intestine, the most notable ileal dysfunction resulting from any medical or surgical cause. We propose that when present in excess, colonic bile salts solubilize unconjugated bilirubin, delay urobilinoid formation, prevent calcium complexing of unconjugated bilirubin and promote passive absorption of unconjugated bilirubin from the large intestine. Following uptake, reconjugation, and resecretion into bile, this source of 'hyperbilirubinbilia' may be the important pathophysiological risk factor for 'black' pigment gallstone formation in predisposed adult humans.     

Diminished gallbladder motility in Rotund leptin-resistant obese mice

Background. Obesity is a risk factor for cholesterol gallstone formation, but the pathogenesis of this phenomenon remains unclear. Most human obesity is associated with diabetes and leptin-resistance. Previous studies from this laboratory have demonstrated that diabetic leptin-resistant (Lep^db) obese mice have low biliary cholesterol saturation indices, enlarged gallbladders and diminished gallbladder response to neurotransmitters. Recently, a novel leptin-resistant mouse strain Lepr^db-rtnd (Rotund) has been discovered. Rotund mice are also obese, diabetic, and have an abnormal leptin receptor. Therefore, we tested the hypothesis that leptin-resistant obese Rotund mice would have large gallbladders and reduced biliary motility.Methods. Eight-week-old control (C57BL/6J, N=12) and Rotund leptin-resistant (Lepr^db-rnd, N=9) mice were fed a non- lithogenic diet for four weeks. Animals were fasted and underwent cholecystectomy. Gallbladder volumes were recorded, and contractile responses (N/cm²) to acetylcholine (10⁻⁵ M), Neuropeptide Y (10^{−8,−7,−6} M), and cholecystokinin (10^{−10,−9,−8,−7} M) were measured. Results were analyzed using the Mann-Whitney Rank Sum Test.Results. Compared to control mice, Rotund mice had larger body weights, higher serum glucose levels, and greater gallbladder volumes (p<0.05). Rotund gallbladders had less contractility (p<0.05)) to acetylcholine and cholecystokinin than control mice. Responses to Neuropeptide Y were also less, but not statistically significant, in the Rotund mice.Conclusions. These data suggest that leptin-resistant Rotund mice have (1) enlarged gallbladders with (2) diminished contractility compared to lean control mice. Therefore, this study confirms that leptin-resistance is associated with abnormal biliary motility and may lead to gallstone formation in leptin-resistant obesity.     

血管内皮生长因子和色素上皮衍生因子在门静脉高压大鼠胃壁中的表达及意义

目的 探讨血管内皮生长因子(VEGF)和色素上皮衍生因子(PEDF)在门静脉高压大鼠胃壁中的表达及意义.方法 以肝前性门静脉高压症大鼠作为研究对象,以PEDF和VEGF作为观察指标,通过免疫组织化学和Western blot等方法检测PEDF和VEGF在胃壁中的表达.结果 免疫组织化学的结果显示,实验组(A组)PEDF、VEGF在胃壁的表达明显多于对照组(B组),主要位于黏膜层腺体的基底层,少量散在表达于黏膜下层及黏膜下血管内皮细胞中.Western blot结果显示,实验组大鼠胃壁PEDF与VEGF的相对表达量较对照组均有升高,在术后7、10、14 d 3个时间点VEGF的表达呈逐渐下降趋势,而PEDF的表达呈逐渐升高的趋势.结论 PEDF和VEGF在肝前性门静脉高压症大鼠胃壁中有明显的表达,主要在黏膜层的基底部.PEDF在胃壁中的表达逐渐升高,而VEGF呈逐渐下降趋势,两者可能参与门静脉高压症胃壁血管增生的调节.