Pancreatic cancer is a highly lethal disease with a poor prognosis for long-term survival rate at all stages of invasiveness. It responds poorly to radio- and chemotherapy because the tumor cells are resistant to apoptosis. Melatonin has been reported to inhibit pancreatic cancer growth in experimental studies in animals but the effect of melatonin on cultured human pancreatic carcinoma cells has not been tested. Moreover, we have recently shown that melatonin stimulates production of two major anti-apoptotic heat shock proteins, HSP27 and HSP 90, in pancreatic carcinoma cells. This study investigated the changes in intrinsic pathway of apoptosis at the mitochondrial level and cascade of caspases in human pancreatic carcinoma cells (PANC-1) cells subjected to melatonin and/or luzindole. Melatonin (10⁻⁸ -10⁻¹² m), the nonselective melatonin receptor antagonist, luzindole (10⁻⁸ -10⁻¹² m) or a combination of both agents were added to PANC-1 cell cultures. Cells were harvested, and the cytoplasmic proteins were isolated after 24 and 48 hr of incubation and analyzed employing co-immunoprecipitation and western blot. Administration of melatonin to the PANC-1 cells resulted in the stimulation of Bcl-2/Bax and caspase-9 proteins levels. The strongest signal of these pro-apoptotic factors was observed at the low concentration (10⁻¹² m) of melatonin. Pretreatment with luzindole alone and prior to the addition of melatonin reversed the stimulatory effect of this indoloamine on Bcl-2/Bax and caspase-9 proteins expression in PANC-1 cells. This is the first study to demonstrate a pro-apoptotic effect of low (physiological) concentration of melatonin on the pancreatic carcinoma cells. In conclusion, melatonin induced pro-apoptotic pathways in human pancreatic carcinoma, probably by interaction with the Mel-1 A/B receptors.
Glycosylation is a topic of intense current interest in the development of biopharmaceuticals because it is related to drug safety and efficacy. This work describes results of an interlaboratory study on the glycosylation of the Primary Sample (PS) of NISTmAb, a monoclonal antibody reference material. Seventy-six laboratories from industry, university, research, government, and hospital sectors in Europe, North America, Asia, and Australia submitted a total of 103 reports on glycan distributions. The principal objective of this study was to report and compare results for the full range of analytical methods presently used in the glycosylation analysis of mAbs. Therefore, participation was unrestricted, with laboratories choosing their own measurement techniques. Protein glycosylation was determined in various ways, including at the level of intact mAb, protein fragments, glycopeptides, or released glycans, using a wide variety of methods for derivatization, separation, identification, and quantification. Consequently, the diversity of results was enormous, with the number of glycan compositions identified by each laboratory ranging from 4 to 48. In total, one hundred sixteen glycan compositions were reported, of which 57 compositions could be assigned consensus abundance values. These consensus medians provide community-derived values for NISTmAb PS. Agreement with the consensus medians did not depend on the specific method or laboratory type. The study provides a view of the current state-of-the-art for biologic glycosylation measurement and suggests a clear need for harmonization of glycosylation analysis methods.
Epidermal growth factor (EGF) has been reported to stimulate epithelial cell proliferation and to inhibit gastric H+ secretion, but no details of the latter effect have been studied. This paper reports the effects of EGF on gastric and pancreatic secretions induced by various stimulants in vivo on conscious dogs and in vitro on isolated rabbit gastric glands. EGF was found to be an effective inhibitor of H+ secretion induced from the fully innervated and vagally denervated portions of the stomach stimulated by secretagogues activating receptors of the parietal cells (pentagastrin, histamine, and urecholine) and by natural stimulants such as sham or ordinary feeding. It appears to act directly on the parietal cells, as the inhibitory effect in vivo was not accompanied by any change in postprandial serum gastrin level. In addition, EGF was found to suppress H+ formation in the isolated gastric glands, both under resting conditions and after stimulation with histamine, carbachol, or dibutyryl cAMP. EGF failed to affect pancreatic response to exogenous hormones (secretin and cholecystokinin) but reduced postprandial secretion probably because of inhibition of H+ secretion from the subsequent reduction in duodenal acid loads. We conclude that EGF is a potent, specific, and direct inhibitor of H+ secretion from the parietal cells and that it does not affect alkaline gastroduodenal or pancreatic secretion.
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