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Background Regular gall bladder contraction reduces bile stasis and prevents gallstone formation. Intraduodenal administration of exogenous pancreatic secretory trypsin inhibitor-I ( PSTI-I, also known as monitor peptide) causes cholecystokinin ( CCK) secretion. Design We proposed that stimulation of CCK release by PSTI would produce gall bladder contraction and prevent gallstones in mice fed a lithogenic diet. Therefore, we tested the effect of overexpression of rat PSTI-I in pancreatic acinar cells on plasma CCK levels and gall bladder function in a transgenic mouse line ( TgN[Psti1]; known hereafter as PSTI-I tg). Results Importantly, PSTI tg mice had elevated fasting and fed plasma CCK levels compared to wild-type ( WT) mice. Only mice fed the lithogenic diet developed gallstones. Both fasting and stimulated plasma CCK levels were substantially reduced in both WT and PSTI-I tg mice on the lithogenic diet. Moreover, despite higher CCK levels PSTI-I tg animals developed more gallstones than WT animals. Conclusions Together with the previously observed decrease in CCK-stimulated gall bladder emptying in mice fed a lithogenic diet, our findings suggest that a lithogenic diet causes gallstone formation by impaired CCK secretion in addition to reduced gall bladder sensitivity to CCK. [ABSTRACT FROM AUTHOR]

Alcohol abuse is a major cause of pancreatitis in people, but die mechanism is unknown. It has been recently demonstrated that transient receptor potential vanilloid 1 (TRPV1) activation causes neurogenic inflammation and plays an important role in acute pancreatitis. Moreover, TRPV1 is activated by ethanol. We examined die direct effects of ethanol on acute pancreatitis. Acute inflammation of die pancreas was produced by injection of ethanol and palmitoleic acid (POA), a nonoxidative metabolite of ethanol, in wild-type C57BL/6J mice and TrpvI-knockout C57BL/6J mice. Inflammatory indexes were analyzed 24 h later. Injection of ethanol + POA produced acute pancreatitis indicated by significant increases in histopathological damage, serum amylase levels, and pancreatic MPO concentrations (P<0.05-0.001). All parameters of pancreatitis were blocked by pretreatment with the TRPV1 antagonist drug AMG9810. In addition, ethanol + POA administration to TrpvIknockout mice did not produce pancreatic inflammation. Treatment with vehicle, ethanol alone, or POA alone had no inflammatory effects. TRPV1 partially mediates inflammation induced by ethanol + POA in the mouse pancreas, consistent with the ability of ethanol to activate TRPV1. We propose that ethanol may contribute to alcohol-induced pancreatitis by a neurogenic mechanism. [ABSTRACT FROM AUTHOR]

It has been hypothesized that the peripheral taste system may be modulated in the context of an animal's metabolic state. One purported mechanism for this phenomenon is that circulating gastrointestinal peptides modulate the functioning of the peripheral gustatory system. Recent evidence suggests endocrine signaling in the oral cavity can influence food intake (FI) and satiety. We hypothesized that these hormones may be affecting FI by influencing taste perception. We used immtmohistochemistry along with genetic knockout models and the specific reconstitution of peptide YY (PYY) in saliva using gene therapy protocols to identify a role for PYY signaling in taste. We show that PYY is expressed in subsets of taste cells in murine taste buds. We also show, using brief-access testing with PYY knockouts, that PYY signaling modulates responsiveness to bitter-tasting stimuli, as well as to lipid emulsions. We show that salivary PYY augmentation, v/a viral vector therapy, rescues behavioral responsiveness to a lipid emulsion but not to bitter stimuli and that this response is likely mediated via activation of Y2 receptors localized apically in taste cells. Our findings suggest distinct functions for PYY produced locally in taste cells vs. that circulating systemically. [ABSTRACT FROM AUTHOR]

Genetic variants in the fatty acid (FA) translocase FAT/CD36 associate with abnormal postprandial lipids and influence risk for the metabolic syndrome. CD36 is abundant on apical enterocyte membranes in the proximal small intestine, where it facilitates FA uptake and FA-initiated signaling. We explored whether CD36 signaling influences FA-mediated secretion of cholecystokinin (CCK) and secretin, peptides released by enteroendocrine cells (EECs) in the duodenum/jejunum, which regulate events important for fat digestion and homeostasis. CD36 was immunodetected on apical membranes of secretin- and CCK-positive EECs and colocalized with cytosolic granules. Intragastric lipid administration to CD36-/- mice released less secretin (-60%) and CCK (-50%) compared with wild-type mice. Likewise, diminished secretin and CCK responses to FA were observed with CD36-/- intestinal segments in vitro, arguing against influence of alterations in fat absorption. Signaling mechanisms underlying peptide release were examined in STC-1 cells stably expressing human CD36 or a signaling-impaired mutant (CD36K/A). FA stimulation of cells expressing CD36 (vs. vector or CD36K/A) released more secretin (3.5- to 4-fold) and CCK (2- to 3-fold), generated more cAMP (2- to 2.5-fold), and enhanced protein kinase A activation. Protein kinase A inhibition (H-89) blunted secretin (80%) but not CCK release, which was reduced (50%) by blocking of calmodulin kinase II (KN-62). Coculture of STC-1 cells with Caco-2 cells stably expressing CD36 did not alter secretin or CCK release, consistent with a minimal effect of adjacent enterocytes. In summary, CD36 is a major mediator of FA-induced release of CCK and secretin. These peptides contribute to the role of CD36 in fat absorption and to its pleiotropic metabolic effects. [ABSTRACT FROM AUTHOR]

Background. Gastrointestinal (GI) neuroendocrine tumor (NET) incidence has been increasing; however, GI NET within the national Veterans Affairs (VA) health system has not been described. Methods. We used the VA Central Cancer Registry to identify the cohort of patients diagnosed with GI NET in 1995-2009. Cox regression models were constructed to explore factors associated with survival. Results. We included 1793 patients with NET of the stomach (9%), duodenum (10%), small intestine (24%), colon (19%) or rectum (38%). Twenty percent were diagnosed in 1995-1999, 35% in 2000-2004, and 45% in 2005-2009. Unadjusted 5- year survival rates were: stomach 56%, duodenum 66%, small intestine 52%, colon 67%, and rectum 84%. Factors associated with shorter survival were increasing age, hazard ratio (HR) 1.05 (95% CI 1.04-1.06), NET location [compared to rectum: stomach HR 2.26 (95% CI 1.68-3.05), duodenum HR 1.70 (95% CI 1.26-2.28), small intestine HR 1.85 (95% CI 1.42-2.42), and colon 1.83 (95% CI 1.41-2.39)], stage [compared to in situ/local: regional HR 1.15 (95% CI 0.90-1.47), distant HR 2.38 (95% CI 1.87-3.05)], and earlier period of diagnosis [compared to 1995-1999: 2000-2004 HR 0.70 (95% CI 0.59-0.85), 2005-2009 HR 0.43 (95% CI 0.34-0.54)]. Conclusions. The incidence of GI NET has also increased over time in the VA system with similar survival rates to those observed in non-VA settings. Worsened survival was associated with older age, tumor site, advanced stage, and earlier year of diagnosis. [ABSTRACT FROM AUTHOR]

Enteroendocrine cells (EECs) play a key role in nutrient digestion and absorption, and are essential for normal life. Recently, EEC function has received considerable attention because several gastrointestinal hormones modulate insulin secretion and food intake; and, gut hormone-based therapies have been developed to treat diabetes mellitus. Despite these advances, the regulation of EECs remains poorly understood. The development of transgenic mouse models that express green fluorescent proteins (GFP) under specific hormone promoters (e.g., peptide YY-GFP) is shedding light onto previously overlooked features of EECs. These cells have prominent cytoplasmic processes that extend underneath enterocytes, and in some EECs, such as the L cell of the distal ileum, the basal process can be over 50 μm long. These basal cytoplasmic processes resemble axons and end in synaptic-like bouton. The location and anatomy of these processes suggest two functions: (1) to monitor absorbed nutrients at the base of enterocytes; and (2) to convey electrochemical information through cell-cell connections with subepithelial myofibroblasts and/or nerves located directly beneath in the lamina propria. Understanding how EECs communicate with cells in the lamina propria may provide novel ways to treat metabolic disorders such as obesity and diabetes. Clin Trans Sci 2011; Volume 4: 387-391 [ABSTRACT FROM AUTHOR]

Keywords: aqueous humour; glaucoma; intraocular pressure; Piezo1; trabecular meshwork tissue; TRPV4 EN aqueous humour glaucoma intraocular pressure Piezo1 trabecular meshwork tissue TRPV4 365 366 2 01/18/21 20210115 NES 210115 Intraocular pressure is controlled by the mechanosensitive trabecular meshwork (TM) tissue which regulates the flow of aqueous humour in the anterior chamber of the eye. Therefore, although both Piezo1 and TRPV4 are expressed in TM cells, it appears that Piezo1 is the principal transducer of rapid pressure changes in cells of the juxtacanalicular and corneoscleral regions and, in healthy eyes, may maintain normal intraocular pressure. It was recently reported that prolonged shear stress in pancreatic acini activates Piezo1 channels and Piezo1-mediated calcium influx caused the opening of TRPV4 channels through calcium-dependent phospholipase A2 (Swain I et al i . 2020). [Extracted from the article]