35 research outputs found
Clarification of Linaclotide Pharmacology Presented in a Recent Clinical Study of Plecanatide
Cellular Mechanisms Underlying the Laxative Effect of Flavonol Naringenin on Rat Constipation Model
BACKGROUND & AIMS: Symptoms of constipation are extremely common, especially in the elderly. The present study aim to identify an efficacious treatment strategy for constipation by evaluating the secretion-promoting and laxative effect of a herbal compound, naringenin, on intestinal epithelial anion secretion and a rat constipation model, respectively. METHODS/PRINCIPAL FINDINGS: In isolated rat colonic crypts, mucosal addition of naringenin (100 microM) elicited a concentration-dependent and sustained increase in the short-circuit current (I(SC)), which could be inhibited in Cl- free solution or by bumetanide and DPC (diphenylamine-2-carboxylic acid), but not by DIDS (4, 4'- diisothiocyanatostilbene-2, 2'-disulfonic acid). Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC). In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion. Naringenin-evoked whole cell current which exhibited a linear I-V relationship and time-and voltage- independent characteristics was inhibited by DPC, indicating that the cAMP activated Cl- conductance most likely CFTR (cystic fibrosis transmembrane conductance regulator) was involved. In rat constipation model, administration of naringenin restored the level of fecal output, water content and mucus secretion compared to loperamide-administrated group. CONCLUSIONS: Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model. Naringenin appears to be a novel alternative treatment strategy for constipation
All-sky search for gravitational-wave bursts in the second joint LIGO-Virgo run
We present results from a search for gravitational-wave bursts in the data
collected by the LIGO and Virgo detectors between July 7, 2009 and October 20,
2010: data are analyzed when at least two of the three LIGO-Virgo detectors are
in coincident operation, with a total observation time of 207 days. The
analysis searches for transients of duration < 1 s over the frequency band
64-5000 Hz, without other assumptions on the signal waveform, polarization,
direction or occurrence time. All identified events are consistent with the
expected accidental background. We set frequentist upper limits on the rate of
gravitational-wave bursts by combining this search with the previous LIGO-Virgo
search on the data collected between November 2005 and October 2007. The upper
limit on the rate of strong gravitational-wave bursts at the Earth is 1.3
events per year at 90% confidence. We also present upper limits on source rate
density per year and Mpc^3 for sample populations of standard-candle sources.
As in the previous joint run, typical sensitivities of the search in terms of
the root-sum-squared strain amplitude for these waveforms lie in the range 5
10^-22 Hz^-1/2 to 1 10^-20 Hz^-1/2. The combination of the two joint runs
entails the most sensitive all-sky search for generic gravitational-wave bursts
and synthesizes the results achieved by the initial generation of
interferometric detectors.Comment: 15 pages, 7 figures: data for plots and archived public version at
https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=70814&version=19, see
also the public announcement at
http://www.ligo.org/science/Publication-S6BurstAllSky