Targeting Bile Acid-Activated Receptors in Bariatric Surgery.

Bariatric surgical procedures, including Roux-en-Y gastric bypass and vertical sleeve gastrectomy, are currently the most effective clinical approaches to achieve a significant and sustainable weight loss. Bariatric surgery also concomitantly improves type 2 diabetes and other metabolic diseases such as nonalcoholic steatohepatitis, cardiovascular diseases, and hyperlipidemia. However, despite the recent exciting progress in the understanding how bariatric surgery works, the underlying molecular mechanisms of bariatric surgery remain largely unknown. Interestingly, bile acids are emerging as potential signaling molecules to mediate the beneficial effects of bariatric surgery. In this review, we summarize the recent findings on bile acids and their activated receptors in mediating the beneficial metabolic effects of bariatric surgery. We also discuss the potential to target bile acid-activated receptors in order to treat obesity and other metabolic diseases.

Targeting the Ca2+/Calmodulin-dependent protein kinase II by Tetrandrine in human liver cancer cells.

Hepatocellular carcinoma (HCC) is the most prevalent malignancy in liver and a leading cause of cancer-related deaths. Despite the pressing need for treatment options, patients with HCC develop significant resistance and adverse side effects to current approved drugs that becomes a major barrier to effective treatment. A natural product Tetrandrine (TET) is a potential alternative treatment option for HCC, with demonstrated effectiveness and low toxicity. However, the mechanisms by which Tetrandrine inhibits HCC are unclear. In the current study, we identify Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) as a potential TET drug target through structural modeling. Screening of a panel of HCC cell lines reveal differential sensitivities toward TET treatment. Interestingly, IC50 of TET inhibition of HCC cell proliferation is positively correlated with CaMKIIδ expression level in these distinct HCC cells. Furthermore, TET treatment resulted in a marked reduction of CaMKIIδ phosphorylation level, and knockdown of CaMKIIδ reduced the sensitivity of HCC cells to TET. Most importantly, CaMKIIδ protein levels in high-grade human HCC samples were significantly elevated as compared to normal liver tissues. Taken together, our studies demonstrate that the natural compound TET targets CaMKIIδ in HCC cells, and that CaMKIIδ level is a potential biomarker to identify HCC patient populations sensitive to Tetrandrine treatment.

Internalizing versus externalizing control: different ways to perform a time-based prospective memory task.

Time-based prospective memory (PM) refers to performing intended actions at a future time. Participants with time-based PM tasks can be slower to perform ongoing tasks (costs) than participants without PM tasks because internal control is required to maintain the PM intention or to make prospective-timing estimates. However, external control can be gained, and internal control minimized, by checking clocks or by using PM reminders. We present 3 experiments that examined how individuals externalize and internalize control of time-based PM tasks. The control condition performed a lexical decision task only, whereas the PM conditions were additionally required to make a time-based PM response after 11 min. We manipulated whether participants received a reminder, and whether clock checking was discouraged. In Experiments 1 and 3, no cost was found under standard clock check conditions. In contrast, when participants were discouraged from clock checking (Experiments 2 and 3), significant costs were found, accompanied by a decrease in clock checking. PM reminders prompted participants to check the clock, and improved PM accuracy if those reminders were expected. However, there was no evidence that participants could localize the internal or external control of the PM task to after the presentation of an expected reminder (Experiment 3). We conclude that much of the need for internal control can be transferred to the external world by performing a well-practiced task such as clock checking, which reminds participants of the PM task and reduces the internal control required to maintain the intention to perform the PM task.

Photochemical restoration of visual responses in blind mice.

Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are degenerative blinding diseases caused by the death of rods and cones, leaving the remainder of the visual system intact but largely unable to respond to light. Here, we show that AAQ, a synthetic small molecule photoswitch, can restore light sensitivity to the retina and behavioral responses in vivo in mouse models of RP, without exogenous gene delivery. Brief application of AAQ bestows prolonged light sensitivity on multiple types of retinal neurons, resulting in synaptically amplified responses and center-surround antagonism in arrays of retinal ganglion cells (RGCs). Intraocular injection of AAQ restores the pupillary light reflex and locomotory light avoidance behavior in mice lacking retinal photoreceptors, indicating reconstitution of light signaling to brain circuits. AAQ and related photoswitch molecules present a potential drug strategy for restoring retinal function in degenerative blinding diseases.

A hormone-activated central pattern generator for courtship.

BACKGROUND: Medicinal leeches (Hirudo spp.) are simultaneous hermaphrodites. Mating occurs after a stereotyped twisting and oral exploration that result in the alignment of the male and/or female gonopores of one leech with the complementary gonopores of a partner. The neural basis of this behavior is presently unknown and currently impossible to study directly because electrophysiological recording techniques disrupt the behavior. RESULTS: Here we report that (Arg(8))-conopressin G and two other members of the oxytocin/vasopressin family of peptide hormones induce in Hirudo verbana a sequence of behaviors that closely mimic elements of spontaneous reproductive behavior. Through a series of progressively more reduced preparations, we show that one of these behaviors, a stereotyped twisting that is instrumental in aligning gonopores in preparation for copulation, is the product of a central pattern generator that consists of oscillators in ganglia M5 and M6 (the ganglia in the reproductive segments of the leech), and also in ganglion M4, which was not previously known to play a role in reproductive behavior. We find that the behavior is periodic, with a remarkably long cycle period of around five minutes, placing it among the slowest behavioral rhythms (other than diurnal and annual rhythms) yet described. CONCLUSION: These results establish the leech as a new model system for studying aspects of the neuronal basis of reproductive behavior.