Ghrelin in Focus: Dissecting Its Critical Roles in Gastrointestinal Pathologies and Therapies.

This review elucidates the critical role of ghrelin, a peptide hormone mainly synthesized in the stomach in various gastrointestinal (GI) diseases. Ghrelin participates in diverse biological functions ranging from appetite regulation to impacting autophagy and apoptosis. In sepsis, it reduces intestinal barrier damage by inhibiting inflammatory responses, enhancing GI blood flow, and modulating cellular processes like autophagy and apoptosis. Notably, in inflammatory bowel disease (IBD), serum ghrelin levels serve as markers for distinguishing between active and remission phases, underscoring its potential in IBD treatment. In gastric cancer, ghrelin acts as an early risk marker, and due to its significant role in increasing the proliferation and migration of gastric cancer cells, the ghrelin-GHS-R axis is poised to become a target for gastric cancer treatment. The role of ghrelin in colorectal cancer (CRC) remains controversial; however, ghrelin analogs have demonstrated substantial benefits in treating cachexia associated with CRC, highlighting the therapeutic potential of ghrelin. Nonetheless, the complex interplay between ghrelin's protective and potential tumorigenic effects necessitates a cautious approach to its therapeutic application. In post-GI surgery scenarios, ghrelin and its analogs could be instrumental in enhancing recovery and reducing complications. This article accentuates ghrelin's multifunctionality, shedding light on its influence on disease mechanisms, including inflammatory responses and cancer progression, and examines its therapeutic potential in GI surgeries and disorders, advocating for continued research in this evolving field.

Ghrelin/GHSR Axis Induced M2 Macrophage and Alleviated Intestinal Barrier Dysfunction in a Sepsis Rat Model by Inactivating E2F1/NF-κB Signaling.

Sepsis is an inflammatory reaction disorder state that is induced by infection. The activation and regulation of the immune system play an essential role in the development of sepsis. Our previous studies have shown that ghrelin ameliorates intestinal dysfunction in sepsis. Very little is known about the mechanism of ghrelin and its receptor (GHSR) on the intestinal barrier and the immune function of macrophage regulation. Our research is to investigate the regulatory effect and molecular mechanism of the ghrelin/GHSR axis on intestinal dysfunction and macrophage polarization in septic rats. A rat model of sepsis was established by cecal ligation and puncture (CLP) operation. Then, the sepsis rats were treated with a ghrelin receptor agonist (TZP-101) or ghrelin inhibitor (obestatin). The results suggested that TZP-101 further enhanced ghrelin and GHSR expressions in the colon and spleen of septic rats and obestatin showed the opposite results. Ghrelin/GHSR axis ameliorated colonic structural destruction and intestinal epithelial tight junction injury in septic rats. In addition, the ghrelin/GHSR axis promoted M2-type polarization of macrophages, which was characterized by the decreases of IL-1ß, IL-6, and TNF-α, as well as the increase of IL-10. Mechanistically, the ghrelin/GHSR axis promoted E2F2 expression and suppressed the activation of the NF-κB signaling pathway in septic rats. Collectively, targeting ghrelin/GHSR during sepsis may represent a novel therapeutic approach for the treatment of intestinal barrier injury.

Cortical theta-gamma coupling tracks the mental workload as an indicator of mental schema development during simulated quadrotor UAV operation.

Objective. In the emerging field of neuroergonomics, mental workload assessment is one of the most important problems. Previous studies have made some progress on the relationship between task difficulties and mental workload, but how the mental schema, a reflection of the understanding and mastery degree of a task, affects mental workload has not been clearly discussed.Approach. There is emerging appreciation for the role of theta-gamma coupling (TGC) in high-level cognitive functions. Here, we attempt to further our understanding of how mental schema development and task difficulty had an impact on mental workload from the perspective of TGC. Specifically, the variation of TGC coupling strength and coupling pattern was estimated with different test orders and task difficulties performed by 51 students in a ten-day simulated quadrotor unmanned aerial vehicle flight training and test tasks.Main results. During the training, TGC increased with mental schema development. For the test tasks, TGC did not change with increasing task difficulty before the operator formed a mental schema but decreased with the increasing mental workload after the formation of the mental schema.Significance. Our results suggest that TGC was a robust indicator of mental schema development and could be biased by task difficulty. In conclusion, TGC can be a promising measure of mental workload, but only for experienced operators.

The Modulating Effect of Top-down Attention on the Optimal Pre-target Onset Oscillatory States of Bottom-up Attention.

Research in both bottom-up and top-down attention has shown that behavioural performance is related to brain oscillations at the time of stimulus presentation: the angle of the theta phase in bottom-up attention and the inhibition of alpha oscillations in top-down attention. However, whether the conditions most favourable for bottom-up attention change with the addition of top-down cues is unclear. To explore the characteristics of favourable oscillations during bottom-up processing, in experiment 1, 36 participants completed a selective attention task (visual search) without cues. Then, in experiment 2, we examined whether favourable oscillatory characteristics were changed by top-down attentional cues; in this experiment, 62 subjects were asked to perform an attention network task. We found that without anticipation, oscillatory states that were associated with better performance were characterized by lower theta power in the frontal area, higher alpha power in the occipital area, higher beta power in the frontal area, and weaker gamma-theta amplitude-envelope coupling in the parietal area. However, some characteristics that were associated with better performance, including theta power and low beta power, were changed after the addition of different cues. In addition, there were some new characteristics related to improved performance under temporal and spatial anticipation. These results suggest that top-down attention implements a more energy-efficient strategy to process information, optimizing the process of bottom-up attention.

A del T poly T (8) mutation in the 3' untranslated region (UTR) of the CDK2-AP1 gene is functionally significant causing decreased mRNA stability resulting in decreased CDK2-AP1 expression in human microsatellite unstable (MSI) colorectal cancer (CRC).

BACKGROUND: We have previously published results indicating that decreased expression of CDK2-AP1 in MSI human colorectal cancer is associated with deletion mutations in the poly (T) 8 repeat sequence within the 3'-UTR of the CDK2-AP1 gene. In this study, we test the hypothesis that the del T mutation results in decreased CDK2-AP1 expression by causing reduced mRNA stability. METHODS: We introduced wild-type and mutant 3'-UTR sequences fused to a green fluorescent protein (GFP) gene separately into human CRC cell lines and quantified the expression of the GFP gene. Native CDK2-AP1 mRNA stability was measured in human CRC cell lines, using an actinomycin D assay and the mRNA structure folding software mfold 3.2. RESULTS: Mutant GFP-3'-UTR samples demonstrated significantly reduced GFP expression compared with wild-type GFP-3'-UTR as measured by both FACS and real-time PCR. Both the actinomycin D assay and mfold software demonstrated significantly reduced mRNA stability for the del T poly (T) 8 transcript compared with the wild type. CONCLUSIONS: In summary, these novel results support our hypotheses that the del T poly (T) 8 observed in the 3'-UTR of the CDK2-AP1 gene in human MSI CRC is functionally significant and results in decreased CDK2-AP1 expression. The results also indicate the mechanism of this decreased expression is caused at least in part by decreased mRNA stability.