Indole produced during dysbiosis mediates host-microorganism chemical communication.

An imbalance of the gut microbiota, termed dysbiosis, has a substantial impact on host physiology. However, the mechanism by which host deals with gut dysbiosis to maintain fitness remains largely unknown. In Caenorhabditis elegans, Escherichia coli, which is its bacterial diet, proliferates in its intestinal lumen during aging. Here, we demonstrate that progressive intestinal proliferation of E. coli activates the transcription factor DAF-16, which is required for maintenance of longevity and organismal fitness in worms with age. DAF-16 up-regulates two lysozymes lys-7 and lys-8, thus limiting the bacterial accumulation in the gut of worms during aging. During dysbiosis, the levels of indole produced by E. coli are increased in worms. Indole is involved in the activation of DAF-16 by TRPA-1 in neurons of worms. Our finding demonstrates that indole functions as a microbial signal of gut dysbiosis to promote fitness of the host.

The signaling pathway of levamisole-sensitive-acetylcholine receptors involved in short-term forgetting of Caenorhabditis elegans.

In contrast to the popular opinion that forgetting is only the opposite of learning and memory, active forgetting explains the intrinsic instability of a labile memory that lasts for hours and has its own signal transduction pathways. However, the detailed mechanisms underlying forgetting are still lacking, though the investigations available in this field offer the first insights into their regulation. To identify the alternative signaling pathways that control the process of forgetting, we used the short-term forgetting model of Caenorhabditis elegans and discovered the involvement of lev-10, a scaffolded transmembrane protein of L-AChR, by screening the candidate genes that potentially functioned in synaptic plasticity. The LEV-9/LEV-10/L-AChR functional complex was confirmed to participate in forgetting occurrence. Furthermore, EGL-9 functioned upstream of LEV-10 and negatively regulated the latter during forgetting. Meanwhile, EGL-9 was also the target of miR-51, and hence the mutation of miR-51 similarly affected the function of L-AChR and delayed the short-term forgetting. Our findings have identified an integrated signaling pathway responsible for active forgetting, which provides the new experimental evidence on the cholinergic forgetting signal.

Fenofibrate Improves Insulin Resistance and Hepatic Steatosis and Regulates the Let-7/SERCA2b Axis in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Mice.

Fenofibrate is widely used in clinical therapy to effectively ameliorate the development of non-alcoholic fatty liver disease (NAFLD); however, its specific molecular mechanism of action remains largely unknown. MicroRNAs (miRNAs) are key mediators in regulating endoplasmic reticulum (ER) stress during NAFLD, and the deregulation of miRNAs has been demonstrated in NAFLD pathophysiology. The present study aimed to identify whether fenofibrate could influence miRNA expression in NAFLD and investigate the specific mechanism of action of fenofibrate in lipid metabolism disorder-associated diseases. We found that fenofibrate alleviated ER stress and increased the levels of SERCA2b, which serves as a regulator of ER stress. Additionally, the levels of let-7 miRNA were regulated by fenofibrate; let-7 was found to target the 3' untranslated region of SERCA2b. The present data suggest that the protective effects of fenofibrate against insulin resistance and its suppressive activity against excessive hepatic lipid accumulation may be related to the alteration of the let-7/SERCA2b axis and alleviation of ER stress.

Biosynthesis of the Nematode Attractant 2-Heptanone and Its Co-evolution Between the Pathogenic Bacterium Bacillus nematocida and Non-pathogenic Bacterium Bacillus subtilis.

Methylketones are broadly distributed in nature and perform a variety of functions. Most microorganisms are thought to produce methylketone by abortive ß-oxidation of fatty acid catalytic metabolism. However, two methylketone synthetase genes in wild tomatoes are reported to synthesize methylketone using intermediates of the fatty acids biosynthetic pathway. In our previous study on Trojan horse-like interactions between the bacterium Bacillus nematocida B16 and its host worm, the chemical 2-heptanone was found to be an important attractant for the hosts. So here we used this model to investigate the genes involved in synthesizing 2-heptanone in microorganisms. We identified a novel methylketone synthase gene yneP in B. nematocida B16 and found enhancement of de novo fatty acid synthesis during 2-heptanone production. Interestingly, a homolog of yneP' existed in the non-pathogenic species Bacillus subtilis 168, a close relative of B. nematocida B16 that was unable to lure worms, but GC-MS assay showed no 2-heptanone production. However, overexpression of yneP' from B. subtilis in both heterologous and homologous systems demonstrated that it was not a pseudogene. The transcriptional analysis between those two genes had few differences under the same conditions. It was further shown that the failure to detect 2-heptanone in B. subtilis 168 was at least partly due to its conversion into 6-methyl-2-heptanone by methylation. Our study revealed methylketone biosynthesis of Bacillus species, and provided a co-evolution paradigm of second metabolites during the interactions between pathogenic/non-pathogenic bacteria and host.

The roles of actin cytoskeleton and actin-associated protein Crn1p in trap formation of Arthrobotrys oligospora.

Nematode-trapping fungi include a variety of species capable of generating specific trapping devices to capture nematodes and the production of devices is also an indicator of a switch from saprophytic to predacious lifestyles. Traps are developed from vegetative mycelia, but they are quite different from hyphae in both morphological and physiological characteristics. Therefore, the molecular mechanisms underlying their formation have attracted much attention. In this investigation, Arthrobotrys oligospora, a nematode-trapping fungus, has three-dimensional networks and genomics and proteomics were recently performed, so as to reveal the relationship between actin cytoskeleton and trap formation. Both actin staining via FITC-phalloidin and treatment of actin polymerization inhibitor Lat-B illustrated that the actin cytoskeleton played an important role in trap development. Furthermore, absence of the conserved actin-associated protein Crn1p caused a structural defect of traps and failure to infect nematodes. It was observed that mutant Δcrn1 represented a reduced number of rings and a lower complexity of three-dimensional networks, likely due to the disturbance of actin branching. Collectively, our study confirmed the involvement of the actin cytoskeleton as well as the conserved actin-associated protein Crn1p in trap formation. It further suggested the manners in which Crn1p influences the development of three-dimensional networks in A. oligospora.

A novel role for the alcohol sensitive ring/PHD finger protein Asr1p in regulating cell cycle mediated by septin-dependent assembly in yeast.

Septin is a conserved eukaryotic family of GTP-binding filament-forming proteins with functions in cytokinesis and other processes. It has been suggested that the dynamic assembly of septin, including the processes from septin initially localizing to the presumptive bud site to the septin collar finally splitting into two cells, coordinates closely with the checkpoint response of cell cycle. Here, we discovered that over-expression of Alcohol sensitive Ring/PHD finger 1 protein (Asr1p) in Saccharomyces cerevisiae triggered the Swe1p-dependent cell cycle checkpoint for a G2/M transition delay, and this G2/M transition delay was caused by the septin defect. Since it was shown that Asr1p affected actin dynamics through the interaction with Crn1p and crn1 should be epistatic to asr1 in the regulation of actin, the gene knockout of crn1 in the Asr1p over-expression strain restored the defects in septin and cell cycle along with the disordered actin dynamics. Our investigation further showed that the disturbed septin assembly caused by abnormal Asr1p lead to the abnormal localization of the checkpoint proteins such as Gla4/PAK and Cdc5/Polo, and finally triggered the Swe1p-dependent G2/M transition arrest. Additionally, the Ring finger/PHD domains of Asr1p were illustrated to be required but not sufficient for its role in septin. Taken together, our current data suggested a close relationship in the assembly between septin and actin cytoskeleton, which also partially explained how actin cytoskeleton participated in the regulation of the checkpoint of G2/M.