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Avoidance of harmful substances is survival strategy used cross invertebrates and vertebrates. For example, the nematode Caenorhabditis elegans evolves a sufficient avoidance response to pathogenic bacteria. Despite G protein has been found to exert neural plasticity for avoidance behaviours in C. elegans, the function of Gi/o and Gq subunit signalling in experience-dependent aversive behaviour remains unclear. In this study, we show that EGL-30/Gq coupled with EGL-8/UNC-13 regulates aversive behaviour of C. elegans to pathogenic bacterium Pseudomonas aeruginosa PA01 via acetylcholine and its receptor nAChR. Pyocyanin, a toxin secreted from P. aeruginosa, acts as a signal molecule to trigger aversive behaviour. ODR-3 and ODR-7 in AWA and AWC neurons function as upstream of EGL-30 to induce experience-dependent aversive behaviour to P. aeruginosa, respectively. These results suggested that a novel signalling pathway to regulate a behavioural response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Pathogen avoidance behaviors are found throughout the animal kingdom and are important for animal's survival in nature. As a free-living nematode, C. elegans is exposed to a variety of microorganisms, including toxic or pathogenic bacteria, in soil. C. elegans can develop efficient avoidance responses to pathogenic bacteria to minimize the infection risk. However, the role of microRNAs (miRNAs) in pathogen avoidance in C. elegans remains unclear. In this report, we showed that the miRNA mir-67 was involved in a behavioral avoidance response to P. aeruginosa PA14. Exposure to P. aeruginosa PA14 induced the expression of mir-67 in worms. mir-67(n4899) mutants exhibited a reduced ability to avoid P. aeruginosa PA14. By combining quantitative proteomic analysis with miRNA target prediction algorithms, we identified SAX-7/L1CAM, which is transmembrane cell adhesion receptor molecule, as the target of mir-67. Silencing of sax-7 by RNAi on mir-67 mutants rescued avoidance behavioral. Our data demonstrate that the mir-67-SAX-7 pathway modulate the behavioral avoidance response to pathogens, thus providing a new perspective in the role of miRNAs in host-microbe interactions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recently, epidemiological and experimental studies have linked hyperhomocysteinemia (HHcy) to insulin resistance. However, whether HHcy impairs glucose homeostasis by affecting glycogenesis in the liver is not clear. In the present study, we investigated the effect of HHcy on hepatic glycogen synthesis. Hyperhomocysteinemia was induced in mice by drinking water containing two percent methionine. Mice with HHcy showed an increase in the phosphorylation of glycogen synthase and a significant decrease in hepatic glycogen content and the rate of glycogen synthesis. The expression of TRB3 (tribbles-related protein 3) was up-regulated in the liver of mice with HHcy, concomitantly with the dephosphorylation of glycogen synthase kinase-3β and Akt. The knockdown of TRB3 by short hairpin RNA suppressed the dephosphorylation of these two kinases. Homocysteine induced an increase in the levels of hepatic cAMP and cAMP response element-binding protein phosphorylation, which in turn up-regulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α and TRB3. The inhibition of PPAR-α by its inhibitor, MK886, or knockdown of PPAR-α by small interfering RNA significantly inhibited the expression of TRB3 induced by homocysteine. The current study demonstrates that HHcy impairs hepatic glycogen synthesis by inducing the expression of TRB3. These results provide a novel explanation for the development and progression of insulin resistance in HHcy., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Epidemiological and experimental studies have correlated hyperhomocysteinemia to a range of neurodegenerative conditions, including Alzheimer's disease, stroke, and Parkinson's disease. Although homocysteine-induced apoptosis in neurons has been extensively studied, little information is available regarding the effect of homocysteine on microglia. In this report, we demonstrated that homocysteine promoted proliferation and up-regulated the expression of CD11b (a marker of microglial activation). Consistent with our in vitro results, a significant increase in the number of CD11b-positive microglia was also observed in brain sections of mice with hyperhomocysteinemia. Homocysteine promoted the activity of NAD(P)H oxidases, resulting in the generation of reactive oxygen species. Up-regulation of NAD(P)H oxidase activity by homocysteine appears to be due to its ability to induce the phosphorylation of p47phox through the p38 MAPK pathway. Furthermore, inhibition of reactive oxygen species significantly blocked cellular proliferation and activation in microglia. Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases., (Copyright © 2008 Elsevier Inc. All rights reserved.)

Elevated homocysteine levels are defined as hyperhomocysteinemia (HHcy), a disorder that is associated with cardiovascular and neurodegenerative diseases as well as with hepatic fibrosis. Recent studies have shown that HHcy promotes hepatic injury by increasing oxidative stress. Although homocysteine induces cell cycle arrest in a variety of different cell types, it is not known whether HHcy has a definitive role in hepatocyte proliferation during liver regeneration. In this report, we investigated the effect of homocysteine on liver regeneration. Our results demonstrated that mice with HHcy exhibited an impairment in liver regeneration after partial hepatectomy, as measured by immunohistochemical staining of proliferation cell nuclear antigen and bromodeoxyuridine incorporation. Impaired proliferation was also correlated with reduced cyclin D1 induction and elevated expression levels of both p53 and p21Cip1. In addition, the phosphorylation of Akt, which plays an essential role in normal regeneration responses, was attenuated during the early phases of liver regeneration in HHcy mice. Our results also indicated that the cAMP/protein kinase A pathway mediated the inhibitory effect of homocysteine on liver regeneration. These findings provide evidence that impairment of liver regeneration by HHcy may result in delayed recovery from liver injury induced by homocysteine itself.

Cystathionine beta-synthase in mammals lies at a pivotal crossroad in methionine metabolism directing flux toward cysteine synthesis and catabolism. The enzyme exhibits a modular organization and complex regulation. It catalyzes the beta-replacement of the hydroxyl group of serine with the thiolate of homocysteine and is unique in being the only known pyridoxal phosphate-dependent enzyme that also contains heme b as a cofactor. The heme functions as a sensor and modulates enzyme activity in response to redox change and to CO binding. Mutations in this enzyme are the single most common cause of hereditary hyperhomocysteinemia. Elucidation of the crystal structure of a truncated and highly active form of the human enzyme containing the heme- and pyridoxal phosphate binding domains has afforded a structural perspective on mechanistic and mutation analysis studies. The C-terminal regulatory domain containing two CBS motifs exerts intrasteric regulation and binds the allosteric activator, S-adenosylmethionine. Studies with mammalian cells in culture as well as with animal models have unraveled multiple layers of regulation of cystathionine beta-synthase in response to redox perturbations and reveal the important role of this enzyme in glutathione-dependent redox homestasis. This review discusses the recent advances in our understanding of the structure, mechanism, and regulation of cystathionine beta-synthase from the perspective of its physiological function, focusing on the clinically relevant human enzyme.

1-chloro-2,4-dinitrobenzene (CDNB), an intracellular glutathione-depleting agent, has been shown to have an adverse effect on erythrocyte membrane integrity. In the current study, we have demonstrated that CDNB caused haemolysis of human red blood cells (RBC) at higher concentrations (>or= 5 mM). The haemolysis induced by CDNB was preceded by the leakage of K(+) from the cells suggesting the colloid-osmotic nature of this lysis. The inclusion of molecules of increasing size in the extracellular media inhibited both the rate and extent of haemolysis thus supporting the proposal of CDNB-induced pore formation. The size of membrane lesions increased with an increase in the concentration of CDNB. SDS-PAGE demonstrated that CDNB causes the polymerisation and/or fragmentation of membrane proteins. Although CDNB has been shown to cause a drastic reduction in membrane thiols, our data suggest that the CDNB-induced formation of membrane disulfide bonds as a prima facie cause of permeability enhancement is unlikely.