TLR9 is important for protection against intestinal damage and for intestinal repair.
Ontology highlight
ABSTRACT:
SUBMITTER: Rose WA
PROVIDER: S-EPMC3418518 | biostudies-other | 2012
REPOSITORIES: biostudies-other
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Project description:Gut-liver axis and cellular homeostasis play key roles in alcohol liver disease (ALD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a stress-sensitive guarantor of cellular homeostasis. We investigated whether the beneficial effects and underlying mechanisms of Jia-ga-song Tang (JGST) against ALD were associated with gut-liver axis and cellular homeostasis. A predictive network depicting the relationship between Jia-Ga-Song-Tang (JGST) and alcoholic liver disease (ALD) was designed by Network pharmacology. Next, 5% v/v Lieber-DeCarli alcohol liquid diet was used to establish the ALD. JGST protected the liver damage, repaired the intestines to alleviate the Two-hit on the liver, and balanced the cellular homeostasis. It was manifested in repairing the liver and intestinal pathological structure, reducing serum ALT, AST, and liver TG, TC, MDA, CAT, and increasing liver GSH, and intestine GSH-Px. JGST mainly inhibited the liver mRNA levels of HO-1, NQO1, GCLC, FASN, and PPARα and activated the intestinal mRNA levels of HO-1 and NQO1, while inhibiting the liver protein levels of HO-1, NQO1. Furthermore, LPS and LBP in the plasma and the expression of inflammatory factors such as IL-1β, TNF-α, IL-6, TGFβ1, CD14, and Myd88 were reduced after treatment to prove that JGST protects the liver from Two-hit. Ethanol was used to intervene in HepG2 and IEC-6 to establish an ALD cell model and treated by Germacrone, ML385, and TBHQ. repaired the intestinal barrier, and inhibited Nrf2 in IEC-6, but protect the HepG2 by activating Nrf2 to balance cellular homeostasis. Our results reinforce that JGST provides an effective protective method for alcoholic liver disease (ALD) by regulating Gut-liver axis and cellular homeostasis.
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Project description:The purpose of this investigation was the determination of the distribution of genotypes at single nucleotide polymorphisms (SNPs) of the toll-like receptor 4 (TLR4) and the toll-like receptor 9 (TLR9) in fetuses and newborns congenitally infected with Toxoplasma gondii and the identification of genetic changes predisposing to infection development. The study involved 20 fetuses and newborns with congenital toxoplasmosis and 50 uninfected controls. The levels of IgG and IgM antibodies against T. gondii, as well as IgG avidity, were estimated by enzyme-linked fluorescent assay (ELFA) tests. T. gondii DNA loads in amniotic fluids were assayed by the real-time (RT) quantitative polymerase chain reaction (Q PCR) technique for parasitic B1 gene. TLR4 and TLR9 SNPs were identified using a self-designed multiplex nested PCR-restriction fragment length polymorphism (RFLP) assay. Randomly selected genotypes at SNPs were confirmed by sequencing. All the genotypes were tested for Hardy-Weinberg equilibrium and TLR4 genotypes were analyzed for linkage disequilibrium. A correlation was studied between the genotypes or haplotypes and the development of congenital toxoplasmosis using a logistic regression model. Single SNP analysis showed no statistically significant differences in the distribution of distinct genotypes at the analyzed TLR4 and TLR9 SNPs between T. gondii-infected fetuses and newborns and the controls. Taking into account the prevalence of alleles residing within polymorphic sites, similar prevalence rates were observed in both of the studied groups. The multiple SNP analysis indicated GTG variants at the TLR4 and TLR9 SNPs to be significantly less frequent in offspring with congenital toxoplasmosis than in uninfected offspring (p ≤ 0.0001). TLR4 and TLR9 SNPs seem to be involved in protection against congenital toxoplasmosis.
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Project description:Extracellular hemoglobin (Hb) has been recognized as a disease trigger in hemolytic conditions such as sickle cell disease, malaria and blood transfusion. In vivo, many of the adverse effects of free Hb can be attenuated by the Hb scavenger acute phase protein haptoglobin (Hp). The primary physiologic disturbances that can be caused be free Hb are found within the cardiovascular system and Hb triggered oxidative toxicity towards the endothelium has been promoted as a potential mechanism. The molecular mechanisms of this toxicity as well as of the protective activities of Hp are not yet clear. Within this study we systematically investigated the structural, biochemical and cell biologic nature of Hb toxicity in an endothelial cell system under peroxidative stress. We identified two principal mechanisms of oxidative Hb toxicity that are mediated by globin degradation products and by modified lipoprotein species, respectively. The two damage pathways trigger diverse and discriminative inflammatory and cytotoxic responses. Hp provides structural stabilization of Hb and shields Hb’s oxidative reactions with lipoproteins providing dramatic protection against both pathways of toxicity. By these mechanisms Hp shifts Hb’s destructive pseudo-peroxidative reaction into a potential anti-oxidative function during peroxidative stress. HPAEC: A two color common reference design was chosen with 4-8 independent biological replicates of each condition. Each experimental sample (Cy5 labeled) was hybridized against a non-treated reference sample (Cy3 labeled). HUVEC: A two color common reference design was chosen with 3-4 independent biological replicates of each condition. Each experimental sample (Cy5 labeled) was hybridized against a non-treated reference sample (Cy3 labeled).
2015-04-30 | E-GEOD-46471 | biostudies-arrayexpress
Project description:During the establishment of an infection, bacterial pathogens encounter oxidative stress resulting in the production of DNA lesions. Majority of these lesions are repaired by base excision repair (BER) pathway. Amongst these, abasic sites are the most frequent lesions in DNA. Class II apurinic/apyrimidinic (AP) endonucleases play a major role in BER of damaged DNA comprising of abasic sites. Mycobacterium tuberculosis, a deadly pathogen, resides in the human macrophages and is continually subjected to oxidative assaults. We have characterized for the first time two AP endonucleases namely Endonuclease IV (End) and Exonuclease III (XthA) that perform distinct functions in M.tuberculosis. We demonstrate that M.tuberculosis End is a typical AP endonuclease while XthA is predominantly a 3'→5' exonuclease. The AP endonuclease activity of End and XthA was stimulated by Mg(2+) and Ca(2+) and displayed a preferential recognition for abasic site paired opposite to a cytosine residue in DNA. Moreover, End exhibited metal ion independent 3'→5' exonuclease activity while in the case of XthA this activity was metal ion dependent. We demonstrate that End is not only a more efficient AP endonuclease than XthA but it also represents the major AP endonuclease activity in M.tuberculosis and plays a crucial role in defense against oxidative stress.
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2015-04-30 | GSE46471 | GEO
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Project description:Inflammatory bowel disease is a chronic gastrointestinal inflammatory disorder associated with changes in neuropeptide expression and function, including vasoactive intestinal peptide (VIP). VIP regulates intestinal vasomotor and secretomotor function and motility; however, VIP's role in development and maintenance of colonic epithelial barrier homeostasis is unclear. Using VIP deficient (VIPKO) mice, we investigated VIP's role in epithelial barrier homeostasis, and susceptibility to colitis. Colonic crypt morphology and epithelial barrier homeostasis were assessed in wildtype (WT) and VIPKO mice, at baseline. Colitic responses were evaluated following dinitrobenzene sulfonic acid (DNBS) or dextran-sodium sulfate (DSS) exposure. Mice were also treated with exogenous VIP. At baseline, VIPKO mice exhibited distorted colonic crypts, defects in epithelial cell proliferation and migration, increased apoptosis, and altered permeability. VIPKO mice also displayed reduced goblet cell numbers, and reduced expression of secreted goblet cell factors mucin 2 and trefoil factor 3. These changes were associated with reduced expression of caudal type homeobox 2 (Cdx2), a master regulator of intestinal function and homeostasis. DNBS and DSS-induced colitis were more severe in VIPKO than WT mice. VIP treatment rescued the phenotype, protecting VIPKO mice against DSS colitis, with results comparable to WT mice. In conclusion, VIP plays a crucial role in the development and maintenance of colonic epithelial barrier integrity under physiological conditions and promotes epithelial repair and homeostasis during colitis.
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