Lactobacillus rhamnosus GG ameliorates DON-induced intestinal damage depending on the enrichment of beneficial bacteria in weaned piglets

Background: Deoxynivalenol(DON) is one of the most common environmental pollutants that induces intestinal inflammation and microbiota dysbiosis. Lactobacillus rhamnosus GG(LGG) is a probiotic that not only has anti-inflammatory effects, but also shows protective effect on the intestinal barrier. However, it is still unknown whether LGG exerts beneficial effects against DON-induced intestinal damage in piglets. In this work, a total of 36 weaned piglets were randomized to one of four treatment groups for 21 d. The treatment groups were CON(basal diet);LGG(basal diet supplemented with 1.77 × 10^(11)CFU/kg LGG);DON(DON-contaminated diet) and LGG + DON(DON-contaminated diet supplemented with 1.77 × 10^(11)CFU/kg LGG).Result: Supplementation of LGG can enhance growth performance of piglets exposed to DON by improving intestinal barrier function. LGG has a mitigating effect on intestinal inflammation induced by DON exposure, largely through repression of the TLR4/NF-κB signaling pathway. Furthermore, supplementation of LGG increased the relative abundances of beneficial bacteria(e.g., Collinsella, Lactobacillus, Ruminococcus_torques_group and Anaerofustis), and decreased the relative abundances of harmful bacteria(e.g., Parabacteroides and Ruminiclostridium_6), and also promoted the production of SCFAs.Conclusions: LGG ameliorates DON-induced intestinal damage, which may provide theoretical support for the application of LGG to alleviate the adverse effects induced by DON exposure.

Gut immune response in the presence of hepatitis C virus infection

Hepatitis C virus(HCV) is an important etiologic agent of hepatitis and a major cause of chronic liver infection that often leads to cirrhosis, fibrosis and hepatocellular carcinoma. Although, HCV is a hepatotropic virus, there is strong evidence that HCV could replicate extrahepatic in the gastrointestinal tissue which could serve as a reservoir for HCV. The outcome of HCV infection depends mainly on the host innate and adaptive immune responses. Innate immunity against HCV includes mainly nuclear factor cells and activation of IFN-related genes. There is an immunologic link between the gut and the liver through a population of T-cells that are capable of homing to both the liver and gut via the portal circulation. However, little is known on the role of Gut immune response in HCV. In this review we discussed the immune regulation of Gut immune cells and its association with HCV pathogenesis, various outcomes of anti-HCV therapy, viral persistence and degree of liver inflammation. Additionally, we investigated the relationship between Gut immune responses to HCV and IL28Bgenotypes, which were identified as a strong predictor for HCV pathogenesis and treatment outcome after acute infection.

Sphingosine 1-phosphate in inflammation

Sphingolipids are formed via the metabolism of sphingomyelin,aconstituent of the plasma membrane.or by denovosynthesis.Enzymatic pathways result in the formation of sevenal different lipid meiators,which are knowm to bave important roles in many elllar proceses.imcluding polfeatioe,apoptosis and migation Several studies nDowr suggest that these shingolipid mediators,inchding cenamide,ceramside i-pbosphate and sphingosine 1-pbosphate(SIP).are likely to have a integral role in infamation.This can involve,for example activation of po-inammatory transcription factors in different cell types and indiuction of cyloxygenase-2.leading t如o productio of pro-inamatory prostaglandins.The mode of action of each sphingolipid is different.Increased ceramide production leads to the formation of ceramide-rich areas of the membnane.which may assemble sigalling compleses,whereas SIP acts via b-affnity G-protein-coupled SIP receptors on the plasma membrane.Recent studies bave demonstated that in vitro efects of sphingolipids o infammation can translate into in vivo models.This review will higblight the areas of research where spbingolipids ae involved in infamomation and the mecharisms of acion of each mediator.In adirion,the therpeutic poternial of dinugs that alter sphingolipid actions mill be exmined with reference to disease states,such as asthma and infammatary bowel disease,which invove importanot ifmaxmsutory components.A signifcant body of research now indicates that sphingolipids ure intimately inolved in the infammatory process and recent studies have demonstated that these lipids.together with associated enzymes and receptors,can provide effective drug targets for the treatment of pathological inflammation.

The risk factors and threshold level of subchronic inhalation exposure of reclaimed water

Inhalation of reclaimed water is known to cause lung infammation,and free endotoxins have been shown to be a major risk factor for acute exposure.Subchronic exposure has also been shown to induce infammatory responses with visible tissue damage.However,subchronic risk factors have yet to be identified,and a threshold for the protection of occupational populations during urban reuse is necessary.In this study,potential risk factors in reclaimed water were examined by subchronic exposure with fractionated reclaimed water,and the health risk threshold was tested with a series of diluted reclaimed water.Accordingly,following a 12-week exposure,macromolecules and microorganisms were found to be two major risk factors in reclaimed water that could cause pulmonary infammation,including increased proportion of polymorphonuclear leukocytes in bronchoalveolar fuid,formation of inducible bronchus-associated lymphoid tissue,and elevation of Immunoglobulin A levels.Moreover,infammation persisted after a 4-week recovery period.The calculated threshold of reclaimed water exposure for mice was 31.8 Endotoxin Unit(EU)/(kg·day)under when exposed to 50%additional relative humidity from reclaimed water at 25℃ for 2 hr/day.Meanwhile,the subchronic threshold estimate for humans under the same exposure conditions was found to be 12.2 EU/(kg·day),corresponding to endotoxin levels of 61.7 EU/mL in reclaimed water.The threshold level of endotoxin was lower than that in most non-potable reclaimed water.The findings of this study suggest that occupational exposure of reclaimed water can serve as a potential risk to workers.

Mitochondrial Regulation of Macrophages in Innate Immunity and Diverse Roles of Macrophages During Cochlear Inflammation

Macrophages are essential components of the innate immune system and constitute a non-specific first line of host defense against pathogens and inflammation.Mitochondria regulate macrophage activation and innate immune responses in various inflammatory diseases,including cochlear inflammation.The distribution,number,and morphological characteristics of cochlear macrophages change significantly across different inner ear regions under various pathological conditions,including noise exposure,ototoxicity,and age-related degeneration.However,the exact mechanism underlying the role of mitochondria in macrophages in auditory function remains unclear.Here,we summarize the major factors and mitochondrial signaling pathways(e.g.,metabolism,mitochondrial reactive oxygen species,mitochondrial DNA,and the inflammasome)that influence macrophage activation in the innate immune response.In particular,we focus on the properties of cochlear macrophages,activated signaling pathways,and the secretion of inflammatory cytokines after acoustic injury.We hope this review will provide new perspectives and a basis for future research on cochlear inflammation.

Role of inflammatory lipid and fatty acid metabolic abnormalities induced by plastic additives exposure in childhood asthma

Lipid metabolism play an essential role in occurrence and development of asthma,and it can be disturbed by phthalate esters(PAEs)and organophosphate fame retardants(OPFRs).As a chronic infammatory respiratory disease,the occurrence risk of childhood asthma is increased by PAEs and OPFRs exposure,but it remains not entirely clear how PAEs and OPFRs contribute the onset and progress of the disease.We have profiled the serum levels of PAEs and OPFRs congeners by liquid chromatography coupled with mass spectrometry,and its relationships with the dysregulation of lipid metabolism in asthmatic,bronchitic(acute infammation)and healthy(non-infammation)children.Eight PAEs and nine OPFRs congeners were found in the serum of children(1–5 years old)from Shenzhen,and their total median levels were 615.16 ng/m L and 17.06 ng/m L,respectively.Moreover,the serum levels of mono-methyl phthalate(MMP),tri-propyl phosphate(TPP)and tri-n-butyl phosphate(TNBP)were significant higher in asthmatic children than in healthy and bronchitic children as control.Thirty-one characteristic lipids and fatty acids of asthma were screened by machine-learning random forest model based on serum lipidome data,and the alterations of infammatory characteristic lipids and fatty acids including palmitic acids,12,13-Di HODE,14,21-Di HDHA,prostaglandin D2 and Lyso PA(18:2)showed significant correlated with high serum levels of MMP,TPP and TNBP.These results imply PAEs and OPFRs promote the occurrence of childhood asthma via disrupting infammatory lipid and fatty acid metabolism,and provide a novel sight for better understanding the effects of plastic additives on childhood asthma.

Discovery of a natural small‑molecule AMP‑activated kinase activator that alleviates nonalcoholic steatohepatitis

Non-alcoholic steatohepatitis(NASH)is a primary cause of cirrhosis and hepatocellular carcinoma.Unfortunately,there is no approved drug treatment for NASH.AMP-activated kinase(AMPK)is an important metabolic sensor and whole-body regulator.It has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity,type 2 diabetes and NASH.In this study,we screened a marine natural compound library by monitoring AMPK activity and found a potent AMPK activator,candidusin A(CHNQD-0803).Further studies showed that CHNQD-0803 directly binds recombinant AMPK with a K_(D) value of 4.728×10^(-8) M and activates AMPK at both molecular and intracellular levels.We then investigated the roles and mechanisms of CHNQD-0803 in PA-induced fat deposition,LPS-stimulated infammation,TGF-β-induced fbrosis cell models and the MCD-induced mouse model of NASH.The results showed that CHNQD-0803 inhibited the expression of adipogenesis genes and reduced fat deposition,negatively regulated the NF-κB-TNFαinfammatory axis to suppress infammation,and ameliorated liver injury and fbrosis.These data indicate that CHNQD-0803 as an AMPK activator is a novel potential therapeutic candidate for NASH treatment.

Schaftoside inhibits 3CL^(pro)and PL^(pro)of SARS-CoV-2 virus and regulates immune response and inflammation of host cells for the treatment of COVID-19

It is an urgent demand worldwide to control the coronavirus disease 2019(COVID-19)pandemic caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)virus.The 3-chymotrypsin-like protease(3CL^(pro))and papain-like protease(PL^(pro))are key targets to discover SARS-CoV-2 inhibitors.After screening 12 Chinese herbal medicines and 125 compounds from licorice,we found that a popular natural product schaftoside inhibited 3CL^(pro)and PL^(pro)with IC_(50)values of 1.73±0.22 and 3.91±0.19μmol/L,respectively,and inhibited SARS CoV-2 virus in Vero E6 cells with EC_(50)of 11.83±3. 23μmol/L. Hydrogen-deuterium exchange mass spectrometry analysis, quantum mechanics/molecular mechanics calculations, together with site-directed mutagenesis indicated the antiviral activities of schaftoside were related with non-covalent interactions with H41, G143 and R188 of3CLpro, and K157, E167 and A246 of PLpro. Moreover, proteomics analysis and cytokine assay revealed that schaftoside also regulated immune response and inflammation of the host cells. The antiinflammatory activities of schaftoside were confirmed on lipopolysaccharide-induced acute lung injury mice. Schaftoside showed good safety and pharmacokinetic property, and could be a promising drug candidate for the prevention and treatment of COVID-19.

Site-selective oral delivery of therapeutic antibodies to the inflamed colon via a folic acid-grafted organic/inorganic hy brid nanocomposite system

This study aimed to develop a pH-responsive folic acid-grafted organic/inorganic hybrid nanocomposite system for site-selective oral delivery of therapeutic antibodies. A folic acid-grafted aminoclay(FA-AC) was prepared via an in situ sol-gel method. Then, a drug-loaded nanocomplex was prepared via the electrostatic interaction of FA-AC with infliximab(IFX), a model antibody, and coated with Eudragit? S100(EFA-AC-IFX). FA-AC exhibited favorable profiles as a drug carrier including low cytotoxicity, good target selectivity, and capability to form a nanocomplex with negatively charged macromolecules. A pH-responsive FA-AC-based nanocomplex containing IFX(EFA-AC-IFX) was also obtained in a narrow size distribution with high entrapment efficiency(>87%). The conformational stability of IFX entrapped in EFA-AC-IFX was well maintained in the presence of proteolytic enzymes. EFA-ACIFX exhibited pH-dependent drug release, minimizing premature drug release in gastric conditions and the upper intestine. Accordingly, oral administration of EFA-AC-IFX to colitis-induced mice was effective in alleviating the progression of ulcerative colitis, while oral IFX solution had no efficacy. These results suggest that a pH-responsive FA-AC-based nanocomposite system can be a new platform for the site-selective oral delivery of therapeutic antibodies.