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,...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.展开更多
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...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.展开更多
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 immun...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.展开更多
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-i...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.展开更多
AIM： To evaluate determinants of infammatory mark-ers in chronic renal failure patients according to the level of glomerular fltration rate. METHODS： One hundred ffty four patients （Age： 44 ± 06 years; male/f...AIM： To evaluate determinants of infammatory mark-ers in chronic renal failure patients according to the level of glomerular fltration rate. METHODS： One hundred ffty four patients （Age： 44 ± 06 years; male/female： 66/88） with chronic renal fail-ure （CRF） were divided into 6 groups according to the National Kidney Foundation （NKF） classification. They included 28 primary stage renal failure patients （CRF 1）, 28 moderate stage renal failure patients （CRF 2）,28 severe stage renal failure patients （CRF 3）, 18 end-stage renal failure patients （CRF 4）, 40 hemodialysis （HD） patients, and 12 peritoneal dialysis （PD） patients. Tumor necrosis factor-α （TNF-α）, interleukin-1β （IL-1β）, interleukin-6 （IL-6） and C-reactive protein （CRP） were analyzed by immunosorbent assay kit （ELISA） （Cayman Chemical’s ACETM EIA kit）. Immunoassay methods were used for total homocysteine （tHcy） （fuorescence polarization immunoanalysis HPLC, PerkinEmer 200 series）, transferrin （MININEPHTM human transferin kit： ZK070.R）, ferritin （ADVIA Centaur ） and fbrinogen analysis （ACL 200）. Differences between groups were performed using SPSS 20.0 and data are expressed as the mean ± SD.RESULTS： Results showed that in comparison with CRF 1 group and other groups, TNF-α and IL-6 levels were respectively more elevated in HD （16.38 ± 5.52 pg/mL vs 0.39 ± 0.03 pg/mL, 11.05 ± 3.59 pg/mL vs 8.20 ± 0.22 pg/mL, P 〈 0.001） and PD （14.04 ± 3.40 pg/mL vs 0.39 ± 0.03 pg/mL, 10.15 ± 1.66 pg/mL vs 8.20 ± 0.22 pg/mL, P 〈 0.001）. IL-1β levels were increased in HD （9.63 ± 3.50 pg/mL vs 3.24 ± 0.10 pg/mL, P 〈 0.001） and CRF 4 （7.76 ± 0.66 pg/mL vs 3.24 ± 0.10 pg/mL, P 〈 0.001） patients than in CRF 1 and in the other groups. Plasma tHcy levels were higher in HD （32.27 ± 12.08 μmol/L） and PD （28.37 ± 4.98 μmol/L） patients compared to the other groups of CRF （P 〈 0.001）. The serum CRP level was signifcantly increased in HD （18.17 ± 6.38 mg/L） and PD （17.97 ± 4.85 mg/L） patients compared to the other groups of CRF patients （P 〈 0.001）. The plasma fbrinogen level was more elevated in HD （6.86 ± 1.06 g/L） and CRF 4 （6.05 ± 0.57 g/L） than in the other groups （ P 〈 0.001）. Furthermore; the ferritin level was higher in HD （169.90 ± 62.16 ng/mL） and PD （90.08 ± 22.09 ng/mL） pa-tients compared to the other groups of CRF （P 〈 0.001）. The serum transferrin value was signifcantly decreased especially in PD （1.78 ± 0.21 g/L） compared to the oth-er groups （P 〈 0.001）. We found a negative correlation between glomerular fltration rate （GFR）, TNF-α levels （ r = -0.75, P 〈 0.001）, and tHcy levels （ r = -0.68, P 〈 0.001）. We observed a positive correlation between GFR and transferrin levels （ r = 0.60, P 〈 0.001）. CONCLUSION： CRF was associated with elevated in-flammatory markers. The inflammation was observed at the severe stage of CRF and increases with progres-sion of renal failure.展开更多
AIM： To investigate the predictive value of low freeT3 for long-term mortality in chronic hemodialysis （HD） patients and explore a possible causative role of chronic infammation.METHODS： One hundred fourteen HD pa...AIM： To investigate the predictive value of low freeT3 for long-term mortality in chronic hemodialysis （HD） patients and explore a possible causative role of chronic infammation.METHODS： One hundred fourteen HD patients （84 males） consecutively entered the study and were assessed for thyroid function and two established markers of inflammation, high sensitivity C-reactive protein （hsCRP） and interleukin-6 （IL-6）. Monthly blood samples were obtained from all patients for three consecutive months during the observation period for evaluation of thyroid function and measurement of infammatory markers. The patients were then divided in two groups based on the cut-off value of 1.8 pg/mL for mean plasma freeT3, and were prospectively studied for a mean of 50.3 ± 30.8 mo regarding cumulative survival. The prognostic power of low serum fT3 levels for mortality was assessed using the Kaplan-Meier method and univariate and multivariate regression analysis.RESULTS： Kaplan-Meier survival curve showed a negative predictive power for low freeT3. In Cox regression analysis low freeT3 remained a significant predictor of mortality after adjustment for age, diabetes mellitus, hypertension, hsCRP, serum creatinine and albumin. Regarding the possible association with inflammation, freeT3 was correlated with hsCRP, but not IL-6, and only at the frst month of the study.CONCLUSION： In chronic hemodialysis patients, low plasma freeT3 is a significant predictor of all-cause mortality. Further studies are required to identify the underlying mechanisms of this association.展开更多
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 hepatocel-lular carcinoma. Although, HCV is a hepatotropi...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 hepatocel-lular carcinoma. Although, HCV is a hepatotropic virus, there is strong evidence that HCV could replicate extra-hepatic 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 im-mune 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 ca-pable 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 as-sociation with HCV pathogenesis, various outcomes of anti-HCV therapy, viral persistence and degree of liver infammation. Additionally, we investigated the relation-ship between Gut immune responses to HCV and IL28B genotypes, which were identifed as a strong predictor for HCV pathogenesis and treatment outcome after acute infection.展开更多
Mammalian chitinases and the related chilectins （ChiLs） belong to the GH18 family, which hydrolyse the glycosidic bond of chitin by a substrate-assisted mechanism. Chitin the fundamental component in the coating of ...Mammalian chitinases and the related chilectins （ChiLs） belong to the GH18 family, which hydrolyse the glycosidic bond of chitin by a substrate-assisted mechanism. Chitin the fundamental component in the coating of numerous living species is the most abundant natural biopolymer. Mounting evidence suggest that the function of the majority of the mammalian chitinases is not exclusive to catalyze the hydrolysis of chitin producing pathogens, but include crucial role specifc in the immunologic activities. The chitinases and chitinase-like proteins are expressed in response to different proinflammatory cues in various tissues by activated macrophages, neutrophils and in different monocyte-derived cell lines. The mechanism and molecular interaction of chitinases in relation to immune regulation embrace bacterial infection, infammation, dismetabolic and degenerative disease. The aim of this review is to update the reader with regard to the role of chitinases proposed in the recent innate and adaptive immunity literature. The deep scrutiny of this family of enzymes could be a useful base for further studies addressed to the development of potential procedure directing these molecules as diagnostic and prognostic markers for numerous immune and infammatory diseases.展开更多
Cluster of differentiation 74 （CD74） performs multiple roles in B cells, T cells, and antigen-presenting cells within the immune system; it also participates in ma-jor histocompatibility complex class Ⅱ-restricted ...Cluster of differentiation 74 （CD74） performs multiple roles in B cells, T cells, and antigen-presenting cells within the immune system; it also participates in ma-jor histocompatibility complex class Ⅱ-restricted an-tigen presentation and inflammation. Recently, a role for CD74 in carcinogenesis has been described. CD74 promotes cell proliferation and motility and prevents cell death in a macrophage migration inhibitory factor-dependent manner. Its roles as an accessory signal receptor on the cell surface and the ability to interact with other signaling molecules make CD74 an attrac-tive therapeutic target for the treatment of cancer. This review focuses on the original role of CD74 in the immune system and its emerging tumor-related func-tions. First, the structure of CD74 will be summarized. Second, the current understandings about the expres-sion, cellular localization, molecular mechanisms and signaling pathways of CD74 in immunity and cancer will be reviewed. Third, the examples that suggest CD74 is a promising molecular therapeutic target are reviewed and discussed. Although the safety and ef-fcacy of CD74-targeted strategies are under develop-ment, deeply understanding of the regulation of CD74 will hold promise for the use of CD74 as a therapeutic target and may develop the CD74-targeted therapeutic agents such as neutralized antibody and compounds.展开更多
Lysophosphatidic acid （LPA） is a pleiotropic lipid med-iator that promotes motility, survival, and the synthesis of chemokines/cytokines in human fbroblast-like syno-viocytes （FLS） from patients with rheumatoid ar...Lysophosphatidic acid （LPA） is a pleiotropic lipid med-iator that promotes motility, survival, and the synthesis of chemokines/cytokines in human fbroblast-like syno-viocytes （FLS） from patients with rheumatoid arthritis. LPA activates several proteins within the mitogen acti-vated protein （MAP） kinase signaling network, including extracellular signal-regulated kinases （ERK） 1/2 and p38 MAP kinase （MAPK）. Upon docking to mitogen and stress-activated kinases （MSKs）, ERK1/2 and p38 MAPK phosphorylate serine and threonine residues within its C-terminal domain and cause autophosphorylation of MSKs. Activated MSKs can then directly phosphorylate cAMP response element-binding protein （CREB） at Ser133 in FLS. Phosphorylation of CREB by MSKs is essential for the production of pro-inflammatory and anti-infammatory cytokines. However, other downstream effectors of MSK1/2 such as nuclear factor-kappa B, histone H3, and high mobility group nucleosome binding domain 1 may also regulate gene expression in immune cells involved in disease pathogenesis. MSKs are master regulators of cell function that integrate signals induced by growth factors, proinflammatory cytokines, and cellular stresses, as well as those induced by LPA.展开更多
Systemic infammation is a recognized feature in chronic kidney disease （CKD）. The role of systemic infammation in the pathogenesis of vascular calcifcation was recently settled. FGF23 was recently accused as a direc...Systemic infammation is a recognized feature in chronic kidney disease （CKD）. The role of systemic infammation in the pathogenesis of vascular calcifcation was recently settled. FGF23 was recently accused as a direct stimulus of systemic inflammation. This finding explains the strong association of FGF23 to vascular calcifcation and increased mortality among CKD.展开更多
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 ...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.展开更多
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 ...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.展开更多
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...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.展开更多
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 prepar...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.展开更多
基金supported by the National Natural Science Foundation of China (Nos.22076197,21707149 and 82127801)the Scientific Instrument Developing Project of the Chinese Academy of Sciences (No.YJKYYQ20200034)+1 种基金Shenzhen Science and Technology Research Funding (Nos.JCYJ20210324115811031 and JCYJ20200109115405930)Guangdong Basic and Applied Basic Research Foundation (No.2020B1515120080)。
文摘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.
基金supported by the National Natural Science Foundation of China (Nos.51738005 and 21777084)。
文摘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.
基金supported by the China Postdoctoral Science Foundation(2022M712892)the Joint project Henan Province Medical Science and Technology Project(LHGJ20210297).
文摘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.
基金supported by the Natural Science Foundation of Heilongjiang Province(TD2019C001)the National Natural Science Foundation of China(U21A20251)the State Key Program of National Natural Science Foundation of China(32030101).
文摘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.
文摘AIM： To evaluate determinants of infammatory mark-ers in chronic renal failure patients according to the level of glomerular fltration rate. METHODS： One hundred ffty four patients （Age： 44 ± 06 years; male/female： 66/88） with chronic renal fail-ure （CRF） were divided into 6 groups according to the National Kidney Foundation （NKF） classification. They included 28 primary stage renal failure patients （CRF 1）, 28 moderate stage renal failure patients （CRF 2）,28 severe stage renal failure patients （CRF 3）, 18 end-stage renal failure patients （CRF 4）, 40 hemodialysis （HD） patients, and 12 peritoneal dialysis （PD） patients. Tumor necrosis factor-α （TNF-α）, interleukin-1β （IL-1β）, interleukin-6 （IL-6） and C-reactive protein （CRP） were analyzed by immunosorbent assay kit （ELISA） （Cayman Chemical’s ACETM EIA kit）. Immunoassay methods were used for total homocysteine （tHcy） （fuorescence polarization immunoanalysis HPLC, PerkinEmer 200 series）, transferrin （MININEPHTM human transferin kit： ZK070.R）, ferritin （ADVIA Centaur ） and fbrinogen analysis （ACL 200）. Differences between groups were performed using SPSS 20.0 and data are expressed as the mean ± SD.RESULTS： Results showed that in comparison with CRF 1 group and other groups, TNF-α and IL-6 levels were respectively more elevated in HD （16.38 ± 5.52 pg/mL vs 0.39 ± 0.03 pg/mL, 11.05 ± 3.59 pg/mL vs 8.20 ± 0.22 pg/mL, P 〈 0.001） and PD （14.04 ± 3.40 pg/mL vs 0.39 ± 0.03 pg/mL, 10.15 ± 1.66 pg/mL vs 8.20 ± 0.22 pg/mL, P 〈 0.001）. IL-1β levels were increased in HD （9.63 ± 3.50 pg/mL vs 3.24 ± 0.10 pg/mL, P 〈 0.001） and CRF 4 （7.76 ± 0.66 pg/mL vs 3.24 ± 0.10 pg/mL, P 〈 0.001） patients than in CRF 1 and in the other groups. Plasma tHcy levels were higher in HD （32.27 ± 12.08 μmol/L） and PD （28.37 ± 4.98 μmol/L） patients compared to the other groups of CRF （P 〈 0.001）. The serum CRP level was signifcantly increased in HD （18.17 ± 6.38 mg/L） and PD （17.97 ± 4.85 mg/L） patients compared to the other groups of CRF patients （P 〈 0.001）. The plasma fbrinogen level was more elevated in HD （6.86 ± 1.06 g/L） and CRF 4 （6.05 ± 0.57 g/L） than in the other groups （ P 〈 0.001）. Furthermore; the ferritin level was higher in HD （169.90 ± 62.16 ng/mL） and PD （90.08 ± 22.09 ng/mL） pa-tients compared to the other groups of CRF （P 〈 0.001）. The serum transferrin value was signifcantly decreased especially in PD （1.78 ± 0.21 g/L） compared to the oth-er groups （P 〈 0.001）. We found a negative correlation between glomerular fltration rate （GFR）, TNF-α levels （ r = -0.75, P 〈 0.001）, and tHcy levels （ r = -0.68, P 〈 0.001）. We observed a positive correlation between GFR and transferrin levels （ r = 0.60, P 〈 0.001）. CONCLUSION： CRF was associated with elevated in-flammatory markers. The inflammation was observed at the severe stage of CRF and increases with progres-sion of renal failure.
文摘AIM： To investigate the predictive value of low freeT3 for long-term mortality in chronic hemodialysis （HD） patients and explore a possible causative role of chronic infammation.METHODS： One hundred fourteen HD patients （84 males） consecutively entered the study and were assessed for thyroid function and two established markers of inflammation, high sensitivity C-reactive protein （hsCRP） and interleukin-6 （IL-6）. Monthly blood samples were obtained from all patients for three consecutive months during the observation period for evaluation of thyroid function and measurement of infammatory markers. The patients were then divided in two groups based on the cut-off value of 1.8 pg/mL for mean plasma freeT3, and were prospectively studied for a mean of 50.3 ± 30.8 mo regarding cumulative survival. The prognostic power of low serum fT3 levels for mortality was assessed using the Kaplan-Meier method and univariate and multivariate regression analysis.RESULTS： Kaplan-Meier survival curve showed a negative predictive power for low freeT3. In Cox regression analysis low freeT3 remained a significant predictor of mortality after adjustment for age, diabetes mellitus, hypertension, hsCRP, serum creatinine and albumin. Regarding the possible association with inflammation, freeT3 was correlated with hsCRP, but not IL-6, and only at the frst month of the study.CONCLUSION： In chronic hemodialysis patients, low plasma freeT3 is a significant predictor of all-cause mortality. Further studies are required to identify the underlying mechanisms of this association.
基金Supported by Egyptian Government Scholarship for Helal HettaMerck Investigator Initiated Studies(IIS)IISP,No.40458(Shata)
文摘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 hepatocel-lular carcinoma. Although, HCV is a hepatotropic virus, there is strong evidence that HCV could replicate extra-hepatic 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 im-mune 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 ca-pable 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 as-sociation with HCV pathogenesis, various outcomes of anti-HCV therapy, viral persistence and degree of liver infammation. Additionally, we investigated the relation-ship between Gut immune responses to HCV and IL28B genotypes, which were identifed as a strong predictor for HCV pathogenesis and treatment outcome after acute infection.
文摘Mammalian chitinases and the related chilectins （ChiLs） belong to the GH18 family, which hydrolyse the glycosidic bond of chitin by a substrate-assisted mechanism. Chitin the fundamental component in the coating of numerous living species is the most abundant natural biopolymer. Mounting evidence suggest that the function of the majority of the mammalian chitinases is not exclusive to catalyze the hydrolysis of chitin producing pathogens, but include crucial role specifc in the immunologic activities. The chitinases and chitinase-like proteins are expressed in response to different proinflammatory cues in various tissues by activated macrophages, neutrophils and in different monocyte-derived cell lines. The mechanism and molecular interaction of chitinases in relation to immune regulation embrace bacterial infection, infammation, dismetabolic and degenerative disease. The aim of this review is to update the reader with regard to the role of chitinases proposed in the recent innate and adaptive immunity literature. The deep scrutiny of this family of enzymes could be a useful base for further studies addressed to the development of potential procedure directing these molecules as diagnostic and prognostic markers for numerous immune and infammatory diseases.
基金Supported by National Science Council of Taiwan,No.NSC 98-2320-B-002-050-MY2 and No.NSC 102-2320-B-039-032-MY3
文摘Cluster of differentiation 74 （CD74） performs multiple roles in B cells, T cells, and antigen-presenting cells within the immune system; it also participates in ma-jor histocompatibility complex class Ⅱ-restricted an-tigen presentation and inflammation. Recently, a role for CD74 in carcinogenesis has been described. CD74 promotes cell proliferation and motility and prevents cell death in a macrophage migration inhibitory factor-dependent manner. Its roles as an accessory signal receptor on the cell surface and the ability to interact with other signaling molecules make CD74 an attrac-tive therapeutic target for the treatment of cancer. This review focuses on the original role of CD74 in the immune system and its emerging tumor-related func-tions. First, the structure of CD74 will be summarized. Second, the current understandings about the expres-sion, cellular localization, molecular mechanisms and signaling pathways of CD74 in immunity and cancer will be reviewed. Third, the examples that suggest CD74 is a promising molecular therapeutic target are reviewed and discussed. Although the safety and ef-fcacy of CD74-targeted strategies are under develop-ment, deeply understanding of the regulation of CD74 will hold promise for the use of CD74 as a therapeutic target and may develop the CD74-targeted therapeutic agents such as neutralized antibody and compounds.
基金Supported by A research grant from the Arthritis Society of CanadaNo.RG10/011(to Bourgoin SG)
文摘Lysophosphatidic acid （LPA） is a pleiotropic lipid med-iator that promotes motility, survival, and the synthesis of chemokines/cytokines in human fbroblast-like syno-viocytes （FLS） from patients with rheumatoid arthritis. LPA activates several proteins within the mitogen acti-vated protein （MAP） kinase signaling network, including extracellular signal-regulated kinases （ERK） 1/2 and p38 MAP kinase （MAPK）. Upon docking to mitogen and stress-activated kinases （MSKs）, ERK1/2 and p38 MAPK phosphorylate serine and threonine residues within its C-terminal domain and cause autophosphorylation of MSKs. Activated MSKs can then directly phosphorylate cAMP response element-binding protein （CREB） at Ser133 in FLS. Phosphorylation of CREB by MSKs is essential for the production of pro-inflammatory and anti-infammatory cytokines. However, other downstream effectors of MSK1/2 such as nuclear factor-kappa B, histone H3, and high mobility group nucleosome binding domain 1 may also regulate gene expression in immune cells involved in disease pathogenesis. MSKs are master regulators of cell function that integrate signals induced by growth factors, proinflammatory cytokines, and cellular stresses, as well as those induced by LPA.
文摘Systemic infammation is a recognized feature in chronic kidney disease （CKD）. The role of systemic infammation in the pathogenesis of vascular calcifcation was recently settled. FGF23 was recently accused as a direct stimulus of systemic inflammation. This finding explains the strong association of FGF23 to vascular calcifcation and increased mortality among CKD.
基金Key Research and Development Project of Shanxi Province(201903D221009)。
文摘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.
基金supported by National Natural Science Foundation of China(Nos.81891010/81891011,81725023,82003614,82173950,31770192,32070187 and 82003681)China Postdoctoral Science Foundation(2022T150029,China)+1 种基金the National Key Research and Development Program of China(No.2017-YFC1700405)the Science&Technology Department of Xinjiang Uygur Autonomous Region(2018AB012,China)。
文摘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.
基金This work was supported by the“Frontier Technology and Free Exploration”Special Project of Laoshan Laboratory(No.8-01)the Program of National Natural Science Foundation of China(Nos.82273846,U1706210,81871868,41776141,and 41322037)+3 种基金the Program of Natural Science Foundation of Shandong Province of China(No.JQ201510)the Fundamental Research Funds for the Central Universities(Nos.201841004 and 202042011)the Marine S&T Fund of Shandong Province for Pilot National Laboratory for Marine Science and Technology(Qingdao)(Nos.2018SDKJ0403-2 and 2015ASKJ02)the Taishan Scholars Program,China(No.tsqn20161010).
文摘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.
基金supported by National Research Foundation of Korea (NRF)South Korea grant funded by the Korea government(MSIT)(Nos. 2019R1A2C2004873 and 2018R1A5A2023127)the BK21 FOUR program through the National Research Foundation (NRF) funded by the Ministry of Education of Korea
文摘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.
