OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a pote...OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.展开更多
OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in hu...OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in human umbilical vein endothelial cells(HUVECs) and smooth muscle cells(SMCs).METHODS 48 Apo-/-E mice,at 6-8 weeks old,were randomly allocated into 4 groups:normal,model,bbr and atorvastatin(positive control) groups with 12 mice in each group.They were fed with high-fat diet for 4 weeks except those in Normal group and then treated with indicated drugs orsolvent for another 4 weeks.The morphology and inflammation infiltration of aortic were examined with HE staining.The expression of BMP-2 in aortic was examined by immumohistochemical staining.Blood lipid levels were examined by automatic biochemical analyzer.The expression of IL-6,TNF-α and BMP-2 in serum and tissues was detected by ELISA method.The expression of ALP and the content of calcium were detected by commercially-available kits.HUVEC cells were stimulated with TNF-α and incubated with various concentrations of BBR for 24 h.The contents of intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule(VCAM-1),matrix metalloprotein-9(MMP-9) in the culture supernatant were detected by ELISA method.Calcification was induced with β-glycerophosphatein SMC cells and the effect of BBR on the content of calcium was examined.RESULTS 4-week berberine treatment markedly lowered serum TC and LDL-c levels and improved the plaque stability in Apo-/-E mice fed with a high-fat diet(P<0.05 or P<0.01) which was comparable with the effect of atorvastatin.Berberineal so significantly decreased the levels of IL-6 and TNF-α in mice serum and aortic tissues(P<0.05 or P<0.001).Berberine tended to decrease ALP,BMP-2 levels and the content of calcium in mice serum and aortic tissues(P<0.05,P<0.01 or P<0.001) which were not observed in atorvastatin group.Berberine significantly lowered the levels of ICAM-1,VCAM-1,and MMP-9 in TNF-α-stimulated HUVECs.It can also lowered the content of calcium in SMCs.CONCLUSION BBR can profitably regulate the levels of blood lipid in mice fed with a high-fat diet,decrease the injury caused by inflammation,and attenuate vascular calcification.It may improve atherosclerosis and play a role in cardiovascular protection.展开更多
OBJECTIVE Hyperactivityof hypothalamic-pituitary-adrenal(HPA) axis is an important aetiological risk factor for the development of depression. Previous studies have demonstrated that the phenolic monomer baicalin has ...OBJECTIVE Hyperactivityof hypothalamic-pituitary-adrenal(HPA) axis is an important aetiological risk factor for the development of depression. Previous studies have demonstrated that the phenolic monomer baicalin has antidepressant-like effects and decreases serum corticosterone levels.However,the mechanism by which baicalin regulates hyperactivity of HPA axis remains unclear. This work aimed to investigate the effects of baicalin on hyperactivity of HPA axis using the olfactory bulbectomised(OBX) rat model of depression. METHODS Animals were anaesthetised with 10% chloral hydrate(3.3 mL·kg^(-1),ip). Using disinfected surgical equipment,the skull covering the olfactory bulbs was exposed by a midline incision. Two burr holes(2 mm diameter) were drilled 8 mm anterior to the bregma and 2 mm lateral to the midline. Both olfactory bulbs were aspirated and the holes filled with glass ionomer cement. The scalp was sutured closed. Sham-operated rats underwent every surgical procedure except the aspiration of the bulbs. The animals received penicillin(8×10~5U) intramuscularly(0.2 mL/300 g) once per day for 3 d post-surgery to prevent infection,and were subsequently housed alone in polypropylene cages. The experiments continued after 14 d of rehabilitation. The following groups were used for experiments: sham-operated(underwent surgical procedure without aspiratedolfactory bulbs and administration of vehicle only),OBX-model(underwent every surgical procedure and administration of vehicle only),OBX-amitriptyline treated(10 mg·kg^(-1)),and OBX-baicalin treatment(20 and 40 mg·kg^(-1)). Amitriptyline and baicalin were dissolved in physiological saline. RESULTS We examined how baicalin altered OBX-induced changes in serum glucocorticoid level as wel as inflammatory responses,sirtuin 1(SIRT1) expression,and p65 acetylation in the hypothalamus. Similar experiments were performed to analyse the effects of baicalin on lipopolysaccharide-induced inflammatory responses inhypothalamus. CONCLUSION Our results indicate that activation of the SIRT1 in the hypothalamus contributes to hyperactivity of HPA axis,which can be alleviated by baicalin.展开更多
Plaque erosion,together with plaque rupture,is a common cause for acute coronary syndrome(ACS).Plaque erosion alone is responsible for about one third of the patients with ACS.Eroded plaque is defined as thrombosed,en...Plaque erosion,together with plaque rupture,is a common cause for acute coronary syndrome(ACS).Plaque erosion alone is responsible for about one third of the patients with ACS.Eroded plaque is defined as thrombosed,endothelium-absent and non-ruptured but often-inflamed plaques based on histological findings.Even though there is efficient imaging technologies to detect the eroded plaque in vivo and tailored treatment strategy has also been developed for ACScaused by erosion in clinics,the pathogenesis mechanisms that cause plaque erosion are not fully understood.It is widely postulated that thrombus formation and endothelial apoptosis(the precursors of plaque erosion)have closed association with biomechanical conditions in the coronary vessel.Revealing of the mechanical conditions in the eroded plaque could advance our knowledge in understanding the formation of plaque erosion.To this end,patient-specific OCT-based fluid-structure interaction(FSI)models were developed to investigate the plaque biomechanical conditions and investigate the impact of erosioninduced inflammation on biomechanical conditions.In vivo OCTand Biplane X-ray angiographic data of eroded coronary plaque were acquired from one male patient(age:64). OCT images were segmented manually with external elastic membrane contour and the trailing edge of the lipid-rich necrotic core(lipid)assumed to have positive remodeling ratio 1.1.Locations with luminal surface having direct contact with intraluminal thrombus on OCT images were identified erosion sites.Fusion of OCT and biplane X-ray angiographic data were performed to obtain the 3D coronary geometry.OCT-based FSI models with pre-shrink-stretch process and anisotropic material properties were constructed following previously established procedures.To reflect tissue weakening caused by erosion-induced inflammation,the material stiffness of plaque intima at the erosion site was adjust to one tenth of un-eroded fibrous plaque tissue.Three FSI models were constructed to investigate the impacts of inflammation and lipid component on plaque biomechanics:M1,without erosion(this means plaque intima at the erosion sites were not softened)and without inclusion of lipid component;M2,with erosion but no lipid;M3,with erosion and inclusion of lipid.FSI models were solved by ADINA to obtain the biomechanical conditions at peak blood pressure including plaque wall stress/strain(PWS/PWSn)and flow wall shear stress(WSS).The average values of three biomechanical conditions at the erosion sites and at the fibrous cap overlaying lipid component were calculated from three models for analysis.The results of M1 and M2 were compared to investigate the impact of erosion-induced inflammation on plaque biomechanics.Mean PWS value decreases from 49.98 kPa to 18.83 kPa(62.32%decrease)while Mean PWSn value increases from 0.123 1 to 0.138 4(12%increase)as the material stiffness becomes 10times soft.Comparing M2 and M3 at the cap sites,M3(with inclusion of lipid)will elevates mean PWS and PWSn values by48.59%and 16.09%,respectively.The impacts of erosion and lipid on flow shear stress were limited(<2%).To conclude,erosion-induced inflammation would lead to lower stress distribution but larger strain distribution,while lipid would elevate both stress and strain conditions.This shows the influence of erosion and lipid component has impacts on stress/strain cal-culations which are closely related to plaque assessment.展开更多
This study aimed to explore the effect of DT-13 （25（R,S）-ruscogenin- 1-O- [ β-d-glucopyranosyl- （1→2） ] [ β-d-xylopyranosyl-（ 1→3） 1-β -d- fucopyranoside） on tumor necrosis factor （TNF）-α-induced vascu...This study aimed to explore the effect of DT-13 （25（R,S）-ruscogenin- 1-O- [ β-d-glucopyranosyl- （1→2） ] [ β-d-xylopyranosyl-（ 1→3） 1-β -d- fucopyranoside） on tumor necrosis factor （TNF）-α-induced vascular inflamma- tion and the potential molecular mechanisms. In vitro, DT-β suppressed TNF-α-induced adhesion and migration of human umbilical vein endothelial cells （HUVECs） by inhibiting the expression of intercellular adhesion molecule-1 （ ICAM-1 ） and vascular cell adhesion molecule-1 （VCAM-1）. DT-β markedly suppressed NF-KB p65 phosphoryl- ation, and when NF-KB p65 was over-expressed, the inhibitory effect of DT-β on adhesion molecular decreased. DT-β also suppressed TNF-α induced luciferase activities of ICAM-1 and VCAM-1 promoter containing NF-KB binding sites. Furthermore DT-β markedly suppressed p38 phosphorylation and Src degradation induced by TNF-α DT-β at 4 mg·kg- 1 prevented vascular , whereas had no significant effect on ERK and JNK activation. In-vivo, inflammation and the expression of adhesion molecules induced by TNF-α in mice. These findings suggest that DT- β abrogates vascular inflammation by down-regulating adhesion molecules associated with modulating the NF-KB, p38MAPK, Src signaling pathways, and NF-KB binding site is at least one of the targets of DT-β. This study pro- vides novel information regarding the mechanism by which DT-β exerts its effects on vascular inflammation, which is important for the onset and progression of various diseases.展开更多
Aim To investigate the nephroprotective activity of berberine in diabetic nephropathy （DN） mice. Methods Diabetic nephropathy was induced by intraperitoneal injection with 55 mg · kg^-1 streptozotocin（STZ） , ...Aim To investigate the nephroprotective activity of berberine in diabetic nephropathy （DN） mice. Methods Diabetic nephropathy was induced by intraperitoneal injection with 55 mg · kg^-1 streptozotocin（STZ） , Berberine was administered at daily doses of 50, 100 and 200 mg· kg^-1 by gavage for 8 weeks. To detect serum creatinine and blood urea nitrogen （BUN） levels, blood were collected after the last dose of berberine, renal cortex was separated on ice after heart peffusion by precooled normal saline. The specimen was stored in -80℃ for the next experiments, and some of the kidney tissue were immobilized by 4% paraformaldehyde solution and 3% glut- araldehyde solution for the preparation of paraffin tissue slides and electron microscope biopsy respectively. After that, PAS staining and electron microscope were used to observe the glomerular morphology changes; ELISA was used to measure proinflammatory chemokines and cytokines levels in renal cortex. Real time RT-PCR was taken to detect the level of nucleotide binding oligomerzation domain 2 （NOD2） mRNA, Western blot was used to test the ex- pression of NOD2 and autophagy marker light chain 3 （LC3） in renal cortex. Results Histopathological changes and the increase in serum creatinine and BUN in DN mice were significantly ameliorated by berberine in a dose-de- pendent manner. Additionally, The expression of tumor necrosis factor-or （TNF-α）, interleukin-6 （IL-6） and in- tercellular adhesion molecule-1 （ICAM-1） was markedly suppressed by berberine, indicating the inhibition of in- flammatory response. Treatment of DN mice with berberine also significantly reduced the expression of NOD2 and LC3 in the kidneys. Conclusion The current study showed the nephroprotective activity of berberine in DN mice could be attributed to the inhibition of inflammation and展开更多
Background The aggravating trend of aging population has brought us with great medical challenges. Calorie restriction （CR） has various beneficial effects on health, including lifespan prolongation and functional im...Background The aggravating trend of aging population has brought us with great medical challenges. Calorie restriction （CR） has various beneficial effects on health, including lifespan prolongation and functional im- provement of multiple organisms. SIRT6, a member of the Sirtuin family of NAD^＋-dependent histone deacetylases, has been shown to play a key role in mediating the effects of CR. Aim Here we show how CR-triggered SIRT6-de- pendent pathways affect aging and the critical role of SIRT6 on inflammation. Methods 24-month-old mice were fed under ad libitum （AL） or CR condition for 6 months to determine the effects of CR. In addition, we took low glucose （LG） cultured WI38 human fibroblasts as a model to mimic CR in vitro. Further more, we stably overex- pressed or knockdown SIRT6 in WI38 to identify the role of SIRT6 in cell senescence and inflammation. Results Aged mice with CR had improved renal pathology and enhanced SIRT6 expression compared with AL group. In ad- dition, compared with normal glucose （NG） group, LG group had prolonged lifespan and increased expression of SIRT6. Furthermore, increased SA-β-gal positive cells were observed in SIRT6-deficient cells while the overexpres- sion of SIRT6 could delay the replicative senescence effectively. NF-KB was involved in the SIRT6 mediated lon- gevity control. SIRT6 overexpressed WI38 had low translocate rate of NF-KB into the nucleus and SIRT6 could at- tenuate the NF-KB signaling by deacetylating the RelA subunit of NF-KB complex. Conclusion In this study, we show that CR prevents age-dependent renal insufficiency by up-regulation of SIRT6. CR-triggered SIRT6 activation suppresses NF-KB signaling via preventing nuclear translocation of NF-KB. Here we identified the beneficial effects of CR on renal aging and determined the crucial role of SIRT6 on CR-mediated lifespan extension.展开更多
Apelin, the endogenous ligand of APJ which is a member of G protein-coupled receptors, expressed in a variety of tissues in vivo and involved in the physiological and pathological processes. Studies had shown that ape...Apelin, the endogenous ligand of APJ which is a member of G protein-coupled receptors, expressed in a variety of tissues in vivo and involved in the physiological and pathological processes. Studies had shown that ape- lin/APJ system was involved in the regulation of cardiovascular function, insulin sensitivity and had a close connec- tion with oxidative stress and inflammatory cytokines. Therefore, this article summarized that apelin/APJ system such as atherosclerosis, hyperten- had the effects of inflammation-related diseases associated with oxidative stress, ischemia-reperfusion injury, tumour and pre-eclampsia, etc. sion, diabetes and its mierovaseular complications, Meanwhile the drugs targeted apelin/APJ was introduced in order to provide the novel therapeutic strategy for in- flammation-related diseases.展开更多
It has been demonstrated that inflammation and dysregulation of immune response are involved in the pathogenesis of Alzheimer disease (AD). Inflammation is an early event in AD development, especially inflammasome and...It has been demonstrated that inflammation and dysregulation of immune response are involved in the pathogenesis of Alzheimer disease (AD). Inflammation is an early event in AD development, especially inflammasome and pro-inflammatory molecules are pathogenic factor in AD. Our data showed that activated immune cells may contribute to the pathogenesis of AD, since the mice with immune cells knock out demonstrated differentsings in the neurodegenerative process and T cells aid clearance of plaques in mice and infiltrating parenchymal T-cell in AD brain mainly in the light of amyloid pathology, and immune treatment is effective, etc. However, the direct evidence on T and B cells infiltrating into the brain of APP transgenic mice have not yet found. Whether aged T cells are pathogenic in AD?How is role of aged B cells? These questions are still unclear. In conclusion, activated immune cells,and inflammatory molecules may play important roles in neurodegenerative disorders, such as AD. The mechanisms of behind this are needed to further study. Inhibiting inflammation in the early phase of AD and restore normal immune regulation are new drug target for the future.展开更多
OBJECTIVE To develop an in vitro airway epithelial cell model suitable for the large-scale studies of compounds that can suppress lipopolysaccharide(LPS)-and tumor necrosis factor alpha(TNFα)-induced airway inflammat...OBJECTIVE To develop an in vitro airway epithelial cell model suitable for the large-scale studies of compounds that can suppress lipopolysaccharide(LPS)-and tumor necrosis factor alpha(TNFα)-induced airway inflammation.METHODS We have optimized the protocols to culture BEAS-2B,a normal human bronchial epithelial cell line,in glass-bottom 384-well microtiter plates.The cells were stimulated with TNFαand LPS from Pseudomonas aeruginosa,a common lunginfection pathogen in cystic fibrosis and chronic obstructive pulmonary disease.We used ELISA to measure the secretion levels of two pro-inflammatory cytokines,interleukin(IL)-6and-8,after 0,4,8,16,24 hof stimulation;and immunofluorescence microscopy to measure the nuclear translocation of RelA,a subunit of the NF-κB complex,after 0,15,30,60,120 min of stimulation.To suppress the inflammatory response,we pre-treated the cells with a specific IκB kinase-2inhibitor,TPCA-1;the main bioactive component of Andrographis paniculata,andrographolide;and DMSO control for 1h.RESULTS We found that individual stimulant(either TNFα10ng·mL-1 or LPS 10μg·mL-1)increased the IL-6and IL-8 secretion levels by^12-17 foldsas compared to DMSO controls after 8h of stimulation.The combined stimulation(10ng·mL-1 TNFαand 10μg·mL-1 LPS)induced even higher IL-6 and -8 levels(~18-21 folds)at the same time points.Importantly,our imaging study shows that the NF-κB activation is early but transient under TNFαstimulation,late but sustained under LPS stimulation,and early and sustained under the combined stimulation.Finally,we also found that TPCA-1 10μmol·L-1 or andrographolide 30μmol·L-1 drastically reduced the IL-6 and -8 levels down to 4.5-9 folds as compared to the controls.CONCLUSIONThe combined TNFαand LPS stimulations induce faster and more sustained inflammatory responses,which can still be suppressed by anti-inflammatory compounds in our cell model.These more comprehensive activations of inflammatory signaling pathways will enable us to study and distinguish the mechanisms of different anti-inflammatory compounds or natural products.展开更多
OBJECTIVE To investigate the effects of IMM-H004 on permanent focal cerebral ischemia injury and associated cardiopulmonary complications,further elucidating the molecular mechanisms.METHODS The effects of IMM-H004 we...OBJECTIVE To investigate the effects of IMM-H004 on permanent focal cerebral ischemia injury and associated cardiopulmonary complications,further elucidating the molecular mechanisms.METHODS The effects of IMM-H004 were investigated in wild-type(WT) and CKLF1-/-rats.The effects of IMM-H004 on ischemic stroke injury and its cardiopulmonary complications were determined using 2,3,5-triphenyltetrazolium chloride(TTC) staining,behavior tests,magnetic resonance imaging(MRI)scans,enzyme-linked immunosorbent assay(ELISA),Nissl staining,and histo-pathological examination.Multiple molecular experiments including immunohistological staining,immunofluorescence staining,quantitative RT-PCR,Western blotting,and co-immunoprecipitation assays were used to elucidate the underlying mechanisms.RESULTS IMM-H004 treatment provided significant protection against ischemic stroke-induced brain injury and associated cardiopulmonary complications,through CKLF1-depedent-anti-inflammation pathway in rats.IMM-H004 downregulated the amount of CKLF1 and disturbed the combination between CKLF1 and C-C chemokine receptor type 4,suppressing the inflammatory response and protecting the damaged organs in ischemic setting.CONCLUSION This preclinical study established efficacy of IMM-H004 as a potential therapeutic medicine for ischemic stroke and associated cardiopulmonary complications.The protective effects of IMM-H004 may due to its specific mechanism through CKLF1.These results support further efforts to develop IMM-H004 for human clinical trials in acute cerebral ischemia,especially for patients who are not suitable for reperfusion therapy.展开更多
Brian ischemic injury and central neurodegenerative diseases as leading contributors to disability and death have become a majorclinical and public health concern worldwide.Neuroinflammation plays a pivotal role in th...Brian ischemic injury and central neurodegenerative diseases as leading contributors to disability and death have become a majorclinical and public health concern worldwide.Neuroinflammation plays a pivotal role in the pathological progression of cerebral ischemia and neurodegenerative diseases including Parkinson disease(PD).Therefore,it is important to find effective therapeutic targets to attenuate inflammation and delay the progression of brain injury.Cysteinyl leukotrienes(CysLTs) are potent inflammatory mediators synthesized from arachidonic acid by 5-lipoxygenase(5-LOX) in the central nervous system.Two distinct G-protein-coupled receptors,CysLT1 R and CysLT2 R,mediate most of the known CysLTs biological responses.Accumulating evidence has demonstrated that postischemic inflammation and neuronal loss are mediated by 5-LOX and CysLTRs fol owing focal cerebral ischemia.We recently reported that the expression of 5-LOX,CysLT1R and inflammatory vascular cell adhesion molecule-1(VCAM-1) was upregulated in the hippocampus of rats with transient global cerebral ischemia,which was closely associated with delayed neuronal death in the hippocampal CA1 area.5-LOX inhibitor zileuton,CysLT1R antagonist ONO-1078 and montelukast dose-dependently reduced hippocampal CA1 neuronal death and inhibited the increased expression of 5-LOX and VCAM-1.In vitro ischemia-like injury in 5-LOXtransfected PC12 cells,oxygen-glucose deprivation(OGD) induced cell death mediated by5-LOX via ROS/P38 MAPK pathway.The nonselective 5-LOX inhibitor caffeic acid inhibited OGDstimulated activation of 5-LOX and ROS/P38 MAPK signaling and improved neuronal survival.In PD model,high concentrations of rotenone caused directly PC12 neurotoxicity,which was modulated by 5-LOX and abolished by suppression of 5-LOX.It is well known that microglia is major modulators of inflammatory response after brain injury.Overactivated microglia and production of proinflammatory cytokine IL-1β,IL-6 and TNF-α contribute to the neuroinflammation and brain injury.5-LOX,CysLT1R and CysLT2R are involved in microglial activation and resultant neurotoxic responses.It has been found that low concentrations of rotenone can activate 5-LOX and CysLT1R on microglial cells to enhance microglial inflammation and microglia-dependent neuronal death in vitro.5-LOX inhibitor zileuton and CysLT1R antagonist montelukast protected neurons from microglia-dependent rotenone neurotoxicity.Furthermore,lipopolysaccharide(LPS)induced microglial activation and microglial neurotoxicity mediated by CysLT2R in vitro.Both pharmacological blockade(CysLT2R antagonist HAMI3379) and RNA interference(specific short hairpin RNA) of CysLT2 R significantly attenuated LPS-triggered microglial inflammation and subsequent neuronal death.Collectively,the present results indicate the role of 5-LOX and CysLTRs in neuroinflammation and brain injury.Modulation of 5-LOX and CysLTRs may be potential therapeutic approaches for inflammation-related brain disorders such as cerebral ischemia and PD.However,further research is needed to clarify the mechanisms underlying the regulation of neuinflammatory processes by 5-LOX and CysLTRs.展开更多
OBJECTIVE E-cadherin is a major component of tubular adherent proteins which maintain intercellular contacts and cell polarity in epithelial tissue,it is involved in the pathological process of renal cell carcinoma an...OBJECTIVE E-cadherin is a major component of tubular adherent proteins which maintain intercellular contacts and cell polarity in epithelial tissue,it is involved in the pathological process of renal cell carcinoma and fibrotic diseases via epithelial-mesenchymal transition.Although we and others found that expression of E-cadherin was significantly down-regulated in kidney suffered acute kidney injury(AKI),its function in AKI was still unknown,which was explored in the current study.METHODS We disrupted E-cadherin or restored E-cadherin with compound 8J in cisplatin-stimulated tubular epithelial cell lines,the cell damage and inflammation were evaluated,additionally,the therapeutic potential of E-cadherin restoration was also determined in vivo.RESULTS We found that cisplatin reduced E-cadherin expression both in mouse kidney and tubular epithelial cell lines(m TECs).Administration of compound 8J restored the level of E-cadherin,thereby increased cell viability while attenuating programmed cell death,which may be mediated by deactivation of RIPK/MLKL axis,reduced membrane translocation of phosphor-MLKL and decreased cleavage of caspase 3.Compound 8J also suppressed inflammatory response in cisplatin-treated m TECs,which was correlated with suppressed NF-κB phorsphorylation and promoter activity.In contrast,disruption of E-cadherin enhanced cell damage and inflammation.Treatment of compound 8J failed to further attenuate kidney damage in E-cadherin knockdown cells,indicating compound 8J protected against mT ECs mainly through restoring E-cadherin.We also found that peritoneal injection of compound 8J protected against renal function and tubular damage by preventing NF-κB-driven renal inflammation and RIPK/MLKL-regulated programmed cell death,which was led by restoration of E-cadherin in cisplatin nephropathy.CONCLUSION More than a victim degraded after kidney injury,E-cadherin also has functional role in controlling tubule integrity,programmed cel death and renal inflammation.In this regard,restoration of E-cadherin by compound 8J should be considered as a novel therapeutic strategy for acute kidney injury.展开更多
OBJECTIVE Platelets play a major role in mediating inflammatory response.The present work was designed to investigate whether arterial baroreflex impairment induced by sinoaortic denervation(SAD)affect platelet activa...OBJECTIVE Platelets play a major role in mediating inflammatory response.The present work was designed to investigate whether arterial baroreflex impairment induced by sinoaortic denervation(SAD)affect platelet activation,leading to the exacerbation of cerebral cortex and hippocampus inflammation in rats.METHODS Adult male SD rats were divided into four groups:the sham control,the sinoaortic denervation(SAD),the sham+LPS,the SAD+LPS.In another experiment,there were also four groups:the sham control,the SAD,the SAD+LPS and the SAD+LPS+asprin.Four weeks after sham or SAD surgery,all rats were examined for the level of CD41,CD45,IL-1βand PF-4 in the cerebral cortex and hippocampus using immunofluorescence and ELISA.Blood platelet and leukocyte count,platelet microaggre⁃gation,expression of CD154 and CD62P on platelet surface and platelet-leukocyte aggregate level was detected by flow cytometry.RESULTS Compared with sham+LPS group,the in SAD+LPS group rats exhibited the high level of CD41,CD45,IL-1βand PF-4 in the cerebral cortex and hippocampus.Leukocyte count,platelet microag⁃gregation,expression of CD154 and CD62P on platelet surface and platelet-leukocyte aggregate level was increased,while blood platelet count was decreased in the SAD+LPS.Moreover,all the above changes were improved in the SAD+LPS+asprin group when compared with the SAD+LPS group.CONCLUSION Arterial baroreflex dysfunction exacerbates inflammation in the rat cerebral cortex and hippocampus,which is likely mediated by platelet.展开更多
OBJECTIVE The present study aimed to investigate the relationship between Wnt/β-catenin and Nrf2 signaling pathways,and understanding the mechanisms underlying the process of inflammatory in chronic obstructive pulmo...OBJECTIVE The present study aimed to investigate the relationship between Wnt/β-catenin and Nrf2 signaling pathways,and understanding the mechanisms underlying the process of inflammatory in chronic obstructive pulmonary disease(COPD),which was a serious disease of respiratory system.METHODS We duplicate the emphysema model with porcine pancreatic elastase(PPE)in Nrf2-/-and WT mouse for 21d,and intraperitoneal injection of Li Cl,the activator of Wnt/β-catenin signaling pathway from 14 d to the end.Hematoxylin and eosin(H&E)staining was performed to assess the histopathologic level,and immunohistochemistry(IHC)for Mac-3(the marker of macrophagocyte)and Ly6G(the marker of neutrophil)was used to observe the inflammatory infiltrate,while the levels of Wnt/β-catenin and Nrf2 signaling pathways related proteins heme oxygenase-1(HO-1),NAD(P)H:quinone oxidoreductase 1(NQO1),and the expression of inflammatory cytokine interleukin-6(IL-6)were detected by Western blotting of lung tissues.In vitro,cigarette smoke extract(CSE)-treated normal human bronchial epithelial(NHBE)cells,cell viability was examined by MTT assay,and then we treated recombinant human Wnt3a,si Nrf2 and si Wnt3a to measure the expression of Wnt3a,β-catenin,Nrf2,HO-1,NQO-1,and IL-6.Cellular immunofluorescence staining was employed to identify the nuclear translocation of Nrf2.RESULTS We found that the Li Cl-treated group has markedly decreased the damage of alveolar structure and inflammatory signs than the model group of WT mice rather than Nrf2-/-group.It also seen that Li Cl not only increasedβ-catenin,but it also led to a comparable increase in Nrf2,HO-1,NQO1,and decrease of IL-6 compared with WT model groups but except to Nrf2-/-group in vivo.And it showed that Wnt3atreatment has significantly increased the nuclear translocation of Nrf2 and the expression of HO-1 and NQO1,reduced the IL-6 release,while there has no significance when Nrf2 was blocked in CSE-induced NHBE cells.CONCLUSION Our results demonstrated that Wnt3a/β-catenin significantly balanced oxidative stress and attenuated inflammation reaction by promoting Nrf2 nuclear translocation and activity.展开更多
OBJECTIVE To establish an in vitro inflammatory model of BV2 by observing the activity,the release amount of NO and the expression of inflammatory factors of microglial cells(BV2)induced by lipopolysaccharides(LPS).ME...OBJECTIVE To establish an in vitro inflammatory model of BV2 by observing the activity,the release amount of NO and the expression of inflammatory factors of microglial cells(BV2)induced by lipopolysaccharides(LPS).METHODS BV2 was routinely cultured in vitro.Cell viability was measured by CCK-8 meth⁃od.And by drew cell growth curve to determine the logarithmic growth cycle of the cells.After 24 h of routine culture,BV2 were induced by adding different concentrations of LPS(0.1,1.0 and 10.0 mg·L-1)for 4,8,12,24 and 48 h,respectively.Meanwhile,the morphological changes of BV2 were observed under inverted microscope to compare the activation degree of microglia at dif⁃ferent time and concentration.Cell activity and nitric oxide(NO)level were determined by CCK-8 and Griess method respectively,which could help to determine the optimal concentration and time of modeling.Finally,It were determined by ELISA that the concentrations of tumor necrosis factorα(TNF-α),interleukin-6(IL-6)and IL-1βin supernatant of LPS 1 mg·L-1 culture for 24 h.RESULTS BV2 were in logarithmic growth phase for 1 to 3 d after subculture.LPS 1 mg·L-1 induced BV2 for 24 or 48 h which could increase the release amount of NO significantly(P<0.05).In order to save time,LPS induced BV2 for 24 h were selected for subsequent experiments.Microglial cells in resting state were observed to be elongated spindle shape under inverted micro⁃scope.After LPS activation,the cell body became larger and the branching processes shrank back,presenting an amoeba-like appearance.ELISA results showed that the concentrations of TNF-α,IL-6 and IL-1βin supernatant of LPS 1 mg·L-1 cultured for 24 h were significantly increased which compared with the control group(P<0.05).CONCLUSION LPS could induce the activation of BV2 and up-regulate the level of inflammatory factors.The optimal condition for establishing stable BV2 microglial inflammatory model was used LPS 1 g·L-1 induced for 24 h.展开更多
Objective Magnetoencephalography(MEG),a non-invasive neuroimaging technique,meticulously captures the magnetic fields emanating from brain electrical activity.Compared with MEG based on superconducting quantum interfe...Objective Magnetoencephalography(MEG),a non-invasive neuroimaging technique,meticulously captures the magnetic fields emanating from brain electrical activity.Compared with MEG based on superconducting quantum interference devices(SQUID),MEG based on optically pump magnetometer(OPM)has the advantages of higher sensitivity,better spatial resolution and lower cost.However,most of the current studies are clinical studies,and there is a lack of animal studies on MEG based on OPM technology.Pain,a multifaceted sensory and emotional phenomenon,induces intricate alterations in brain activity,exhibiting notable sex differences.Despite clinical revelations of pain-related neuronal activity through MEG,specific properties remain elusive,and comprehensive laboratory studies on pain-associated brain activity alterations are lacking.The aim of this study was to investigate the effects of inflammatory pain(induced by Complete Freund’s Adjuvant(CFA))on brain activity in a rat model using the MEG technique,to analysis changes in brain activity during pain perception,and to explore sex differences in pain-related MEG signaling.Methods This study utilized adult male and female Sprague-Dawley rats.Inflammatory pain was induced via intraplantar injection of CFA(100μl,50%in saline)in the left hind paw,with control groups receiving saline.Pain behavior was assessed using von Frey filaments at baseline and 1 h post-injection.For MEG recording,anesthetized rats had an OPM positioned on their head within a magnetic shield,undergoing two 15-minute sessions:a 5-minute baseline followed by a 10-minute mechanical stimulation phase.Data analysis included artifact removal and time-frequency analysis of spontaneous brain activity using accumulated spectrograms,generating spectrograms focused on the 4-30 Hz frequency range.Results MEG recordings in anesthetized rats during resting states and hind paw mechanical stimulation were compared,before and after saline/CFA injections.Mechanical stimulation elevated alpha activity in both male and female rats pre-and post-saline/CFA injections.Saline/CFA injections augmented average power in both sexes compared to pre-injection states.Remarkably,female rats exhibited higher average spectral power 1 h after CFA injection than after saline injection during resting states.Furthermore,despite comparable pain thresholds measured by classical pain behavioral tests post-CFA treatment,female rats displayed higher average power than males in the resting state after CFA injection.Conclusion These results imply an enhanced perception of inflammatory pain in female rats compared to their male counterparts.Our study exhibits sex differences in alpha activities following CFA injection,highlighting heightened brain alpha activity in female rats during acute inflammatory pain in the resting state.Our study provides a method for OPM-based MEG recordings to be used to study brain activity in anaesthetized animals.In addition,the findings of this study contribute to a deeper understanding of pain-related neural activity and pain sex differences.展开更多
Objective Ulcerative colitis is a prevalent immunoinflammatory disease.Th17/Treg cell imbalance and gut microbiota dysregulation are key factors in ulcerative colitis pathogenesis.The actin cytoskeleton contributes to...Objective Ulcerative colitis is a prevalent immunoinflammatory disease.Th17/Treg cell imbalance and gut microbiota dysregulation are key factors in ulcerative colitis pathogenesis.The actin cytoskeleton contributes to regulating the proliferation,differentiation,and migration of Th17 and Treg cells.Wdr63,a gene containing the WD repeat domain,participates in the structure and functional modulation of actin cytoskeleton.Recent research indicates that WDR63 may serve as a regulator of cell migration and metastasis via actin polymerization inhibition.This article aims to explore the effect of Wdr63 deletion on Th17/Treg cells and ulcerative colitis.Methods We constructed Wdr63-/-mice,induced colitis in mice using dextran sulfate sodium salt,collected colon tissue for histopathological staining,collected mesenteric lymph nodes for flow cytometry analysis,and collected healthy mouse feces for microbial diversity detection.Results Compared with wild-type colitis mice,Wdr63-/-colitis mice had a more pronounced shortening of colonic tissue,higher scores on disease activity index and histological damage index,Treg cells decreased and Th17 cells increased in colonic tissue and mesenteric lymph nodes,a lower level of anti-inflammatory cytokine IL-10,and a higher level of pro-inflammatory cytokine IL-17A.In addition,WDR63 has shown positive effects on maintaining intestinal microbiota homeostasis.It maintains the balance of Bacteroidota and Firmicutes,promoting the formation of beneficial intestinal bacteria linked to immune inflammation.Conclusion Wdr63 deletion aggravates ulcerative colitis in mice,WDR63 inhibits colonic inflammation likely by regulating Th17/Treg balance and maintains intestinal microbiota homeostasis.展开更多
Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(...Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(anti⁃MDA5+)dermatomyositis(DM)develop into the rapidly progressive interstitial lung disease(RPILD).Methods:We retrospectively analyzed the clinical and laboratory data of 124 anti⁃MDA5+DM patients from the First Affiliated Hospital of Nanjing Medical University between March 2019 and September 2023.We identified independent risk factors associated with the development and mortality of RPILD with the Cox regression analysis,and determined the optimal cut⁃off values for predicting adverse outcomes with the receiver operating characteristic(ROC)curve analysis.Results:Among the 124 patients,36 patients(29.03%)developed RPILD,and 39 patients(31.45%)died during the follow⁃up period.The results of multivariate Cox regression analysis showed that the elevated NLR was an independent risk factor for RPILD development,while the elevated SII expression was independently associated with the increased mortality of RPILD.Based on the ROC curve analysis,NLR>6.12 was a predictor for RPILD,and SII>875.79 was associated with increased mortality risk of RPILD.Conclusion:Both NLR and SII are accessible,cost⁃effective,and reliable prognostic indicators for the prognosis of patients with anti⁃MDA5^(+)DM,providing a valuable guidance for clinical management and risk stratification of the disease.展开更多
The trace element selenium(Se)occurs naturally throughout the earth.Se deficiency has been linked to impaired breast health and other diseases in human and animals.Compared to severe Se deficiency,marginal dietary Se ...The trace element selenium(Se)occurs naturally throughout the earth.Se deficiency has been linked to impaired breast health and other diseases in human and animals.Compared to severe Se deficiency,marginal dietary Se deficiency accusers more frequently in low-Se regions.Therefore,to investigate the Se status and inflammatory response of the mammary gland under marginal dietary Se levels,an lipopolysaccharide(LPS)induced mouse mastitis model was established.Mice were fed with moderate Se diet(0.087 mg•kg^(-1) Se),adequate Se diet(0.15 mg•kg^(-1) Se)or excessive Se diet(1.5 mg•kg^(-1) Se)for 60 days.Se status and inflammatory factors were investigated.Results showed that the Se status of mammary gland correlated with dietary Se levels.Marginal Se deficiency exacerbated mammary tissue histopathology;increased the mRNA level of inflammatory genes tumor necrosis factor alpha(TNF-α),interleukin-1β(IL-1β)and cyclooxygenase-2(COX-2);and enhanced the phosphorylation of NF-κB p65 in mammary gland tissues.Supplementation of Se in diet higher than recommended levels reduced the inflammatory reaction of mammary glands in LPS-induced mastitis model and provided a protective effect.展开更多
基金supported by National Natural Science Foundation of China(81402482,91313303)
文摘OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
基金supported by National Science Foundation of China(81402943)CAMS Major Collaborative Innovation Project(2016-I2M-1-011)PUMC Youth Fund(3332015168)
文摘OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in human umbilical vein endothelial cells(HUVECs) and smooth muscle cells(SMCs).METHODS 48 Apo-/-E mice,at 6-8 weeks old,were randomly allocated into 4 groups:normal,model,bbr and atorvastatin(positive control) groups with 12 mice in each group.They were fed with high-fat diet for 4 weeks except those in Normal group and then treated with indicated drugs orsolvent for another 4 weeks.The morphology and inflammation infiltration of aortic were examined with HE staining.The expression of BMP-2 in aortic was examined by immumohistochemical staining.Blood lipid levels were examined by automatic biochemical analyzer.The expression of IL-6,TNF-α and BMP-2 in serum and tissues was detected by ELISA method.The expression of ALP and the content of calcium were detected by commercially-available kits.HUVEC cells were stimulated with TNF-α and incubated with various concentrations of BBR for 24 h.The contents of intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule(VCAM-1),matrix metalloprotein-9(MMP-9) in the culture supernatant were detected by ELISA method.Calcification was induced with β-glycerophosphatein SMC cells and the effect of BBR on the content of calcium was examined.RESULTS 4-week berberine treatment markedly lowered serum TC and LDL-c levels and improved the plaque stability in Apo-/-E mice fed with a high-fat diet(P<0.05 or P<0.01) which was comparable with the effect of atorvastatin.Berberineal so significantly decreased the levels of IL-6 and TNF-α in mice serum and aortic tissues(P<0.05 or P<0.001).Berberine tended to decrease ALP,BMP-2 levels and the content of calcium in mice serum and aortic tissues(P<0.05,P<0.01 or P<0.001) which were not observed in atorvastatin group.Berberine significantly lowered the levels of ICAM-1,VCAM-1,and MMP-9 in TNF-α-stimulated HUVECs.It can also lowered the content of calcium in SMCs.CONCLUSION BBR can profitably regulate the levels of blood lipid in mice fed with a high-fat diet,decrease the injury caused by inflammation,and attenuate vascular calcification.It may improve atherosclerosis and play a role in cardiovascular protection.
文摘OBJECTIVE Hyperactivityof hypothalamic-pituitary-adrenal(HPA) axis is an important aetiological risk factor for the development of depression. Previous studies have demonstrated that the phenolic monomer baicalin has antidepressant-like effects and decreases serum corticosterone levels.However,the mechanism by which baicalin regulates hyperactivity of HPA axis remains unclear. This work aimed to investigate the effects of baicalin on hyperactivity of HPA axis using the olfactory bulbectomised(OBX) rat model of depression. METHODS Animals were anaesthetised with 10% chloral hydrate(3.3 mL·kg^(-1),ip). Using disinfected surgical equipment,the skull covering the olfactory bulbs was exposed by a midline incision. Two burr holes(2 mm diameter) were drilled 8 mm anterior to the bregma and 2 mm lateral to the midline. Both olfactory bulbs were aspirated and the holes filled with glass ionomer cement. The scalp was sutured closed. Sham-operated rats underwent every surgical procedure except the aspiration of the bulbs. The animals received penicillin(8×10~5U) intramuscularly(0.2 mL/300 g) once per day for 3 d post-surgery to prevent infection,and were subsequently housed alone in polypropylene cages. The experiments continued after 14 d of rehabilitation. The following groups were used for experiments: sham-operated(underwent surgical procedure without aspiratedolfactory bulbs and administration of vehicle only),OBX-model(underwent every surgical procedure and administration of vehicle only),OBX-amitriptyline treated(10 mg·kg^(-1)),and OBX-baicalin treatment(20 and 40 mg·kg^(-1)). Amitriptyline and baicalin were dissolved in physiological saline. RESULTS We examined how baicalin altered OBX-induced changes in serum glucocorticoid level as wel as inflammatory responses,sirtuin 1(SIRT1) expression,and p65 acetylation in the hypothalamus. Similar experiments were performed to analyse the effects of baicalin on lipopolysaccharide-induced inflammatory responses inhypothalamus. CONCLUSION Our results indicate that activation of the SIRT1 in the hypothalamus contributes to hyperactivity of HPA axis,which can be alleviated by baicalin.
基金supported in part by NSFC ( 11672001,11802060)Jiangsu NSF ( BK20180352)Jiangsu Province Science and Technology Agency ( BE2016785)
文摘Plaque erosion,together with plaque rupture,is a common cause for acute coronary syndrome(ACS).Plaque erosion alone is responsible for about one third of the patients with ACS.Eroded plaque is defined as thrombosed,endothelium-absent and non-ruptured but often-inflamed plaques based on histological findings.Even though there is efficient imaging technologies to detect the eroded plaque in vivo and tailored treatment strategy has also been developed for ACScaused by erosion in clinics,the pathogenesis mechanisms that cause plaque erosion are not fully understood.It is widely postulated that thrombus formation and endothelial apoptosis(the precursors of plaque erosion)have closed association with biomechanical conditions in the coronary vessel.Revealing of the mechanical conditions in the eroded plaque could advance our knowledge in understanding the formation of plaque erosion.To this end,patient-specific OCT-based fluid-structure interaction(FSI)models were developed to investigate the plaque biomechanical conditions and investigate the impact of erosioninduced inflammation on biomechanical conditions.In vivo OCTand Biplane X-ray angiographic data of eroded coronary plaque were acquired from one male patient(age:64). OCT images were segmented manually with external elastic membrane contour and the trailing edge of the lipid-rich necrotic core(lipid)assumed to have positive remodeling ratio 1.1.Locations with luminal surface having direct contact with intraluminal thrombus on OCT images were identified erosion sites.Fusion of OCT and biplane X-ray angiographic data were performed to obtain the 3D coronary geometry.OCT-based FSI models with pre-shrink-stretch process and anisotropic material properties were constructed following previously established procedures.To reflect tissue weakening caused by erosion-induced inflammation,the material stiffness of plaque intima at the erosion site was adjust to one tenth of un-eroded fibrous plaque tissue.Three FSI models were constructed to investigate the impacts of inflammation and lipid component on plaque biomechanics:M1,without erosion(this means plaque intima at the erosion sites were not softened)and without inclusion of lipid component;M2,with erosion but no lipid;M3,with erosion and inclusion of lipid.FSI models were solved by ADINA to obtain the biomechanical conditions at peak blood pressure including plaque wall stress/strain(PWS/PWSn)and flow wall shear stress(WSS).The average values of three biomechanical conditions at the erosion sites and at the fibrous cap overlaying lipid component were calculated from three models for analysis.The results of M1 and M2 were compared to investigate the impact of erosion-induced inflammation on plaque biomechanics.Mean PWS value decreases from 49.98 kPa to 18.83 kPa(62.32%decrease)while Mean PWSn value increases from 0.123 1 to 0.138 4(12%increase)as the material stiffness becomes 10times soft.Comparing M2 and M3 at the cap sites,M3(with inclusion of lipid)will elevates mean PWS and PWSn values by48.59%and 16.09%,respectively.The impacts of erosion and lipid on flow shear stress were limited(<2%).To conclude,erosion-induced inflammation would lead to lower stress distribution but larger strain distribution,while lipid would elevate both stress and strain conditions.This shows the influence of erosion and lipid component has impacts on stress/strain cal-culations which are closely related to plaque assessment.
文摘This study aimed to explore the effect of DT-13 （25（R,S）-ruscogenin- 1-O- [ β-d-glucopyranosyl- （1→2） ] [ β-d-xylopyranosyl-（ 1→3） 1-β -d- fucopyranoside） on tumor necrosis factor （TNF）-α-induced vascular inflamma- tion and the potential molecular mechanisms. In vitro, DT-β suppressed TNF-α-induced adhesion and migration of human umbilical vein endothelial cells （HUVECs） by inhibiting the expression of intercellular adhesion molecule-1 （ ICAM-1 ） and vascular cell adhesion molecule-1 （VCAM-1）. DT-β markedly suppressed NF-KB p65 phosphoryl- ation, and when NF-KB p65 was over-expressed, the inhibitory effect of DT-β on adhesion molecular decreased. DT-β also suppressed TNF-α induced luciferase activities of ICAM-1 and VCAM-1 promoter containing NF-KB binding sites. Furthermore DT-β markedly suppressed p38 phosphorylation and Src degradation induced by TNF-α DT-β at 4 mg·kg- 1 prevented vascular , whereas had no significant effect on ERK and JNK activation. In-vivo, inflammation and the expression of adhesion molecules induced by TNF-α in mice. These findings suggest that DT- β abrogates vascular inflammation by down-regulating adhesion molecules associated with modulating the NF-KB, p38MAPK, Src signaling pathways, and NF-KB binding site is at least one of the targets of DT-β. This study pro- vides novel information regarding the mechanism by which DT-β exerts its effects on vascular inflammation, which is important for the onset and progression of various diseases.
文摘Aim To investigate the nephroprotective activity of berberine in diabetic nephropathy （DN） mice. Methods Diabetic nephropathy was induced by intraperitoneal injection with 55 mg · kg^-1 streptozotocin（STZ） , Berberine was administered at daily doses of 50, 100 and 200 mg· kg^-1 by gavage for 8 weeks. To detect serum creatinine and blood urea nitrogen （BUN） levels, blood were collected after the last dose of berberine, renal cortex was separated on ice after heart peffusion by precooled normal saline. The specimen was stored in -80℃ for the next experiments, and some of the kidney tissue were immobilized by 4% paraformaldehyde solution and 3% glut- araldehyde solution for the preparation of paraffin tissue slides and electron microscope biopsy respectively. After that, PAS staining and electron microscope were used to observe the glomerular morphology changes; ELISA was used to measure proinflammatory chemokines and cytokines levels in renal cortex. Real time RT-PCR was taken to detect the level of nucleotide binding oligomerzation domain 2 （NOD2） mRNA, Western blot was used to test the ex- pression of NOD2 and autophagy marker light chain 3 （LC3） in renal cortex. Results Histopathological changes and the increase in serum creatinine and BUN in DN mice were significantly ameliorated by berberine in a dose-de- pendent manner. Additionally, The expression of tumor necrosis factor-or （TNF-α）, interleukin-6 （IL-6） and in- tercellular adhesion molecule-1 （ICAM-1） was markedly suppressed by berberine, indicating the inhibition of in- flammatory response. Treatment of DN mice with berberine also significantly reduced the expression of NOD2 and LC3 in the kidneys. Conclusion The current study showed the nephroprotective activity of berberine in DN mice could be attributed to the inhibition of inflammation and
文摘Background The aggravating trend of aging population has brought us with great medical challenges. Calorie restriction （CR） has various beneficial effects on health, including lifespan prolongation and functional im- provement of multiple organisms. SIRT6, a member of the Sirtuin family of NAD^＋-dependent histone deacetylases, has been shown to play a key role in mediating the effects of CR. Aim Here we show how CR-triggered SIRT6-de- pendent pathways affect aging and the critical role of SIRT6 on inflammation. Methods 24-month-old mice were fed under ad libitum （AL） or CR condition for 6 months to determine the effects of CR. In addition, we took low glucose （LG） cultured WI38 human fibroblasts as a model to mimic CR in vitro. Further more, we stably overex- pressed or knockdown SIRT6 in WI38 to identify the role of SIRT6 in cell senescence and inflammation. Results Aged mice with CR had improved renal pathology and enhanced SIRT6 expression compared with AL group. In ad- dition, compared with normal glucose （NG） group, LG group had prolonged lifespan and increased expression of SIRT6. Furthermore, increased SA-β-gal positive cells were observed in SIRT6-deficient cells while the overexpres- sion of SIRT6 could delay the replicative senescence effectively. NF-KB was involved in the SIRT6 mediated lon- gevity control. SIRT6 overexpressed WI38 had low translocate rate of NF-KB into the nucleus and SIRT6 could at- tenuate the NF-KB signaling by deacetylating the RelA subunit of NF-KB complex. Conclusion In this study, we show that CR prevents age-dependent renal insufficiency by up-regulation of SIRT6. CR-triggered SIRT6 activation suppresses NF-KB signaling via preventing nuclear translocation of NF-KB. Here we identified the beneficial effects of CR on renal aging and determined the crucial role of SIRT6 on CR-mediated lifespan extension.
文摘Apelin, the endogenous ligand of APJ which is a member of G protein-coupled receptors, expressed in a variety of tissues in vivo and involved in the physiological and pathological processes. Studies had shown that ape- lin/APJ system was involved in the regulation of cardiovascular function, insulin sensitivity and had a close connec- tion with oxidative stress and inflammatory cytokines. Therefore, this article summarized that apelin/APJ system such as atherosclerosis, hyperten- had the effects of inflammation-related diseases associated with oxidative stress, ischemia-reperfusion injury, tumour and pre-eclampsia, etc. sion, diabetes and its mierovaseular complications, Meanwhile the drugs targeted apelin/APJ was introduced in order to provide the novel therapeutic strategy for in- flammation-related diseases.
文摘It has been demonstrated that inflammation and dysregulation of immune response are involved in the pathogenesis of Alzheimer disease (AD). Inflammation is an early event in AD development, especially inflammasome and pro-inflammatory molecules are pathogenic factor in AD. Our data showed that activated immune cells may contribute to the pathogenesis of AD, since the mice with immune cells knock out demonstrated differentsings in the neurodegenerative process and T cells aid clearance of plaques in mice and infiltrating parenchymal T-cell in AD brain mainly in the light of amyloid pathology, and immune treatment is effective, etc. However, the direct evidence on T and B cells infiltrating into the brain of APP transgenic mice have not yet found. Whether aged T cells are pathogenic in AD?How is role of aged B cells? These questions are still unclear. In conclusion, activated immune cells,and inflammatory molecules may play important roles in neurodegenerative disorders, such as AD. The mechanisms of behind this are needed to further study. Inhibiting inflammation in the early phase of AD and restore normal immune regulation are new drug target for the future.
基金The project supported by National Medical Research Council Cooperative Basic Research Grant(CBRG11nov032)the Bioinformatics Institute,Biomedical Research Council,A*STAR,Singapore
文摘OBJECTIVE To develop an in vitro airway epithelial cell model suitable for the large-scale studies of compounds that can suppress lipopolysaccharide(LPS)-and tumor necrosis factor alpha(TNFα)-induced airway inflammation.METHODS We have optimized the protocols to culture BEAS-2B,a normal human bronchial epithelial cell line,in glass-bottom 384-well microtiter plates.The cells were stimulated with TNFαand LPS from Pseudomonas aeruginosa,a common lunginfection pathogen in cystic fibrosis and chronic obstructive pulmonary disease.We used ELISA to measure the secretion levels of two pro-inflammatory cytokines,interleukin(IL)-6and-8,after 0,4,8,16,24 hof stimulation;and immunofluorescence microscopy to measure the nuclear translocation of RelA,a subunit of the NF-κB complex,after 0,15,30,60,120 min of stimulation.To suppress the inflammatory response,we pre-treated the cells with a specific IκB kinase-2inhibitor,TPCA-1;the main bioactive component of Andrographis paniculata,andrographolide;and DMSO control for 1h.RESULTS We found that individual stimulant(either TNFα10ng·mL-1 or LPS 10μg·mL-1)increased the IL-6and IL-8 secretion levels by^12-17 foldsas compared to DMSO controls after 8h of stimulation.The combined stimulation(10ng·mL-1 TNFαand 10μg·mL-1 LPS)induced even higher IL-6 and -8 levels(~18-21 folds)at the same time points.Importantly,our imaging study shows that the NF-κB activation is early but transient under TNFαstimulation,late but sustained under LPS stimulation,and early and sustained under the combined stimulation.Finally,we also found that TPCA-1 10μmol·L-1 or andrographolide 30μmol·L-1 drastically reduced the IL-6 and -8 levels down to 4.5-9 folds as compared to the controls.CONCLUSIONThe combined TNFαand LPS stimulations induce faster and more sustained inflammatory responses,which can still be suppressed by anti-inflammatory compounds in our cell model.These more comprehensive activations of inflammatory signaling pathways will enable us to study and distinguish the mechanisms of different anti-inflammatory compounds or natural products.
基金The project supported by ZYBZH-Y-HUN-24National Natural Science Foundation of China(81730096+6 种基金U1402221)National Mega-project for Innovative Drugs(2018ZX09711001-002-0072018ZX09711001-003-0052018ZX09711001-009-013)CAMS Innovation Fund for Medical Sciences(2016-I2M-1-004)Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150)PUMC Graduate Educationand Teaching Reform Project(10023201600801)
文摘OBJECTIVE To investigate the effects of IMM-H004 on permanent focal cerebral ischemia injury and associated cardiopulmonary complications,further elucidating the molecular mechanisms.METHODS The effects of IMM-H004 were investigated in wild-type(WT) and CKLF1-/-rats.The effects of IMM-H004 on ischemic stroke injury and its cardiopulmonary complications were determined using 2,3,5-triphenyltetrazolium chloride(TTC) staining,behavior tests,magnetic resonance imaging(MRI)scans,enzyme-linked immunosorbent assay(ELISA),Nissl staining,and histo-pathological examination.Multiple molecular experiments including immunohistological staining,immunofluorescence staining,quantitative RT-PCR,Western blotting,and co-immunoprecipitation assays were used to elucidate the underlying mechanisms.RESULTS IMM-H004 treatment provided significant protection against ischemic stroke-induced brain injury and associated cardiopulmonary complications,through CKLF1-depedent-anti-inflammation pathway in rats.IMM-H004 downregulated the amount of CKLF1 and disturbed the combination between CKLF1 and C-C chemokine receptor type 4,suppressing the inflammatory response and protecting the damaged organs in ischemic setting.CONCLUSION This preclinical study established efficacy of IMM-H004 as a potential therapeutic medicine for ischemic stroke and associated cardiopulmonary complications.The protective effects of IMM-H004 may due to its specific mechanism through CKLF1.These results support further efforts to develop IMM-H004 for human clinical trials in acute cerebral ischemia,especially for patients who are not suitable for reperfusion therapy.
基金The project supported by National Natural Science Foundation of China(81671188)Zhejiang Provincial Natural Science Foundation of China(LY12H31010)Key Laboratory of Hangzhou City Project(20090233T12)
文摘Brian ischemic injury and central neurodegenerative diseases as leading contributors to disability and death have become a majorclinical and public health concern worldwide.Neuroinflammation plays a pivotal role in the pathological progression of cerebral ischemia and neurodegenerative diseases including Parkinson disease(PD).Therefore,it is important to find effective therapeutic targets to attenuate inflammation and delay the progression of brain injury.Cysteinyl leukotrienes(CysLTs) are potent inflammatory mediators synthesized from arachidonic acid by 5-lipoxygenase(5-LOX) in the central nervous system.Two distinct G-protein-coupled receptors,CysLT1 R and CysLT2 R,mediate most of the known CysLTs biological responses.Accumulating evidence has demonstrated that postischemic inflammation and neuronal loss are mediated by 5-LOX and CysLTRs fol owing focal cerebral ischemia.We recently reported that the expression of 5-LOX,CysLT1R and inflammatory vascular cell adhesion molecule-1(VCAM-1) was upregulated in the hippocampus of rats with transient global cerebral ischemia,which was closely associated with delayed neuronal death in the hippocampal CA1 area.5-LOX inhibitor zileuton,CysLT1R antagonist ONO-1078 and montelukast dose-dependently reduced hippocampal CA1 neuronal death and inhibited the increased expression of 5-LOX and VCAM-1.In vitro ischemia-like injury in 5-LOXtransfected PC12 cells,oxygen-glucose deprivation(OGD) induced cell death mediated by5-LOX via ROS/P38 MAPK pathway.The nonselective 5-LOX inhibitor caffeic acid inhibited OGDstimulated activation of 5-LOX and ROS/P38 MAPK signaling and improved neuronal survival.In PD model,high concentrations of rotenone caused directly PC12 neurotoxicity,which was modulated by 5-LOX and abolished by suppression of 5-LOX.It is well known that microglia is major modulators of inflammatory response after brain injury.Overactivated microglia and production of proinflammatory cytokine IL-1β,IL-6 and TNF-α contribute to the neuroinflammation and brain injury.5-LOX,CysLT1R and CysLT2R are involved in microglial activation and resultant neurotoxic responses.It has been found that low concentrations of rotenone can activate 5-LOX and CysLT1R on microglial cells to enhance microglial inflammation and microglia-dependent neuronal death in vitro.5-LOX inhibitor zileuton and CysLT1R antagonist montelukast protected neurons from microglia-dependent rotenone neurotoxicity.Furthermore,lipopolysaccharide(LPS)induced microglial activation and microglial neurotoxicity mediated by CysLT2R in vitro.Both pharmacological blockade(CysLT2R antagonist HAMI3379) and RNA interference(specific short hairpin RNA) of CysLT2 R significantly attenuated LPS-triggered microglial inflammation and subsequent neuronal death.Collectively,the present results indicate the role of 5-LOX and CysLTRs in neuroinflammation and brain injury.Modulation of 5-LOX and CysLTRs may be potential therapeutic approaches for inflammation-related brain disorders such as cerebral ischemia and PD.However,further research is needed to clarify the mechanisms underlying the regulation of neuinflammatory processes by 5-LOX and CysLTRs.
基金supported by National Natural Science Foundation of China(81570623)Science and Technological Fund of Anhui Province for Outstanding Youth of China(1608085J07)
文摘OBJECTIVE E-cadherin is a major component of tubular adherent proteins which maintain intercellular contacts and cell polarity in epithelial tissue,it is involved in the pathological process of renal cell carcinoma and fibrotic diseases via epithelial-mesenchymal transition.Although we and others found that expression of E-cadherin was significantly down-regulated in kidney suffered acute kidney injury(AKI),its function in AKI was still unknown,which was explored in the current study.METHODS We disrupted E-cadherin or restored E-cadherin with compound 8J in cisplatin-stimulated tubular epithelial cell lines,the cell damage and inflammation were evaluated,additionally,the therapeutic potential of E-cadherin restoration was also determined in vivo.RESULTS We found that cisplatin reduced E-cadherin expression both in mouse kidney and tubular epithelial cell lines(m TECs).Administration of compound 8J restored the level of E-cadherin,thereby increased cell viability while attenuating programmed cell death,which may be mediated by deactivation of RIPK/MLKL axis,reduced membrane translocation of phosphor-MLKL and decreased cleavage of caspase 3.Compound 8J also suppressed inflammatory response in cisplatin-treated m TECs,which was correlated with suppressed NF-κB phorsphorylation and promoter activity.In contrast,disruption of E-cadherin enhanced cell damage and inflammation.Treatment of compound 8J failed to further attenuate kidney damage in E-cadherin knockdown cells,indicating compound 8J protected against mT ECs mainly through restoring E-cadherin.We also found that peritoneal injection of compound 8J protected against renal function and tubular damage by preventing NF-κB-driven renal inflammation and RIPK/MLKL-regulated programmed cell death,which was led by restoration of E-cadherin in cisplatin nephropathy.CONCLUSION More than a victim degraded after kidney injury,E-cadherin also has functional role in controlling tubule integrity,programmed cel death and renal inflammation.In this regard,restoration of E-cadherin by compound 8J should be considered as a novel therapeutic strategy for acute kidney injury.
基金Natural Science Foundation of Shandong Province(ZR2017MH048)。
文摘OBJECTIVE Platelets play a major role in mediating inflammatory response.The present work was designed to investigate whether arterial baroreflex impairment induced by sinoaortic denervation(SAD)affect platelet activation,leading to the exacerbation of cerebral cortex and hippocampus inflammation in rats.METHODS Adult male SD rats were divided into four groups:the sham control,the sinoaortic denervation(SAD),the sham+LPS,the SAD+LPS.In another experiment,there were also four groups:the sham control,the SAD,the SAD+LPS and the SAD+LPS+asprin.Four weeks after sham or SAD surgery,all rats were examined for the level of CD41,CD45,IL-1βand PF-4 in the cerebral cortex and hippocampus using immunofluorescence and ELISA.Blood platelet and leukocyte count,platelet microaggre⁃gation,expression of CD154 and CD62P on platelet surface and platelet-leukocyte aggregate level was detected by flow cytometry.RESULTS Compared with sham+LPS group,the in SAD+LPS group rats exhibited the high level of CD41,CD45,IL-1βand PF-4 in the cerebral cortex and hippocampus.Leukocyte count,platelet microag⁃gregation,expression of CD154 and CD62P on platelet surface and platelet-leukocyte aggregate level was increased,while blood platelet count was decreased in the SAD+LPS.Moreover,all the above changes were improved in the SAD+LPS+asprin group when compared with the SAD+LPS group.CONCLUSION Arterial baroreflex dysfunction exacerbates inflammation in the rat cerebral cortex and hippocampus,which is likely mediated by platelet.
基金The project supported by National Natural Science Foundation of China(81274172,81473267,30801535,81470003)
文摘OBJECTIVE The present study aimed to investigate the relationship between Wnt/β-catenin and Nrf2 signaling pathways,and understanding the mechanisms underlying the process of inflammatory in chronic obstructive pulmonary disease(COPD),which was a serious disease of respiratory system.METHODS We duplicate the emphysema model with porcine pancreatic elastase(PPE)in Nrf2-/-and WT mouse for 21d,and intraperitoneal injection of Li Cl,the activator of Wnt/β-catenin signaling pathway from 14 d to the end.Hematoxylin and eosin(H&E)staining was performed to assess the histopathologic level,and immunohistochemistry(IHC)for Mac-3(the marker of macrophagocyte)and Ly6G(the marker of neutrophil)was used to observe the inflammatory infiltrate,while the levels of Wnt/β-catenin and Nrf2 signaling pathways related proteins heme oxygenase-1(HO-1),NAD(P)H:quinone oxidoreductase 1(NQO1),and the expression of inflammatory cytokine interleukin-6(IL-6)were detected by Western blotting of lung tissues.In vitro,cigarette smoke extract(CSE)-treated normal human bronchial epithelial(NHBE)cells,cell viability was examined by MTT assay,and then we treated recombinant human Wnt3a,si Nrf2 and si Wnt3a to measure the expression of Wnt3a,β-catenin,Nrf2,HO-1,NQO-1,and IL-6.Cellular immunofluorescence staining was employed to identify the nuclear translocation of Nrf2.RESULTS We found that the Li Cl-treated group has markedly decreased the damage of alveolar structure and inflammatory signs than the model group of WT mice rather than Nrf2-/-group.It also seen that Li Cl not only increasedβ-catenin,but it also led to a comparable increase in Nrf2,HO-1,NQO1,and decrease of IL-6 compared with WT model groups but except to Nrf2-/-group in vivo.And it showed that Wnt3atreatment has significantly increased the nuclear translocation of Nrf2 and the expression of HO-1 and NQO1,reduced the IL-6 release,while there has no significance when Nrf2 was blocked in CSE-induced NHBE cells.CONCLUSION Our results demonstrated that Wnt3a/β-catenin significantly balanced oxidative stress and attenuated inflammation reaction by promoting Nrf2 nuclear translocation and activity.
基金Natural science foundation of Hebei Province(H2020405298)。
文摘OBJECTIVE To establish an in vitro inflammatory model of BV2 by observing the activity,the release amount of NO and the expression of inflammatory factors of microglial cells(BV2)induced by lipopolysaccharides(LPS).METHODS BV2 was routinely cultured in vitro.Cell viability was measured by CCK-8 meth⁃od.And by drew cell growth curve to determine the logarithmic growth cycle of the cells.After 24 h of routine culture,BV2 were induced by adding different concentrations of LPS(0.1,1.0 and 10.0 mg·L-1)for 4,8,12,24 and 48 h,respectively.Meanwhile,the morphological changes of BV2 were observed under inverted microscope to compare the activation degree of microglia at dif⁃ferent time and concentration.Cell activity and nitric oxide(NO)level were determined by CCK-8 and Griess method respectively,which could help to determine the optimal concentration and time of modeling.Finally,It were determined by ELISA that the concentrations of tumor necrosis factorα(TNF-α),interleukin-6(IL-6)and IL-1βin supernatant of LPS 1 mg·L-1 culture for 24 h.RESULTS BV2 were in logarithmic growth phase for 1 to 3 d after subculture.LPS 1 mg·L-1 induced BV2 for 24 or 48 h which could increase the release amount of NO significantly(P<0.05).In order to save time,LPS induced BV2 for 24 h were selected for subsequent experiments.Microglial cells in resting state were observed to be elongated spindle shape under inverted micro⁃scope.After LPS activation,the cell body became larger and the branching processes shrank back,presenting an amoeba-like appearance.ELISA results showed that the concentrations of TNF-α,IL-6 and IL-1βin supernatant of LPS 1 mg·L-1 cultured for 24 h were significantly increased which compared with the control group(P<0.05).CONCLUSION LPS could induce the activation of BV2 and up-regulate the level of inflammatory factors.The optimal condition for establishing stable BV2 microglial inflammatory model was used LPS 1 g·L-1 induced for 24 h.
文摘Objective Magnetoencephalography(MEG),a non-invasive neuroimaging technique,meticulously captures the magnetic fields emanating from brain electrical activity.Compared with MEG based on superconducting quantum interference devices(SQUID),MEG based on optically pump magnetometer(OPM)has the advantages of higher sensitivity,better spatial resolution and lower cost.However,most of the current studies are clinical studies,and there is a lack of animal studies on MEG based on OPM technology.Pain,a multifaceted sensory and emotional phenomenon,induces intricate alterations in brain activity,exhibiting notable sex differences.Despite clinical revelations of pain-related neuronal activity through MEG,specific properties remain elusive,and comprehensive laboratory studies on pain-associated brain activity alterations are lacking.The aim of this study was to investigate the effects of inflammatory pain(induced by Complete Freund’s Adjuvant(CFA))on brain activity in a rat model using the MEG technique,to analysis changes in brain activity during pain perception,and to explore sex differences in pain-related MEG signaling.Methods This study utilized adult male and female Sprague-Dawley rats.Inflammatory pain was induced via intraplantar injection of CFA(100μl,50%in saline)in the left hind paw,with control groups receiving saline.Pain behavior was assessed using von Frey filaments at baseline and 1 h post-injection.For MEG recording,anesthetized rats had an OPM positioned on their head within a magnetic shield,undergoing two 15-minute sessions:a 5-minute baseline followed by a 10-minute mechanical stimulation phase.Data analysis included artifact removal and time-frequency analysis of spontaneous brain activity using accumulated spectrograms,generating spectrograms focused on the 4-30 Hz frequency range.Results MEG recordings in anesthetized rats during resting states and hind paw mechanical stimulation were compared,before and after saline/CFA injections.Mechanical stimulation elevated alpha activity in both male and female rats pre-and post-saline/CFA injections.Saline/CFA injections augmented average power in both sexes compared to pre-injection states.Remarkably,female rats exhibited higher average spectral power 1 h after CFA injection than after saline injection during resting states.Furthermore,despite comparable pain thresholds measured by classical pain behavioral tests post-CFA treatment,female rats displayed higher average power than males in the resting state after CFA injection.Conclusion These results imply an enhanced perception of inflammatory pain in female rats compared to their male counterparts.Our study exhibits sex differences in alpha activities following CFA injection,highlighting heightened brain alpha activity in female rats during acute inflammatory pain in the resting state.Our study provides a method for OPM-based MEG recordings to be used to study brain activity in anaesthetized animals.In addition,the findings of this study contribute to a deeper understanding of pain-related neural activity and pain sex differences.
文摘Objective Ulcerative colitis is a prevalent immunoinflammatory disease.Th17/Treg cell imbalance and gut microbiota dysregulation are key factors in ulcerative colitis pathogenesis.The actin cytoskeleton contributes to regulating the proliferation,differentiation,and migration of Th17 and Treg cells.Wdr63,a gene containing the WD repeat domain,participates in the structure and functional modulation of actin cytoskeleton.Recent research indicates that WDR63 may serve as a regulator of cell migration and metastasis via actin polymerization inhibition.This article aims to explore the effect of Wdr63 deletion on Th17/Treg cells and ulcerative colitis.Methods We constructed Wdr63-/-mice,induced colitis in mice using dextran sulfate sodium salt,collected colon tissue for histopathological staining,collected mesenteric lymph nodes for flow cytometry analysis,and collected healthy mouse feces for microbial diversity detection.Results Compared with wild-type colitis mice,Wdr63-/-colitis mice had a more pronounced shortening of colonic tissue,higher scores on disease activity index and histological damage index,Treg cells decreased and Th17 cells increased in colonic tissue and mesenteric lymph nodes,a lower level of anti-inflammatory cytokine IL-10,and a higher level of pro-inflammatory cytokine IL-17A.In addition,WDR63 has shown positive effects on maintaining intestinal microbiota homeostasis.It maintains the balance of Bacteroidota and Firmicutes,promoting the formation of beneficial intestinal bacteria linked to immune inflammation.Conclusion Wdr63 deletion aggravates ulcerative colitis in mice,WDR63 inhibits colonic inflammation likely by regulating Th17/Treg balance and maintains intestinal microbiota homeostasis.
文摘Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(anti⁃MDA5+)dermatomyositis(DM)develop into the rapidly progressive interstitial lung disease(RPILD).Methods:We retrospectively analyzed the clinical and laboratory data of 124 anti⁃MDA5+DM patients from the First Affiliated Hospital of Nanjing Medical University between March 2019 and September 2023.We identified independent risk factors associated with the development and mortality of RPILD with the Cox regression analysis,and determined the optimal cut⁃off values for predicting adverse outcomes with the receiver operating characteristic(ROC)curve analysis.Results:Among the 124 patients,36 patients(29.03%)developed RPILD,and 39 patients(31.45%)died during the follow⁃up period.The results of multivariate Cox regression analysis showed that the elevated NLR was an independent risk factor for RPILD development,while the elevated SII expression was independently associated with the increased mortality of RPILD.Based on the ROC curve analysis,NLR>6.12 was a predictor for RPILD,and SII>875.79 was associated with increased mortality risk of RPILD.Conclusion:Both NLR and SII are accessible,cost⁃effective,and reliable prognostic indicators for the prognosis of patients with anti⁃MDA5^(+)DM,providing a valuable guidance for clinical management and risk stratification of the disease.
基金Supported by the Natural Science Foundation of the Heilongjiang Province of China(C2016003)China Postdoctoral Science Foundation(2015M581415)Heilongjiang Postdoctoral Fund(LBH-Z15005)。
文摘The trace element selenium(Se)occurs naturally throughout the earth.Se deficiency has been linked to impaired breast health and other diseases in human and animals.Compared to severe Se deficiency,marginal dietary Se deficiency accusers more frequently in low-Se regions.Therefore,to investigate the Se status and inflammatory response of the mammary gland under marginal dietary Se levels,an lipopolysaccharide(LPS)induced mouse mastitis model was established.Mice were fed with moderate Se diet(0.087 mg•kg^(-1) Se),adequate Se diet(0.15 mg•kg^(-1) Se)or excessive Se diet(1.5 mg•kg^(-1) Se)for 60 days.Se status and inflammatory factors were investigated.Results showed that the Se status of mammary gland correlated with dietary Se levels.Marginal Se deficiency exacerbated mammary tissue histopathology;increased the mRNA level of inflammatory genes tumor necrosis factor alpha(TNF-α),interleukin-1β(IL-1β)and cyclooxygenase-2(COX-2);and enhanced the phosphorylation of NF-κB p65 in mammary gland tissues.Supplementation of Se in diet higher than recommended levels reduced the inflammatory reaction of mammary glands in LPS-induced mastitis model and provided a protective effect.
