The immunogenic involvement of miRNA-492 in mycoplasma pneumoniae infection in pediatric patients

Abstract Objective: This study aimed to evaluate the role of miRNA-492 in the progression of mycoplasma pneumoniae (MP) infection in pediatric patients. Methods: Forty-six children admitted to the present study's hospital and diagnosed with mycoplasma pneumonia were recruited as the study group from March 2018 to August 2019, and 40 healthy children were selected as the control group. Results: The expression levels of miRNA-492, TNF-α, IL-6 and IL-18 in the study group were significantly higher than those in the control group (p < 0.05). There was no significant correlation between miRNA-492 and most of the immune-correlated indicators in the study group, except for IL-6, IL-18 and HMGB1. Meanwhile, overexpression of miRNA-492 increased IL-6 secretion in PMA-activated monocytes (p < 0.01). Conclusion: The present study's results suggested that miRNA-492 might play a role in the pathogenesis of mycoplasma pneumoniae pneumonia in children by regulating the secretion of immune-inflammatory factors such as IL-6 and IL-18 in the mononuclear macrophages.

Research Progressin the Relationship between Interleukin-6 and Intervertebral Disc Degeneration / 中国医学科学院学报

Intervertebral disc degeneration (IDD) is one of the main diseases causing low back pain,which seriously affects the quality of life of patients.Recent studies have discovered that interleukin-6 (IL-6) is highly expressed in the tissues and cells of degenerative intervertebral disc and is closely related to the occurrence and development of IDD.However,the signaling pathway and role of IL-6 in IDD remain to be understood.Therefore,this article reviews the recent studies about the signaling pathway and role of IL-6 in IDD,aiming to facilitate the clinical work and subsequent research progress.

Pathological Mechanisms of Brain-Heart Mutual Damage and Treatment with Traditional Chinese Medicine: A review / 中国实验方剂学杂志

The brain and heart has a tight relationship upon physiology and pathology during the development of cardiovascular and cerebrovascular diseases with clinical conditions interacting with each other and complex pathological mechanisms. Clinical studies prove that cerebral diseases such as stroke usually happen with cardiac diseases as complications， and cardiac diseases such as atrial fibrillation can also cause cerebral diseases， which can even aggravate brain atrophy and lead to cognitive impairment. Traditional Chinese medicine （TCM） also believes that “the substance of Shenming is located in the brain and the function in the heart.” Specifically， Yuanshen is in the brain and Shishen is in the heart， which thus makes the heart and brain closely related. If Shenming in any of them is impaired， the other one would also be injured. Therefore， the pathological mechanisms of brain-heart mutual damage have become one of the current research hotspots. This paper， combined with the clinical research status of the brain-heart mutual damage， summarized its pathological mechanisms from the perspectives of inflammatory responses， dysregulation of autonomic nervous system， apoptosis， energy metabolism and oxidative stress. The necessity of “brain-heart concurrent regulation” was proposed and the research progress on the treatment of cerebral and cardiac diseases with TCM represented by Naoxintong capsule was profiled in the light of heart and brain function described by TCM and the holistic concept of TCM treating cerebral and cardiac diseases. This paper reviews the pathological mechanisms of brain-heart mutual damage and the research progress on its treatment with TCM， which can provide reference for the prevention and treatment of cardiovascular and cerebrovascular diseases and further research on them.

Diagnostic value of circulating lncRNA ANRIL and its correlation with coronary artery disease parameters

This study aimed to detect the expression of the long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) and evaluate its correlation with disease risk, stenosis degree, inflammation, as well as overall survival (OS) in coronary artery disease (CAD) patients. A total of 230 patients who underwent diagnostic coronary angiography were consecutively recruited and assigned to CAD group (n=125) or control group (n=105) according to presence or absence of CAD. Gensini score was calculated to assess the severity of coronary artery damage. Plasma samples were collected and the expression ANRIL was detected in all participants. High-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, IL-10, and IL-17 in CAD patients were measured and OS was calculated. The relative expression of ANRIL was higher in CAD patients compared to controls (P<0.001). Receiver operating characteristic disclosed that ANRIL could distinguish CAD patients from controls with an area under the curve of 0.789 (95%CI: 0.731-0.847). Spearman's rank correlation test revealed that expression of ANRIL was positively correlated with Gensini score (P=0.001), levels of hs-CRP (P=0.001), ESR (P=0.038), TNF-α (P=0.004), and IL-6 (P<0.001), while negatively correlated with IL-10 level (P=0.008) in CAD patients. Kaplan-Meier curve revealed that high expression of ANRIL was associated with shorter OS (P=0.013). In conclusion, circulating ANRIL presented a good diagnostic value for CAD, and its high expression was associated with increased stenosis degree, raised inflammation, and poor OS in CAD patients.

Effect and mechanism of dihydromyricetin on cognitive dysfunction in model rats with Alzheimer's disease / 中华行为医学与脑科学杂志

Objective@#To explore the protective effect and mechanism of the dihydromyricetin (DHM) on cognitive dysfunction in Alzheimer’s disease (AD) rat model.@*Methods@#The AD model of rats was established by injecting Aβ1-42 oligomolymer into the hippocampus. According to the random number table, 30 successfully constructed AD model rats were divided into AD group, AD+ DHM1 group and AD+ DHM2 group, with 10 in each group.And the rats in the three groups were intraperitoneally injected with normal saline, 100 mg/kg DHM and 200 mg/kg DHM for 21 days, respectively.Another 10 rats with body mass matching were taken as the control group.Morris water maze was used to evaluate the spatial learning and memory ability of rats in each group, the expression of inflammatory cytokines were detected by Elisa, and the expressions of AMPK and SIRT1 proteins were detected by Western blot.@*Results@#Compared with the control group, the escape incubation period of rats in AD group was prolonged, and the difference was statistically significant (day 5 : (10.36±2.80)s, (22.40±2.98)s; t=-18.63, P<0.05). Compared with AD group, the escape latency of rats in AD+ DHM1 group and AD+ DHM2 group were shortened (day 5: AD+ DHM1 group (15.68±3.06) s, AD+ DHM2 group (18.85±3.22) s; t=10.65, 4.13, both P<0.05). Compared with AD group, rats in AD+ DHM1 group and AD+ DHM2 group had more crossing times ((1.87±0.76), (2.75±0.63) and (3.78±0.71); t=-6.86, -9.83, both P<0.05), and the target quadrant residence time were extended ((17.08±1.99) s, (16.33±4.33) s, (22.59±4.21) s; t= 28.5, 8.63, both P<0.05). Compared with the control group, the levels of IL-1β, IL-6 and TNF-α in the serum and hippocampus of the AD group were significantly increased (serum: t=4.98, 7.87, 5.43, all P<0.05; hippocampus: t=11.13, 30.50, 23.38, all P<0.05). Compared with the AD group, the levels of IL-1β, IL-6 and TNF-α in the serum and hippocampus of the AD+ DHM1 group and the AD+ DHM2 group were significantly decreased, the difference was statistically significant(serum: AD+ DHM1 group t=-4.13, -10.70, -9.22, AD+ DHM2 group t=-1.75, -3.63, -18.75, all P<0.05; hippocampus: AD+ DHM1 group t=-69.13, -15.13, -6.50, AD+ DHM2 group t=-10.25, -39.00, -8.00, all P<0.05). Compared with the control group, the expression of p-AMPK/AMPK protein and SIRT1 protein in the AD group were decreased.The expression of the two proteins in the AD+ DHM1 group and the AD+ DHM2 group were increased, comparing with those of AD group, and the difference was statistically significant(all P<0.05).@*Conclusion@#DHM exerts protective role in AD model rats, which may be related to the activation of AMPK/SIRT1 pathway and the inhibition of inflammatory response.

Effect and mechanism of dihydromyricetin on cognitive dysfunction in model rats with Alzheimer's disease / 中华行为医学与脑科学杂志

Objective To explore the protective effect and mechanism of the dihydromyricetin (DHM) on cognitive dysfunction in Alzheimer’s disease (AD) rat model. Methods The AD model of rats was established by injecting Aβ1-42 oligomolymer into the hippocampus. According to the random number table,30 successfully constructed AD model rats were divided into AD group,AD+DHM1 group and AD+DHM2 group,with 10 in each group. And the rats in the three groups were intraperitoneally injected with nor-mal saline,100 mg/kg DHM and 200 mg/kg DHM for 21 days,respectively. Another 10 rats with body mass matching were taken as the control group. Morris water maze was used to evaluate the spatial learning and memory ability of rats in each group,the expression of inflammatory cytokines were detected by Elisa,and the expressions of AMPK and SIRT1 proteins were detected by Western blot. Results Compared with the con-trol group,the escape incubation period of rats in AD group was prolonged,and the difference was statistically significant (day 5 :(10. 36±2. 80)s,(22. 40±2. 98)s;t=-18. 63,P<0. 05). Compared with AD group,the escape latency of rats in AD+DHM1 group and AD+DHM2 group were shortened (day 5:AD+DHM1 group (15. 68±3. 06) s,AD+DHM2 group (18. 85±3. 22) s; t=10. 65,4. 13,both P<0. 05). Compared with AD group,rats in AD+DHM1 group and AD+DHM2 group had more crossing times ((1. 87± 0. 76),( 2. 75± 0. 63) and (3. 78±0. 71);t=-6. 86,-9. 83,both P<0. 05),and the target quadrant residence time were ex-tended ((17. 08±1. 99) s,(16. 33±4. 33) s,(22. 59±4. 21) s;t= 28. 5,8. 63,both P<0. 05). Compared with the control group,the levels of IL-1β,IL-6 and TNF-α in the serum and hippocampus of the AD group were significantly increased (serum: t=4. 98, 7. 87, 5. 43, all P<0. 05; hippocampus: t=11. 13, 30. 50, 23. 38,all P<0. 05). Compared with the AD group,the levels of IL-1β,IL-6 and TNF-α in the serum and hippocampus of the AD+DHM1 group and the AD+DHM2 group were significantly decreased,the difference was statistically significant ( serum: AD+DHM1 group t=-4. 13,-10. 70,-9. 22, AD+DHM2 group t=-1. 75,-3. 63,-18. 75,all P<0. 05;hippocampus:AD+DHM1 group t=-69. 13,-15. 13,-6. 50,AD+DHM2 group t=-10. 25,-39. 00,-8. 00,all P<0. 05). Compared with the control group,the expression of p-AMPK/AMPK protein and SIRT1 protein in the AD group were decreased. The expression of the two pro-teins in the AD+DHM1 group and the AD+DHM2 group were increased,comparing with those of AD group, and the difference was statistically significant(all P<0. 05). Conclusion DHM exerts protective role in AD model rats,which may be related to the activation of AMPK/SIRT1 pathway and the inhibition of inflammato-ry response.

Adipose-Derived Stem Cell Transplantation Inhibits Vascular Inflammatory Responses and Endothelial Dysfunction in Rats with Atherosclerosis

PURPOSE: This study aimed to investigate the effect of adipose-derived stem cell (ADSC) transplantation on atherosclerosis (AS) and its underlying mechanisms. MATERIALS AND METHODS: In our study, rat AS model was established, and ADSCs were isolated and cultured. Atherosclerotic plaque and pathological symptoms of thoracic aorta were measured by Oil Red O staining and Hematoxylin-Eosin staining, respectively. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were measured by an automatic biochemical analyzer. Expressions of vascular endothelial growth factor (VEGF), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), aortic endothelin-1 (ET-1), interleukin-6 (IL-6), c-reactive protein (CRP), and tumor necrosis factor α (TNF-α) were measured by enzyme linked immunosorbent assay, VEGF, VCAM-1, ICAM-1, ET-1, respectively, and NF-κB p65 mRNA expressions were detected by quantitative real-time polymerase chain reaction. Protein expressions of VEGF, VCAM-1, ICAM-1, ET-1, NF-κB p65, p-NF-κB p65, and IκBα were measured by western blot. Moreover, NF-κB p65 expression was measured by immunofluorescence staining. RESULTS: ADSC transplantation alleviated the pathological symptoms of aortic AS. ADSC transplantation decreased the levels of TC, TG, and LDL-C and increased serum HDL-C level. Meanwhile, ADSC transplantation decreased the levels of IL-6, CRP, and TNF-α in AS rats. Moreover, the expressions of VEGF, ET-1, VCAM-1, and ICAM-1 were decreased by ADSC transplantation. ADSC transplantation inhibited phosphorylation of NF-κB p65 and promoted IκBα expression in AS rats. CONCLUSION: Our study demonstrated that ADSC transplantation could inhibit vascular inflammatory responses and endothelial dysfunction by suppressing NF-κB pathway in AS rats.

Toll-like receptor 4-related regulation of Ornithogalum caudatum extract on inflammatory responses in LPS activated macrophages / 中国药理学与毒理学杂志

OBJECTIVE To investigate toll-like receptor 4(TLR4)-related the regulation of Ornithog-alum caudatum extract(OCE)on inflammatory responses in lipopolysaccharide(LPS)activated macro-phages.METHODS Primary peritoneal macrophage,Raw 264.7,and THP-1 were incubated in 96-well plate for 24 h and treated with OCE of the concentration of 0-400 μg/ml for 4h.The viability of cells was measured by MTT assay.Specific concentrations of OCE were added into the medium of primary peri-toneal macrophage, Raw 264.7, and THP-1, respectively, then following with lipopolysaccharides (LPS). Cells were harvested and the total cellular protein and nuclear protein were extracted, and the protein content was determined using BCA protein assay Kit.The expressions of TLR4,inducible nitric oxide synthase(iNOS),cyclooxygenase 2(COX-2),α-inhibitor of NF-κB(IκB-α)and nuclear factor-κB (NF-κB)were assayed by Western blot.The expressions of interleukin-1α(IL-1α),interleukin-1β(IL-1β), interleukin-18(IL-18),and tumor necrosis factor-α(TNF-α)were measured by RT-PCR.RESULTS The results of MTT showed that OCE has no cytotoxicity in Raw 264.7 cells between 1.56 μg/ml and 400 μg/ml. Compared with normal group,the expressions of TLR4,iNOS,COX-2,NF-κB and IL-1α,IL-1β,IL-18, TNF-α,the level of nitric oxide(NO)were significantly increased by LPS stimulation,while OCE pretreat-ment reduced these increase induced by LPS. However, OCE pretreatment reversed the reduction of IκB-α after LPS stimulation.CONCLUSION OCE might suppress TLR4 expression and block the inflamma-tion process of NF-κB and iNOS,further decrease the expression of COX-2 and inhibit the release of inflammatory factors.

Pyroptosis mediated by mitochondrial DNA amplifies the inflammatory response of alveolar macrophage / 中华危重病急救医学

Objective To observe the amplification effect of mitochondrial DNA (mtNDA) on the inflammatory response of rat alveolar macrophage induced by lipopolysaccharide (LPS), and to preliminarily explore its mechanism. Methods mtDNA of Sprague-Dawley (SD) rat liver tissue was harvested, ultra-micro spectrophotometer and 1% agarose gel electrophoresis were used to detect the concentration and quality of mtDNA. The alveolar macrophages of SD rat were isolated and cultured, the macrophages in logarithmic growth phase were divided into phosphatic buffer solution (PBS) group, LPS group, mtDNA group and LPS+mtDNA group. The first three groups were added equal volumes of PBS, LPS 1 mg/L or mtDNA 10 mg/L to the alveolar macrophages medium for 6 hours and 12 hours, respectively; the alveolar macrophage medium of LPS+mtDNA group was stimulated with 1 mg/L LPS for 6 hours and then stimulated with 10 mg/L mtDNA for 6 hours. The levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the cell supernatant were detected by enzyme linked immunosorbent assay (ELISA);the expression of the key protein of Pyroptosis-Gasdermin D (GSDMD) was detected by Western Blot. Results ① The mtDNA A260/280 ratios were between 1.8-2.0, and agarose gel electrophoresis showed a single band, with a size of about 16 kb. ② After alveolar macrophages stimulated by LPS or mtDNA for 6 hours or 12 hours, respectively, the levels of IL-1β and TNF-α were higher than those in PBS group. When cells were treated with mtDNA for 6 hours after LPS stimulation 6 hours, the levels of IL-1β were higher than those in LPS 12 hours group (ng/L: 366.27±23.35 vs. 154.70±23.32, 1 < 0.01), but the levels of TNF-α had no significant difference compared with LPS 12 hours group (ng/L: 836.13±25.01 vs. 802.67±30.48, 1 > 0.05). ③ The protein expressions of GSDMD in LPS group, mtDNA group and LPS+mtDNA group were significantly higher than those in PBS group (GSDMD/β-actin: 1.77±0.05, 1.65±0.04,2.40±0.05, 1.00±0.02, all 1 < 0.01), and the protein expression of GSDMD in LPS+mtDNA group was higher than that in LPS group (1 < 0.01). Conclusion mtDNA amplifies LPS-induced alveolar macrophage inflammatory responses,which mechanism may be related to the increase in pyroptosis mediated by mtDNA.

Study on the mechanism of PSGL-1 in salt-sensitive hypertension via inflammation in mice / 中国比较医学杂志

Objective To investigate the role and mechanism of PSGL-1 in development of salt-sensitive hypertension in mice. Methods PSGL-1 knockout(PSGL-1 -/-)and wild type(PSGL-1 +/ +)mice were fed a high salt (6% NaCl)or normal salt(0.4% NaCl)diet for three months. Blood pressure was measured under anesthesia via the carotid artery. The status of tissue inflammation and kidney injury was tested by flow cytometry, immunohistochemistry, and western blotting. Results Compared with mice fed a normal salt diet, PSGL-1 +/ +mice fed a high salt diet for three months showed high blood pressure, increased inflammatory cell infiltration in the aorta and skin, and increased inflammatory cytokine expression(interleukin-6, interleukin-1β, and tumor necrosis factor-α)in the kidney, as well as elevated expression of the kidney injury marker, connective tissue growth factor. In contrast, inflammation and kidney injury were not found in PSGL-1 -/-mice fed a high-salt diet. Conclusions In mice,PSGL-1 via inflammation plays a key role in development of hypertension and kidney injury caused by high salt intake.

Roles of transient receptor potential melastatin 7 in hippocampal neuron injury / 临床麻醉学杂志

Objective To investigate the role of transient receptor potential melastatin 7 (TR PM7) in the protective role of sevoflurane preconditioning against hippocampal neuron injury caused by oxygen glucose deprivation (OGD).Methods Hippocampal neurons were harvested from postnatal day 1 SD rats,and randomly divided into 5 groups:control group (group C),sevoflurane group (group Sev),oxygen-glucose deprivation group (group OGD),sevoflurane+ OGD group (group SD) and sevoflurane+OGD+bradykinin group (group B).To build up the model of OGD,the neurons were cultured in a deoxygenated glucose-free medium and exposed to 95％ N2 and 5％％ CO2 in an anaerobic chamber equilibrated at 37℃ for 1.5 h,followed by replacement with glucose containing medium and return to a standard incubator for additional 24 h.The neurons in group C received no treatment.Group OGD was preconditioned with 2 ％ sevoflurane for 1 h.The neurons in group OGD were subjected to OGD.Group SD was preconditioned with 2％ sevoflurane for 1 h,followed by OGD at 24 h after the sevoflurane exposure.The neurons in group B was incubated in a medium supplemented with 200 μmol/L bradykinin (the selective agonist of TRPM7),followed sequen tially by the preconditioning of 2％ sevoflurane for 1 h and then OGD challenge.Twenty-four hours after re-oxygenation,The relative neuronal cell viability was determined by MTT assay,the neuronal apoptotic rate was analyzed by TUNEL assay,the protein expression of TRPM7 was detected by Western blot,the mRNA level of TRPM7 was estimated by real-time PCR,the neuronal release of IL-1β and TNF-α in the serum was measured by ELISA.Results Compared with group C,the mR NA and protein levels of TRPM7,the neuronal apoptotic rate,the mRNA and supernatant protein levels of IL-1β and TNFα were significantly up-regulated in group OGD (P＜0.05),whereas the cell viability was decreased (P＜0.05).Compared with group OGD,the mRNA and protein levels of TRPM7,the neuronal apoptotic rate,the mRNA and supernatant protein levels of IL1β and TNF-α were significantly down-regulated in group SD (P＜0.05),whereas the cell viability was increased (P＜0.05).Compared with group SD,the mRNA and protein levels of TRPM7,the neuronal apoptotic rate,the mRNA and supernatant protein levels of IL-1β and TNF-α were significantly up-regula ted in group B (P＜0.05),whereas the cell viability was decreased (P＜0.05).Conclusion Sevoflurane attenuates apoptosis and inflammatory responses induced by OGD via reduction of the overex pression of TRPM7 in the hippocampal neurons.

Effect and mechanism of astragaloside Ⅳ on Toll-like receptor pathway in fibrotic mice after renal ischemia-reperfusion / 中国中药杂志

The aim of this paper is to study the effect of astragaloside Ⅳ on renal fibrosis mice with ischemia-reperfusion injury (IRI) and discuss the mechanism. Male C57BL/6 50 mice were randomly divided into four groups, namely Sham-operated group, model group, AS-Ⅳ prevention group and AS-Ⅳ treatment group. Since the day of surgery, the mice in astragaloside Ⅳ prevention group were treated with astragaloside Ⅳ by gavage for 30 days at the dose of 30 mg·kg⁻¹·d⁻¹. At the 60th day after surgery, the mice in astragaloside Ⅳ treatment group were treated with astragaloside Ⅳ 100 by gavage for 30 days at the dose of 30 mg·kg⁻¹·d⁻¹. The mice in Sham-operated group and model group were treated with double distilled water containing 0.1% ethanol instead of astragaloside Ⅳ. Serum creatinine and blood urea nitrogen were detected by chemical methods. Histopathological changes and collagen deposition of affected kidneys were observed under optical microscope by HE and Masson staining. The expression levels of Toll like receptor pathway related molecules (TLR4,MyD88,TRAF6,TRAM,TRIF,NF-κB,TNF-α,IL-6, IFN-) in affected kidneys were observed by immunohistochemistry, Western blot methods and reverse transcription-PCR atprotein and mRNA levels in each group. The results showed that the degrees of fibrosis and histopathological damage of affected kidneys of mice in model group were the most obvious. And the expression levels of TLR4/MyD88 dependent signaling pathway-related molecules (TLR4 and MyD88, TRAF6 and NF-κB) in affected kidneys of mice in model group were the highest. At the same time, there was no difference in the expression levels of TLR4/MyD88 independent signaling pathway-related molecules（TRAM, TRIF）among sham-operated group, model group, astragaloside IV prevention group and astragaloside Ⅳ treatment group. In astragaloside Ⅳ prevention group and astragaloside Ⅳ treatment group, the injury of affected kidney was obviously reduced, and the protein expression levels of TLR4/MyD88 dependent signaling pathway-related molecules were also correspondingly reduced; at the same time, the expressions of terminal inflammatory cytokines (TNF-α,IL-6, IFN-) were suppressed. Therefore, astragaloside Ⅳ may improve renal interstitial fibrosis in mice after IRI by inhibiting the expression of TLR4/MyD88 dependent signaling pathway and the release of inflammatory cytokines (TNF-α,IL-6, IFN-), while the TLR4/MyD88 independent signaling pathway may not be involved in the process of renal fibrosis after ischemia-reperfusion injury.

LRRK2/NF-κB signaling modulates inflammatory responses in BCG-in-fected RAW264.7 macrophages / 中国病理生理杂志

AIM:To investigate the biological function and potential mechanism of leucine-rich repeat kinase 2 (LRRK2)in RAW264.7 macrophages during Mycobacterium tuberculosis infection.METHODS: The bacillus Calmette-Guerin(BCG)-infected RAW264.7 cell model was established.Colony-forming unit(CFU)analysis was used to deter-mine the mycobacterial viability.The releases of interleukin(IL)-1β,IL-6 and interferon-γ(IFN-γ)in the RAW264.7 cells were detected by ELISA.qPCR and Western blot were used to measure the mRNA and protein expression levels,re-spectively.RESULTS:LRRK2 was robustly enhanced in the RAW264.7 cells in response to BCG infection.Additional-ly,silencing of LRRK2 suppressed intracellular growth of mycobacteria during BCG challenge.Moreover, silencing of LRRK2 dramatically attenuated the accumulation of inflammatory cytokines IL-1β,IL-6 and IFN-γinduced by BCG infec-tion.More importantly,LRRK2 modulated BCG-induced inflammatory responses by positively regulating the nuclear factor-κB(NF-κB)signaling pathway.CONCLUSION: LRRK2/NF-κB signaling pathway positively modulates inflammatory responses during BCG infection,which may provide a better understanding of the pathogenesis of tuberculosis and useful in -formation for developing potential therapeutic interventions against the disease.

Regulatory Roles of the Caspase-11 Non-Canonical Inflammasome in Inflammatory Diseases

Inflammation is an immune response mediated by innate immune cells of tissues, against invading microbes and cellular stress. The hallmark of inflammatory responses is the activation of inflammasomes — multiprotein oligomers comprising intracellular pattern recognition receptors and inflammatory effectors — such as ASC and pro-cysteine-aspartic protease (pro-caspase)-1. Inflammasomes can be classified as canonical or non-canonical, and their activation in response to various ligands commonly induces caspase-1 activation and gasdermin D (GSDMD) processing, leading to caspase-1-mediated maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18, and GSDMD-mediated pyroptosis through pore generation in cell membranes. Although inflammation protects the host from harmful stimuli, chronic inflammation is a critical risk factor for inflammatory diseases, and several studies have investigated the role of canonical inflammasomes in inflammatory responses and diseases, with emerging studies focusing on the role of non-canonical inflammasomes. This review discusses recent studies on the regulatory roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory diseases. Additionally, it provides an insight into the development of novel therapeutics based on targeting caspase-11 non-canonical inflammasome and its downstream effectors to prevent and treat human inflammatory conditions.

Effects of total saponins of Panax japonicuson liver inflammation natural aging rats / 中国药理学通报

Aim To study the effects of total saponins of Panax japonicus(TSPJ) on liver inflammation of natural aging rats.Methods The experimental rats were allocated into seven groups (twelve rats in each group): three months group, nine months group, fifteen months group, twenty-four months group, and TSPJ low-, mid-and high-dose groups(10, 30, 60 mg·kg-1).When the rats were eighteen months old, the TSPJ low-, mid-and high-dose groups of rats were given lavage treatments with TSPJ 10,30, 60 mg·kg-1 respectively until twenty-four months.During lavage, we stopped a day every week for six consecutive months.HE staining was used to observe the pathological morphological changes.Western blot was utilized to test IL-1β and TNF-α protein expressions.RT-PCR method was adopted to test IL-1β, IL-6, IL-12, IL-17α, TNF-α, IFN-γ mRNA expressions.Results HE staining observation showed that as the rats grew older the hepatic cord and sinusoid were arranged in more severe disorder, and the fat vacuole and inflammatory cells were increased significantly.While every dose group of TSPJ could improve these pathological changes distinctly.The IL-1β, TNF-α protein and IL-1β, IL-6, IL-12, IL-17α, TNF-α, IFN-γ mRNA expressions were increased gradually as the rats grew older, and every dose group of TSPJ could reduce their expressions to some extent.Conclusion TSPJ could protect the aging rat liver to some extent by inhibiting the liver inflammation.

Effect of astragaloside IV based on Toll/MyD88 dependent signaling pathway in treatment of renal fibrosis mice / 中草药

Objective To study the effect of astragaloside IV on renal fibrosis mice with unilateral ureteral obstruction (UUO) and discuss the mechanism. Methods Male C57BL/6 50 mice were divided into five groups randomly, such as Sham-operated group, model group and high-, medium-, and low-dose astragaloside IV groups. From the day of surgery, the mice in astragaloside IV groups (high-, medium- and low-dose) were treated by gavage of astragaloside IV for 2 weeks in doses of 50, 30, and 10 mg/(kg∙d) separately. The mice in Sham-operated group and model group were treated with saline instead of astragaloside IV. Serum creatinine and blood urea nitrogen were detected by chemical methods. Histopathological changes and collagen deposition of affected kidney were observed under optical microscope with HE and MASSON staining. The expression levels of Toll/MyD88 dependent signaling pathway related molecules (TLR4, TLR2, MyD88, TRAF6, NF-Kappa B, TNF-α, and IL-6) in affected kidney were measured by immunohistochemistry and Western blotting methods and observed from protein levels in each group. Results The degree of fibrosis and histopathological damage of affected kidney of mice in model group is the most obvious. And the expression levels of Toll/MyD88 dependent signaling pathway related molecules in affected kidney of mice in model group were the highest. With drug concentration increased in groups of astragaloside IV, in these groups, the injury of affected kidney had been obviously reduced, and the protein expression levels of Toll/MyD88 dependent signaling pathway related molecules (TLR4, TLR2, MyD88, TRAF6, and NF-Kappa B) were also in corresponding reduced, at the same time the expression of terminal inflammatory cytokines (TNF-alpha and IL-6) has been suppressed. Conclusion Astragaloside IV may improve renal interstitial fibrosis in mice after UUO by inhibiting the expression of Toll/MyD88 dependent signaling pathway and release of inflammatory cytokines (TNF-alpha and IL-6).

The effect of artesunate on inflammatory responses to severe pneumonia by regulating MIF in rats / 中华急诊医学杂志

Objective To study the effect of artesunate on inflammatory responses to severe pneumonia by regulating macrophage migration inhibitory factor (MIF) in rats.Methods Total of 100 SD by random (random number) assigned,20 rats were control group,80 SD rats with severe pneumonia were caused by Klebsiella pneumoniae,60 SD rats were treated with different concentrations (20,40,80 mk/kg) of artesunate after modeling.The pathological changes of lung tissue,the level of MIF myeloperoxidase activity and inflammatory cell infiltration in lung tissue of rats were evaluated.Results After treatment with artesunate,the severity of inflammation was significantly alleviated in rats with severe pneumonia evidenced by decrease in myeloperoxidase activity [severe pneumonia:(17.5 ± 1.5) vs.treatment group:(7.5 ±2.0)] and reduction in inflammatory cell infiltration (severe pneumonia:27 × 106 vs.treatment group:12.5 × 106).Similarly,the artesunate also reduced the production of inflammatory cytokines significantly in bronchoalveolar lavage fluid (IL-1 in severe pneumonia group:(1 100 ± 50) pg/ml vs.treatment group:(400 ± 60) pg/ml;IL-6 in severe pneumonia group:(700-± 30) pg/ml vs.treatment group:(200 ±40) pg/ml;IL-10 in severe pneumonia group:(500 ± 70) pg/ml vs.treatment group:(200 ± 40) pg/ml;TNF-αin severe pneumonia group:(500 ± 80) pg/ml vs.treatment group:(150 ± 50) pg/ml.In addition,artesunate inhibited the level and production of MIF,thus inhibiting the inflammatory responses mediated by MIF.Conclusions Artesunate had a protective effect on pneumonia caused by Klebsiella pneumoniae in rats via inhibiting the inflammation responses mediated by MIF.This study provided a molecular basis for newly developed drugs applied to the treatment of pneumonia caused by Klebsiella pneumoniae in rats.

Interleukin-1 receptor type 1 signaling induces excessive inflammatory responses in H1N1 influenza ;virus infection / 中华微生物学和免疫学杂志

Objective To investigate the role of interleukin-1 receptor type 1 (IL-1R1) signaling in H1N1 influenza virus infection. Methods IL-1R1 knockout ( IL-1R1-/-) mice and wild type ( WT) mice were infected intranasally with 2×104 TCID50(50% tissue culture infective dose) of influenza virus H1N1 PR8. Changes in clinical signs, survivals and bodyweights of those mice were monitored daily for 14 consecutive days. Three mice from each group were sacrificed at 3, 7 and 14 days post infection (d. p. i), from which whole lungs were harvested. A part of the lobes was fixed in 4% paraformaldehyde for histopatho-logical assessment and the rest were split and stored at-80 centigrade for further analysis. Real-time quanti-tative PCR and cytometric bead array ( CBA) were performed to detect viral loads in lungs and inflammatory cytokines in supernatants of lung homogenates. Results The mice in both groups showed severe symptoms after the infection of PR8. The maximum bodyweight loss of IL-1R1-/- mice [(24. 22±0. 80) % at 8 d. p. i] was lower than that of WT mice [(28. 03±1. 51)% at 9 d. p. i] (P<0. 05). The IL-1R1-/- mice with PR8 infection showed a higher survival rate (90%) as compared with that of the control group (40%) (P<0. 05). No statistical differences in virus loads were observed between the two groups at 3, 7 and 14 d. p. i. The lung weight to body weight ratio of IL-1R1-/-mice [(1. 42±0. 03) %] was lower than that of WT mice [(1. 79±0. 08) %] at 3 d. p. i (P<0. 05). Pathological changes in IL-1R1-/- mice were less severe than those in WT mice. CBA detection assay revealed that the proinflammatory cytokines in lungs of IL-1R1-/-mice were less than those in WT mice. Conclusion IL-1R1 signaling plays a pathogenic role in mice infec-ted with 2×104 TCID50 of influenza virus PR8 by promoting inflammatory responses.

Effects of dexmedetomidine on inflammatory responses and insulin resistance during cardiac operations with car-diopulmonary bypass / 临床麻醉学杂志

Objective To observe the effects of dexmedetomidine on inflammatory responses and insulin resistance during cardiac operations with cardiopulmonary bypass(CPB).Methods Fifty patients scheduled for elective cardiac valve replacement with CPB were equally and randomly divided into two groups using a random number table:observation group and control group(n =25).A loading dose of dexmedetomidine 1.0 μg/kg was injected intravenously over 1 5 min after induction,followed by continuous infusion at 0.4 μg·kg-1 ·h-1 until the end of CPB in doservation group.While the e-qual volume of normal saline was given in control group.After induction(T1 ),at 30 min after the be-ginning of CPB(T2 ),at the end of CPB(T3 ),and at 2 h after the end of CPB(T4 ),the jugular venous blood samples were taken for determination of serum concentrations of TNF-a,IL-6,insulin and blood glucose.The insulin sensitivity index (ISI ) = 1/(glucose × insulin )was obtained. Results Compared with control group,the serum TNF-a and IL-6 concentrations at T2-T4 were sig-nificantly decreased in observation group(P <0.05),the serum insulin and blood glucose concentra-tions at T2 ,T3 were significantly decreased in observation group(P <0.05 ),the ISI at T2 ,T3 were significantly increased in observation group(P <0.05).Conclusion Dexmedetomidine can reduce in-flammatory responses,thus reducing insulin resistance and blood glucose during cardiac operations with CPB.

The Anti-Inflammatory Activity of Eucommia ulmoides Oliv. Bark. Involves NF-κB Suppression and Nrf2-Dependent HO-1 Induction in BV-2 Microglial Cells

In the present study, we investigated the anti-inflammatory properties of Eucommia ulmoides Oliv. Bark. (EUE) in lipopolysaccharide (LPS)-stimulated microglial BV-2 cells and found that EUE inhibited LPS-mediated up-regulation of pro-inflammatory response factors. In addition, EUE inhibited the elevated production of pro-inflammatory cytokines, mediators, and reactive oxygen species (ROS) in LPS-stimulated BV-2 microglial cells. Subsequent mechanistic studies revealed that EUE suppressed LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs), phosphoinositide-3-kinase (PI3K)/Akt, glycogen synthase kinase-3β (GSK-3β), and their downstream transcription factor, nuclear factor-kappa B (NF-κB). EUE also blocked the nuclear translocation of NF-κB and inhibited its binding to DNA. We next demonstrated that EUE induced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated heme oxygenase-1 (HO-1) expression. We determined that the significant up-regulation of HO-1 expression by EUE was a consequence of Nrf2 nuclear translocation; furthermore, EUE increased the DNA binding of Nrf2. In contrast, zinc protoporphyrin (ZnPP), a specific HO-1 inhibitor, blocked the ability of EUE to inhibit NO and PGE2 production, indicating the vital role of HO-1. Overall, our results indicate that EUE inhibits pro-inflammatory responses by modulating MAPKs, PI3K/Akt, and GSK-3β, consequently suppressing NF-κB activation and inducing Nrf2-dependent HO-1 activation.