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Fasudil-modified macrophages reduce inflammation and regulate the immune response in experimental autoimmune encephalomyelitis

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Neural Regeneration Research 2024年第3期19卷 671-679页

作者： Chunyun Liu Shangde Guo Rong Liu Minfang Guo Qing Wang Zhi Chai Baoguo Xiao Cungen Ma Institute of Brain Science Shanxi Datong UniversityDatongShanxi ProvinceChina The Key Research Laboratory of Benefiting Qi for Acting Blood Cireulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology Shanxi University of Chinese MedicineTaiyuanShanxi ProvinceChina Institute of Neurology Huashan HospitalInstitutes of Brain Science and State Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina

Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple sclerosis.This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis.We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6.Crucially,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified macrophages.In addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced inflammation.These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for multiple sclerosis.

关键词： anti-inflammatory experimental autoimmune encephalomyelitis Fasudil macrophage multiple sclerosis pro-inflammatory Rho kinase

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pro-inflammatory cytokines profiles in Nigerian pregnant women infected with Plasmodium falciparum malaria

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Asian Pacific Journal of Tropical Medicine 2010年第9期3卷 731-733页

作者： Nmorsi OPG Isaac C Ohaneme BA Obiazi HAK Tropical Diseases Research Unit Department of ZoologyAmbrose Alli UniversityEkpomaNigeria Department of Medical Laboratory Sciences Ambrose Alli UniversityEkpomaNigeria

Objective:To investigate the pro-inflammatory cytokines profiles in in Nigerian pregnant women infected with Plasmodium falciparum(P.falciparum) malaria.Methods:Peripheral, and placental blood samples were collected from 96 consenting volunteers comprising 76 P.falciparium infected pregnant women and 20 healthy uninfected pregnant women in Ekpoma.Nigeria,and subjected to ELISA for cytokines evaluation.Results:Increased serum concentrations of interferon-gamma(IFN-γ) was observed in infected pregnant women than their uninfected counterparts[(31.2±20.9) pg/mL vs(1.8±0.9) pg/mL]and these differences were statistically significant(χ~2= 26.18,P0.05). The interleukin-6(IL-6) was significantly elevated in infected pregnant women(81.0±26.1 pg/mL) than in the uninfected pregnant women[(25.0±5.0) pg/mL](χ~2 = 29.58,P<0.05).In all, mean cytokines concentration of IL-6,IL-12 and IFN-γin the placental blood from infected pregnant women were(53.5±23.4) pg/mL,(8.7±6.9) pg/mL and(16.4±4.0) pg/mL,respectively. The multigravidae had a higher haemoglobin level of 10.2 g/dL and birth weight of 3 000 g than the primigrivadae with lower haemoglobin level of 7.5 g/dL and birth weight of 2 430 g. Conclusions:The elevated IFN-γamong the malarous pregnant women implicates it as the major cytokine mediator in the host responses to systematic P.falciparum malaria in our locality.

关键词： pro-inflammatory cytokines Pregnant women Plasmodium falciparum Nigeria

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Reduction of pro-inflammatory cytokines in rats following 7-day oral supplementation with a proprietary eggshell membrane-derived product

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Modern Research in Inflammation 2014年第1期3卷 19-25页

作者： Kevin J. Ruff Dale P. DeVore ESM Technologies LLC Carthage USA Membrell LLC Carthage USA

NEM®?brand eggshell membrane is a novel dietary supplement that has been clinically shown to alleviate arthritis joint pain and stiffness;however the mechanism of action is not well understood. Preliminary evidence from an?in vitro?study of?NEM®?indicated that the mechanism of action may be based on the reduction of pro-inflammatory cytokines.?In vivo?studies were therefore initiated to evaluate the effects of?NEM®?on pro-inflammatory and anti-inflammatory cytokines following oral administration in rats.?NEM®?was administered daily at doses of 6.13 mg/kg bw/day (Study 1), 10.0 mg/kg bw/day (Study 2), or at doses of 0 (control), 26.0 or 52.0 mg/kg bw/day (Study 3) by oral gavage for 7 consecutive days. Inflammation was induced in the Study 3 rats by intraperitoneal injection of lipopolysaccharide. Changes in plasma cytokine levels from baseline following 7 days of oral supplementation with?NEM®?at 6.13 mg/kg bw/ day (Study 1) were statistically significant at Day 8 for IL-2, TIMP-1 and VEGF, at Day 21 for IL-10, and at Day 35 for MCP-1, MCP-3 and TIMP-1, and at 10.0 mg/kg bw/day (Study 2) were statistically significant at Day 8 for VEGF, at Day 21 for MIP-1β, MIP-2 and VEGF, and at Day 35 for MCP-3, MIP-1β, MIP-2 and VEGF. Changes in serum cytokine levels versus control at 26.0 mg/kg bw/day (Study 3) were statistically significant at all time-points for IL-1β?and at 1.5 hours for IL-10, and at 52.0 mg/kg bw/day (Study 3) were statistically significant at 1.5 hours for IFN-γ, IL-1β?and IL-10, and at 3 hours for IL-1β, and at 24 hours for IL-10. Taken together, these studies demonstrate that oral supplementation with?NEM®?can influence both early-phase pro-inflammatory cytokines like IL-1β?and TNF-α?(Study 3), as well as later-phase cytokines like MCP-1, MIP-1α?&?β, RANTES and VEGF (Study 1 & 2). These studies provide a possible basis for the mechanism of action of?NEM®?in vivo.

关键词： pro-inflammatory Cytokines Eggshell Membrane

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<i>Ratanasampil</i>(Tibetan Medicine, RNSP) Reduces <i>β</i>-Amyloid protein (Aβ) and pro-inflammatory Factor Levels and Improves Cognitive Functions in Mild-to-Moderate Alzheimer’s Disease (AD) Patients Living at High Altitude

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Journal of Behavioral and Brain Science 2012年第1期2卷 82-91页

作者： Aiqin Zhu Aiqi Xi Guofeng Li Yinglan Li Baoxia Liao Xing Zhong Jingping Zhou Sonqin Gu Meihua Yu Yide Chu Institution of Geriatric Qinghai Provincial Hospital Xining Qinghai China

Ratanasampil (RNSP) is a traditional Tibetan medicine used for the treatment of stroke and cerebrovascular diseases. Previous discoveries that RNSP can reduce β-amyloid protein levels and increase learning and memory in Alzheimer’s mouse models (Tg2576) led us to investigate whether RNSP can improve cognitive functions in Alzheimer’s patients. In this study, 146 AD patients living in Qinghai province received either one gram or 0.33 gram daily of RNSP for 16 weeks. Placebo patients received Piracetam. Serum Aβ40 and Aβ42 levels were measured at the beginning of the study and after 4 and 16 weeks of treatment. Compared to the same group before treatment, MMSE scores, ADAS-cog scores and ADL scores were significantly improved (p 0.05, p > 0.05). After 16-week treatment, serum TNF-α, IL-1β, IL-6 and Aβ42 levels were significantly decreased (p < 0. 01) in the high-dose RNSP group, whereas no significant differences were found in the low-dose and placebo groups. The Aβ42/Aβ40 ratio was significantly decreased after 4-week and 16-week treatment in the high-dose RNSP group (p < 0. 05, p < 0.01). Furthermore, serum Aβ42 concentrations had a strong positive correlation with TNF-α, IL-1β and IL-6 levels. There were no observable adverse effects in either treatment or control groups. We conclude that further clinical trials of RNSP in Alzheimer disease are warranted.

关键词： Ratanasampil (RNSP Tibetan Medicine) Alzheimer’s Disease β-Amyloid Peptide Aβ42/Aβ40 Ratio pro-inflammatory Factors Cognitive Function

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Correlation of serum Hcy metabolism with pro-inflammatory factors, chemokines and oxidative stress response in patients with senile dementia

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Journal of Hainan Medical University 2018年第4期24卷 43-46页

作者： Jun-Yi Li Cheng-Kai Wang Neurology Department Tongchuan People's Hospital in Shaanxi ProvinceTongchuanShaanxi Province727001China

Objective: To investigate the correlation of serum Hcy metabolism with pro-inflammatory factors, chemokines and oxidative stress response in patients with senile dementia. Methods:A total of 50 patients who were diagnosed with senile dementia in our hospital between August 2012 and June 2016 were selected as the senile dementia group, and 50 elderly patients who underwent physical examination in this hospital during the same period were selected as normal control group. The differences in serum levels of Hcy, pro-inflammatory cytokines, chemokines and oxidative stress indexes were compared between the two groups, and Pearson test was adopted to assess the correlation between serum Hcy level and illness. Results: Serum Hcy level of senile dementia group was higher than that of control group;serum pro-inflammatory cytokines IL-1, IL-6, TNF-α and CRP levels were higher than those of control group;serum chemokines MCP-1, CCL2 and RANTES levels were higher than those of control group;serum oxidative stress indexes ROS, MDA and 4-HNE contents were higher than those of control group. Pearson test showed that the serum Hcy level in patients with senile dementia was positively correlated with the levels of pro-inflammatory factors, chemokines and oxidative stress indexes. Conclusions: The serum Hcy metabolism disorder in patients with senile dementia is closely related to the inflammatory response and oxidative stress response.

关键词： Senile dementia Hcy pro-inflammatory cytokine Chemokine Oxidative stress response

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Inhibition of MALT1 paracaspase activity improves lesion recovery following spinal cord injury

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Science Bulletin 2019年第16期64卷 1179-1194页

作者： Hua Zhang Guodong Sun Xiaowei Li Zhen Fu Chengbin Guo Guangchao Cao Baocheng Wang Qian Wang Shuxian Yang Dehai Li Xichun Xia Peng Li Jing Zhu Wei Zhou Liangyan Zheng Jingxia Li Lei Zhang Jianlei Hao Libing Zhou Frederic Bornancin Zhizhong Li Zhinan Yin Yunfei Gao The First Affiliated Hospital Biomedical Translational Research Institute and School of PharmacyJinan UniversityGuangzhou 510632China Department of Orthopedics First Affiliated HospitalJinan UniversityGuangzhou 510632China Shandong provincial Qianfoshan Hospital Shandong First Medical UniversityJinan 250014China Guangdong-Hongkong-Macao Institute of CNS Regeneration Ministry of Education CNS Regeneration Collaborative Joint LaboratoryJinan UniversityGuangzhou 510632China Novartis Institutes for BioMedical Research CH-4002 BaselSwitzerland Department of Orthopedics Heyuan People’s Hospital(Heyuan Affiliated Hospital of Jinan University)Heyuan 517199China State Key Laboratory of Biotherapy Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Spinal cord injury(SCI) is a devastating traumatic injury that causes persistent, severe motor and sensory dysfunction. Immune responses are involved in functional recovery after SCI. Mucosa-associated lymphoid tissue lymphoma translocation 1(MALT1) has been shown to regulate the survival and differentiation of immune cells and to play a critical role in many diseases, but its function in lesion recovery after SCI remains unclear. In this paper, we generated KI(knock in) mice with a point mutation(C472 G) in the active center of MALT1 and found that the KI mice exhibited improved functional recovery after SCI.Fewer macrophages were recruited to the injury site in KI mice and these macrophages differentiated into anti-inflammatory macrophages. Moreover, macrophages from KI mice exhibited reduced phosphorylation of p65, which in turn resulted in decreased SOCS3 expression and increased pSTAT6 levels.Similar results were obtained upon inhibition of MALT1 paracaspase with the small molecule inhibitor‘‘MI-2' or the more specific inhibitor ‘‘MLT-827'. In patients with SCI, peripheral blood mononuclear cells(PBMC) displayed increased MALT1 paracaspase. Human macrophages showed reduced proinflammatory and increased anti-inflammatory characteristics following the inhibition of MALT1 paracaspase. These findings suggest that inhibition of MALT1 paracaspase activity in the clinic may improve lesion recovery in subjects with SCI.

关键词： Anti-inflammatory macrophage pro-inflammatory macrophage Spinal cord injury NF-j B MALT1 paracaspase activity

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Chicken gga-miR-1306-5p targets Tollip and plays an important role in host response against Salmonella enteritidis infection

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Journal of Animal Science and Biotechnology 2019年第4期10卷 873-883页

作者： Weiwei Sun Ranran Liu Peng Li Qinghe Li Huanxian Cui Maiqing Zheng Jie Wen Guiping Zhao Institute of Animal Sciences Chinese Academy of Agricultural Sciences State Key Laboratory of Animal Nutrition

Background: Increasing evidence indicates that micro RNAs(mi RNAs) are involved in inflammatory response and immune regulation following pathogen invasion. The purpose of this study was to elucidate the roles played by Gallus gallus micro RNA-1306-5 p(gga-mi R-1306-5 p) in host responses against potential invasion by Salmonella enteritidis(SE) in chickens and the underlying mechanisms.Results: In present study, the expression levels of gga-mi R-1306-5 p were determined in both tissues and HD11 cells. The results showed that gga-mi R-1306-5 p was significantly increased following SE infection or lipopolysaccharide(LPS) stimulation. The dual luciferase reporter assay further validated that gga-mi R-1306-5 p targeted the Toll-interacting protein(Tollip), and thereby participated in the regulation of immune response against SE or LPS stimulation through binding with the 3′-untranslated region(3’UTR) of Tollip. Additionally, the expression of Tollip was significantly blocked by over-expressed gga-mi R-1306-5 p. The underlying mechanisms by which ggami R-1306-5 p modulated the production of pro-inflammatory cytokines were also investigated. Molecular biological assays demonstrated that overexpression of gga-mi R-1306-5 p promoted the production of pro-inflammatory mediators, including NF-κB, TNF-α, IL-6, and IL-1β, which produced effects similar to those of Tollip knockdown.Conclusions: Taken together, gga-mi R-1306-5 p induced by SE or LPS, regulates the immune response by inhibiting Tollip, which activates the production of inflammatory cytokines. This study has provided the first direct evidence that gga-mi R-1306-5 p targets Tollip, and is involved in the host response against SE.

关键词： gga-miR-1306-5p LPS pro-inflammatory cytokine Salmonella enteritidis Tollip

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Smoking under hypoxic conditions: a potent environmental risk factor for inflammatory and autoimmune diseases

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Military Medical Research 2018年第3期5卷 263-278页

作者： Md.Saddam Hussain Vishwas Tripathi School of Biotechnology Gautam Buddha University

Autoimmune disease management presents a significant challenge to medical science. Environmental factors potentially increase the risk of developing inflammatory and autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and lupus. Among various environmental stresses, cigarette smoke and hypoxia have both been reported to lead to an enhanced risk of inflammatory and autoimmune diseases. In this review, we shed light on all reported mechanisms whereby cigarette smoke and a hypoxic environment can induce inflammatory and autoimmune diseases and discuss how hypoxic conditions influence the cigarette smoke-induced threat of inflammatory and autoimmune disease development. Cigarette smoke and hypoxia both lead to increased oxidative stress and production of reactive oxygen species and other free radicals, which have various effects including the generation of autoreactive pro-inflammatory T cells and autoantibodies, reductions in T regulatory(Treg) cell activity, and enhanced expression of pro-inflammatory mediators [e.g., interleukin-6(IL-6), interleukin-4(IL-4) and interleukin-8(IL-8)]. Accordingly, smoking and hypoxic environments may synergistically act as potent environmental risk factors for inflammatory and autoimmune diseases. To our knowledge, no studies have reported the direct association of cigarette smoke and hypoxic environments with the risk of developing inflammatory and autoimmune diseases. Future studies exploring the risk of autoimmune disease development in smokers at high altitudes, particularly military personnel and mountaineers who are not acclimatized to high-altitude regions, are required to obtain a better understanding of disease risk as well as its management.

关键词： inflammatory and autoimmune diseases Cigarette smoke Hypobaric hypoxia Oxidative stress Epigenetic modifications pro-inflammatory mediators Autoantibody

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Pretreated Oenan the Javanica extract increases anti-inflammatory cytokines, attenuates gliosis, and protects hippocampal neurons following transient global cerebral ischemia in gerbils

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Neural Regeneration Research 2019年第9期14卷 1536-1543页

作者： Joon Ha Park In Hye Kim Ji Hyeon Ahn YooHun Noh Sung-Su Kim Tae-Kyeong Lee Jae-Chul Lee Bich-Na Shin Tae Heung Sim Hyun Sam Lee Jeong Hwi Cho In Koo Hwang Il Jun Kang Jong Dai Kim Moo-Ho Won Department of Biomedical Science and Research Institute for Bioscience and Biotechnology Hallym UniversityChuncheonGangwonRepublic of Korea Famenity Company GwacheonGeyonggiRepublic of Korea Department of Neurobiology School of MedicineKangwon National UniversityChuncheonGangwonRepublic of Korea Danchunok Company ChuncheonGangwonRepublic of Korea Department of Histology College of Veterinary MedicineChonbuk National UniversityIksanJeollabuk.doRepublic of Korea Department of Anatomy and Cell Biology College of Veterinary Medicineand Research Institute for Veterinary ScienceSeoul National UniversitySeoulRepublic of Korea Department of Food Science and Nutrition Hallym UniversityChuncheonGangwonRepublic of Korea Division of Food Biotechnology School of BiotechnologyKangwon National UniversityChuncheonGangwonRepublic of Korea

Recently,we have reported that Oenanthe javanica extract(OJE)displays strong neuroprotective effect against ischemic damage after transient global cerebral ischemia.However,neuroprotective mechanisms of OJE have not been fully identified.Thus,this study investigated the neuroprotection of OJE in the hippocampal CA1 area and its anti-inflammatory activity in gerbils subjected to 5 minutes of transient global cerebral ischemia.We treated the animals by intragastrical injection of OJE(100 and 200 mg/kg)once daily for 1 week prior to transient global cerebral ischemia.Neuroprotection of OJE was observed by immunohistochemistry for neuronal nuclear antigen and histofluorescence staining for Fluoro-Jade B.Immunohistochemistry of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 was done for astrocytosis and microgliosis,respectively.To investigate the neuroprotective mechanisms of OJE,we performed immunohistochemistry of tumor necrosis factor-alpha and interleukin-2 for pro-inflammatory function and interleukin-4 and interleukin-13 for anti-inflammatory function.When we treated the animals by intragastrical administration of 200 mg/kg of OJE,hippocampal CA1 pyramidal neurons were protected from transient global cerebral ischemia and cerebral ischemia-induced gliosis was inhibited in the ischemic hippocampal CA1 area.We also found that interleukin-4 and-13 immunoreactivities were significantly increased in pyramidal neurons of the ischemic CA1 area after OJE pretreatment,and the increased immunoreactivities were sustained in the CA1 pyramidal neurons after transient global cerebral ischemia.However,OJE pretreatment did not increase interleukin-2 and tumor necrosis factor-alpha immunoreactivities in the CA1 pyramidal neurons.Our findings suggest that pretreatment with OJE can protect neurons and attenuate gliosis from transient global cerebral ischemia via increasing expressions of interleukin-4 and-13.The experimental plan of this study was reviewed and approved by the Institutional Animal C

关键词： Oenanthe javanica extract transient global cerebral ischemia hippocampus ischemic damage cerebral ischemia neuroprotection glial activation pro-inflammatory cytokines anti-inflammatory cytokines inflammation neural regeneration

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In vivo and in vitro anti-sepsis effects of physcion 8-O-β- glu- copyranoside extracted from Rumexjaponicus

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Chinese Journal of Natural Medicines 2017年第7期15卷 534-539页

作者： FU Wei-Jun TANG Jian-Jun WANG Hui WEI Hong-Yun CAI Shu-Min ZENG Zhen-Hua CHEN Hui CHEN Zhong-Qing Department of Intensive Care Medicine Nanfang Hospital Southern Medical University Guangzhou 510515 China Department of Anesthesiology Nan fang Hospital Southern Medical University Guangzhou 510515 China Department of Plastic and Reconstructive Surgery Nanfang Hospital Southern Medical University Guangzhou 510515 China

The present study was designed to investigate the anti-sepsis effects of physcion 8-O-β-glucopyranoside (POG) isolated from Rumex japonicas and explore its possible pharmacological mechanisms. POG was extracted from R. japonicas by bioactivity-guided isolation with the anti-sepsis agents. Survival analysis in septic mouse induced by LPS and heat-killed Escherichia coli were used to evaluate the protective effect of POG(40 mg·kg^(-1), i.p.) on sepsis. Cytokines including TNF-α, IL-1β and IL-6 in RAW 264.7 cells induced by LPS(100 ng·mL^(-1)) were determined by ELISA. In addition, the proteins expressions of TLR2 and TLR4 were determined by Western blotting assay. Our results demonstrated that POG(40 mg·kg^(-1), i.p.) possessed significant protective activity on the endotoxemic mice. The POG treatment(20, 40, and 80 μg·mL^(-1)) significantly decreased the TNF-α, IL-1β and IL-6 induced by LPS(P proteins were also down-regulated by POG at 20(P < 0.01), 40(P < 0.01), and 80 μg·mL^(-1)(P < 0.01). The present study demonstrated that the POG extracted from R. japonicas possessed significant anti-sepsis effect on endotoxemic mice, and can be developed as a novel drug for treating sepsis in the future.

关键词： Anti-sepsis TLR-4 TLR-2 pro-inflammatory cytokines LPS

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