Progranulin is closely related to neuronal survival in a neuroinflammatory mouse model and attenuates inflammatory reactions. Atsttrin is an engineered protein composed of three progranulin fragments and has been show...Progranulin is closely related to neuronal survival in a neuroinflammatory mouse model and attenuates inflammatory reactions. Atsttrin is an engineered protein composed of three progranulin fragments and has been shown to have an effect similar to that of progranulin. Atsttrin has anti-inflammatory actions in multiple arthritis mouse models, and it protects against further arthritis development. However, whether Atsttrin has a role in neuroinflammation remains to be elucidated. In this study, we produced a neuroinflammatory mouse model by intracerebroventricular injection of 1 μL lipopolysaccharide(10 μg/μL). Atsttrin(2.5 mg/kg) was administered via intraperitoneal injection every 3 days over a period of 7 days before intracerebroventricular injection of 1 μL lipopolysaccharide(10 μg/μL). In addition, astrocyte cultures were treated with 0, 100 or 300 ng/mL lipopolysaccharide, with 200 ng/mL Atsttrin simultaneously. Immunohistochemistry, enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction were performed to examine the protein and mRNA levels of inflammatory mediators and to assess activation of the nuclear factor kappa B signaling pathway. Progranulin expression in the brain of wild-type mice and in astrocyte cultures was increased after lipopolysaccharide administration. The protein and mRNA expression levels of tumor necrosis factor-α, interleukin-1β and inducible nitric oxide synthase were increased in the brain of progranulin knockout mice after lipopolysaccharide administration. Atsttrin treatment reduced the lipopolysaccharide-induced increase in the protein and mRNA levels of tumor necrosis factor-α, interleukin-1β, matrix metalloproteinase-3 and inducible nitric oxide synthase in the brain of progranulin knockout mice. Atsttrin also reduced the expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase 3 mRNA in lipopolysaccharide-treated astrocytes in vitro, and decreased the concentration of tumor necrosis factor α and interleukin-1β in the supernatant. Furthermore, Atsttrin significantly reduced the levels of phospho-nuclear factor kappa B inhibitor α in the brain of lipopolysaccharide-treated progranulin knockout mice and astrocytes, and it decreased the expression of nuclear factor kappa B2 in astrocytes. Collectively, our findings show that the anti-neuroinflammatory effect of Atsttrin involves inhibiton of the nuclear factor kappa B signaling pathway, and they suggest that Atsttrin may have clinical potential in neuroinflammatory therapy.展开更多
AIM:To construct the CABYR RNAi plasmid and study its relation with the nuclear factor(NF)-κB signal transduction pathway.METHODS:Human CABYR mRNA sequence was obtained from GenBank.The structure of cDNA sequence for...AIM:To construct the CABYR RNAi plasmid and study its relation with the nuclear factor(NF)-κB signal transduction pathway.METHODS:Human CABYR mRNA sequence was obtained from GenBank.The structure of cDNA sequence for the short hairpin RNA was BbsⅠ+sense+loop+ antisense+transcription terminator+KpnⅠ+Bam HⅠ.A CABYR silencing plasmid was constructed and transfected into the human embryo cell line 293T.Quantitative real-time polymerase chain reaction was used to analyze CABYR and NF-κB gene expression.RESULTS:The CABYR and NF-κB expressions were detected in 293T cells.The oligonucleotide(5'-GCT-CAGATGTTAGGTAAAG-3')efficiently silenced the expression of CABYR.The expression of NF-κB was not significantly affected by silencing CABYR(P=0.743).CONCLUSION:CABYR can be found in the human embryo cell line 293T.Cabyrmid 2 can efficiently silence its target,CABYR,indicating that CABYR is not related with the NF-κB signal transduction pathway.展开更多
Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs regulate these pathw...Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs regulate these pathways by targeting specific proteins to cellular sub-domains where the levels of intracellular freecalcium are kept low by the calcium ejection properties of PMCAs. According to this model, PMCAs have been shown to interact functionally with the calcium-sensitive proteins neuronal nitric oxide synthase, calmodulindependent serine protein kinase, calcineurin and endothelial nitric oxidase synthase. Transgenic animals with altered expression of PMCAs are being used to evaluate the physiological significance of these interactions. To date, PMCA interactions with calcium-dependent partner proteins have been demonstrated to play a crucial role in the pathophysiology of the cardiovascular system via regulation of the nitric oxide and calcineurin/nuclear factor of activated T cells pathways. This new evidence suggests that PMCAs play a more sophisticated role than the mere ejection of calcium from the cells, by acting as modulators of signaling transduction pathways.展开更多
OBJECTIVE:To examine the nephroprotective mechanism of modified Huangqi Chifeng decoction(加味黄芪赤风汤,MHCD)in immunoglobulin A nephropathy(IgAN)rats.METHODS:To establish the IgAN rat model,the bovine serum albumin,...OBJECTIVE:To examine the nephroprotective mechanism of modified Huangqi Chifeng decoction(加味黄芪赤风汤,MHCD)in immunoglobulin A nephropathy(IgAN)rats.METHODS:To establish the IgAN rat model,the bovine serum albumin,lipopolysaccharide,and carbon tetrachloride 4 method was employed.The rats were then randomly assigned to the control,model,telmisartan,and high-,medium-,and low-dose MHCD groups,and were administered the respective treatments via intragastric administration for 8 weeks.The levels of 24-h urinary protein,serum creatinine(CRE),and blood urea nitrogen(BUN)were measured in each group.Pathological alterations were detected.IgA deposition was visualized through the use of immunofluorescence staining.The ultrastructure of the kidney was observed using a transmission electron microscope.The expression levels of interleukin-6(IL-6),monocyte chemoattractant protein-1(MCP-1),and transforming growth factor-β1(TGF-β1)were examined by immunohistochemistry and quantitative polymerase chain reaction.Levels of toll-like receptor 4(TLR4),myeloid differentiation factor 88(MyD88),and nuclear factor-kappa B(NF-κB)P65,were examined by immunohistochemistry,Western blotting,and quantitative polymerase chain reaction.RESULTS:The 24-h urine protein level in each group increased significantly at week 6,and worsen from then on.But this process can be reversed by treatments of telmisartan,and high-,medium-,and low-dose of MHCD,and these treatments did not affect renal function.Telmisartan,and high-,and medium-dose of MHCD reduced IgA deposition.Renal histopathology demonstrated the protective effect of high-,medium-,and low-dose of MHCD against kidney injury.The expression levels of MCP-1,IL-6,and TGF-β1 in kidney tissues were downregulated by low,medium and high doses of MHCD treatment.Additionally,treatment of low,medium and high doses of MHCD decreased the protein and mRNA levels of TLR4,MyD88,and NF-κB.CONCLUSIONS:MHCD exerted nephroprotective effects on IgAN rats,and MHCD regulated the expressions of key targets in TLR4/MyD88/NF-κB signaling pathway,thereby alleviating renal inflammation by inhibiting MCP-1,IL-6 expressions,and ameliorating renal fibrosis by inhibiting TGF-β1 expression.展开更多
OBJECTIVE:To investigate the impact of Yemazhui(Herba Eupatorii Lindleyani,HEL)against lipopolysaccharide(LPS)-induced acute lung injury(ALI)and explore its underlying mechanism in vivo.METHODS:The chemical constituen...OBJECTIVE:To investigate the impact of Yemazhui(Herba Eupatorii Lindleyani,HEL)against lipopolysaccharide(LPS)-induced acute lung injury(ALI)and explore its underlying mechanism in vivo.METHODS:The chemical constituents of HEL were analyzed by ultra-high performance liquid chromatographyquadrupole time-of-flight mass spectrometry method.Then,HEL was found to suppress LPS-induced ALI in vivo.Six-week-old male Sprague-Dawley rats were randomly divided into 6 groups:control,LPS,Dexamethasone(Dex),HEL low dose 6 g/kg(HEL-L),HEL medium dose 18 g/kg(HEL-M)and HEL high dose 54 g/kg(HEL-H)groups.The model rats were intratracheally injected with 3 mg/kg LPS to establish an ALI model.Leukocyte counts,lung wet/dry weight ratio,as well as myeloperoxidase(MPO)activity were determined followed by the detection with hematoxylin and eosin staining,enzyme linked immunosorbent assay,quantitative real time polymerase chain reaction,western blotting,immunohistochemistry,and immunofluorescence.Besides,to explore the effect of HEL on ALI-mediated intestinal flora,we performed 16s rRNA sequencing analysis of intestinal contents.RESULTS:HEL attenuated LPS-induced inflammation in lung tissue and intestinal flora disturbance.Mechanism study indicated that HEL suppressed the lung coefficient and wet/dry weight ratio of LPS-induced ALI in rats,inhibited leukocytes exudation and MPO activity,and improved the pathological injury of lung tissue.In addition,HEL reduced the expression of tumor necrosis factoralpha,interleukin-1beta(IL-1β)and interleukin-6(IL-6)in bronchoalveolar lavage fluid and serum,and inhibited nuclear displacement of nuclear factor kappa-B p65(NF-κBp65).And 18 g/kg HEL also reduced the expression levels of toll-like receptor 4(TLR4),myeloid differentiation factor 88,NF-κBp65,phosphorylated inhibitor kappa B alpha(phospho-IκBα),nod-like receptor family pyrin domain-containing 3 protein(NLRP3),IL-1β,and interleukin-18(IL-18)in lung tissue,and regulated intestinal flora disturbance.CONCLUSIONS:In summary,our findings revealed that HEL has a protective effect on LPS-induced ALI in rats,and its mechanism may be related to inhibiting TLR4/NF-κB/NLRP3 signaling pathway and improving intestinal flora disturbance.展开更多
Acacetin(5,7-dihydroxy-4′-methoxyflavone), a potential neuroprotective agent, has an inhibitory effect on lipopolysaccharide-induced neuroinflammatory reactions. However, whether acacetin has an effect on inflammator...Acacetin(5,7-dihydroxy-4′-methoxyflavone), a potential neuroprotective agent, has an inhibitory effect on lipopolysaccharide-induced neuroinflammatory reactions. However, whether acacetin has an effect on inflammatory corpuscle 3(NLRP3) after cerebral ischemia-reperfusion injury has not been fully determined. This study used an improved suture method to establish a cerebral ischemia-reperfusion injury model in C57BL/6 mice. After ischemia with middle cerebral artery occlusion for 1 hour, reperfusion with intraperitoneal injection of 25 mg/kg of acacetin(acacetin group) or an equal volume of saline(0.1 mL/10 g, middle cerebral artery occlusion group) was used to investigate the effect of acacetin on cerebral ischemia-reperfusion injury. Infarct volume and neurological function scores were determined by 2,3,5-triphenyltetrazolium chloride staining and the Zea-Longa scoring method. Compared with the middle cerebral artery occlusion group, neurological function scores and cerebral infarction volumes were significantly reduced in the acacetin group. To understand the effect of acacetin on microglia-mediated inflammatory response after cerebral ischemia-reperfusion injury, immunohistochemistry for the microglia marker calcium adapter protein ionized calcium-binding adaptor molecule 1(Iba1) was examined in the hippocampus of ischemic brain tissue. In addition, tumor necrosis factor-α, interleukin-1β, and interleukin-6 expression in ischemic brain tissue of mice was quantified by enzyme-linked immunosorbent assay. Expression of Iba1, tumor necrosis factor-α, interleukin-1β and interleukin-6 was significantly lower in the acacetin group compared with the middle cerebral artery occlusion group. Western blot assay results showed that expression of Toll-like receptor 4, nuclear factor kappa B, NLRP3, procaspase-1, caspase-1, pro-interleukin-1β, and interleukin-1β were significantly lower in the acacetin group compared with the middle cerebral artery occlusion group. Our findings indicate that acacetin has a protective effect on cerebral ischemia-reperfusion injury, and its mechanism of action is associated with inhibition of microglia-mediated inflammation and the NLRP3 signaling pathway.展开更多
骨结核是一种严重危害人体健康的骨科感染性疾病,其病灶组织破坏的最大特点是骨质的吸收及破坏,其中破骨细胞是骨吸收的主要细胞。破骨细胞是由造血干细胞分化而来的多核细胞,通常是由核因子κB受体活化因子配体(receptor activator of ...骨结核是一种严重危害人体健康的骨科感染性疾病,其病灶组织破坏的最大特点是骨质的吸收及破坏,其中破骨细胞是骨吸收的主要细胞。破骨细胞是由造血干细胞分化而来的多核细胞,通常是由核因子κB受体活化因子配体(receptor activator of nuclear factor-κB ligand,RANKL)与核因子κB受体活化因子(receptor activator for nuclear factor-κB,RANK)调控产生。结核分枝杆菌可以通过RANKL信号通路激活破骨细胞生成转录因子,以增强破骨细胞对骨质的吸收。笔者通过综述RANKL信号通路的结构及破骨细胞的研究进展,以及它们在骨结核临床治疗中可能发挥的潜在作用,为该领域的研究提供新的思路。展开更多
背景:基于核转录因子κB通路探究神经炎症的靶向治疗越来越值得探究,中药靶点多、范围广、机制丰富及不良反应少等优点在治疗各类疾病时都具有十分巨大的潜力。目的:基于核转录因子κB信号通路,对近年研究中出现的山奈酚、红花黄、汉黄...背景:基于核转录因子κB通路探究神经炎症的靶向治疗越来越值得探究,中药靶点多、范围广、机制丰富及不良反应少等优点在治疗各类疾病时都具有十分巨大的潜力。目的:基于核转录因子κB信号通路,对近年研究中出现的山奈酚、红花黄、汉黄芩苷及雷公藤甲素等中药单体治疗脊髓损伤后神经炎症的研究进展进行系统的阐述与归纳。方法:以“脊髓损伤,炎症,抗炎,中药单体,单体化合物,NF-κB信号通路,黄酮,糖苷,酚类,酯类,生物碱”为检索词在中国知网数据库中进行检索;以“Spinal cord injury,inflammation,anti-inflammatory,traditional Chinese medicine monomer,monomeric compound,NF-κB signaling pathway,flavonoids,glycosides,phenols,esters,alkaloids”为检索词在PubMed数据库中进行检索,最终共纳入67篇文献进行综述分析。结果与结论:①核转录因子κB信号通路在神经系统中的作用复杂多样,能够调控中性粒细胞、小胶质细胞、星形胶质细胞和巨噬细胞等,介导损伤后炎症的发生与发展;②中药单体如汉黄芩苷对核转录因子κB抑制蛋白的降解、红花黄素对核转录因子κB信号通路磷酸化过程的抑制、山奈酚对核转录因子κB信号通路p65核易位的抑制等作用可以降低炎症反应对机体造成的影响,从而促进神经功能恢复;③核转录因子κB信号通路在损伤早期能够促进炎症反应和免疫细胞迁移活化,在损伤中后期能够促进损伤部位的修复和纤维化的发生等,适当的激活核转录因子κB信号通路具有促进炎症因子的释放、提高细胞的抗氧化能力及促进免疫细胞的活化等能力,但过度激活的核转录因子κB信号通路则容易导致慢性炎症的发生和持续、细胞凋亡受到抑制等;④未来的研究可以进一步探索如何准确调控核转录因子κB信号通路的活化水平、如何实现对神经系统炎症和损伤的精准干预展开,也可围绕中药单体的制备及中药单体对信号通路的作用机制展开,以期为神经系统疾病的康复和功能恢复提供更有效的治疗策略。展开更多
OBJECTIVE:To investigate the effect of Taohong Siwu decoction(桃红四物汤,TSD)on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking.METHODS:Sixty healthy male Sprague-Daw...OBJECTIVE:To investigate the effect of Taohong Siwu decoction(桃红四物汤,TSD)on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking.METHODS:Sixty healthy male Sprague-Dawley rats were randomly divided into 6 groups with 10 rats in each group:control group,model group,atorvastatin group(AT,2.0 mg/kg),and TSD groups(20,10,5 g/kg)after 7 d of acclimation.The model of atherosclerosis was successfully established except the control group by high fat diet(HFD)and vitamin D2.Biochemical analyzers were used to detect the levels of triglyceride(TG),total cholestero(TC),low density lipoprotein-cholesterol(LDLC)and high density lipid-cholesterol(HDL-C)in blood lipid.The levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and interleukin-1β(IL-1β)were determined by enzyme-linked immunosorbent assay.Sudan IV staining and Hematoxylin and eosin staining(HE staining)were performed to observe the pathological changes in aortic tissue.Molecular docking technology was used to predict the best matching between the main components of TSD and the target proteins.The expression of target proteins was further detected by quantitative real time polymerase chain reaction(q RTPCR)and Western blot analysis.RESULTS:The results showed that TSD restricted atherosclerosis development and decreased the inflammatory cytokines in plasma.Molecular docking results predicted that the main components of TSD showed a strong binding ability with toll-like receptor(TLR4),myeloid differentiation primary response protein 88(My D88),and nuclear factor kappa-B(NF-κB).The results of q RT-PCR and Western blot analysis showed that the m RNA and protein expressions of TLR4,My D88 and NF-κB p65 in the aorta were reduced in atorvastatin group and TSD group.CONCLUSIONS:TSD can ameliorate atherosclerosis in rats,and the underlying mechanism is supposed be related to the suppression of inflammatory response by regulating TLR4/My D88/NF-κB signal pathway.展开更多
基金supported by the National Natural Science Foundation of China,No.81572191(to LC)and 81601067(to HZ)
文摘Progranulin is closely related to neuronal survival in a neuroinflammatory mouse model and attenuates inflammatory reactions. Atsttrin is an engineered protein composed of three progranulin fragments and has been shown to have an effect similar to that of progranulin. Atsttrin has anti-inflammatory actions in multiple arthritis mouse models, and it protects against further arthritis development. However, whether Atsttrin has a role in neuroinflammation remains to be elucidated. In this study, we produced a neuroinflammatory mouse model by intracerebroventricular injection of 1 μL lipopolysaccharide(10 μg/μL). Atsttrin(2.5 mg/kg) was administered via intraperitoneal injection every 3 days over a period of 7 days before intracerebroventricular injection of 1 μL lipopolysaccharide(10 μg/μL). In addition, astrocyte cultures were treated with 0, 100 or 300 ng/mL lipopolysaccharide, with 200 ng/mL Atsttrin simultaneously. Immunohistochemistry, enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction were performed to examine the protein and mRNA levels of inflammatory mediators and to assess activation of the nuclear factor kappa B signaling pathway. Progranulin expression in the brain of wild-type mice and in astrocyte cultures was increased after lipopolysaccharide administration. The protein and mRNA expression levels of tumor necrosis factor-α, interleukin-1β and inducible nitric oxide synthase were increased in the brain of progranulin knockout mice after lipopolysaccharide administration. Atsttrin treatment reduced the lipopolysaccharide-induced increase in the protein and mRNA levels of tumor necrosis factor-α, interleukin-1β, matrix metalloproteinase-3 and inducible nitric oxide synthase in the brain of progranulin knockout mice. Atsttrin also reduced the expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase 3 mRNA in lipopolysaccharide-treated astrocytes in vitro, and decreased the concentration of tumor necrosis factor α and interleukin-1β in the supernatant. Furthermore, Atsttrin significantly reduced the levels of phospho-nuclear factor kappa B inhibitor α in the brain of lipopolysaccharide-treated progranulin knockout mice and astrocytes, and it decreased the expression of nuclear factor kappa B2 in astrocytes. Collectively, our findings show that the anti-neuroinflammatory effect of Atsttrin involves inhibiton of the nuclear factor kappa B signaling pathway, and they suggest that Atsttrin may have clinical potential in neuroinflammatory therapy.
基金Supported by Grants from Natural Science Foundation of China, No.30940034
文摘AIM:To construct the CABYR RNAi plasmid and study its relation with the nuclear factor(NF)-κB signal transduction pathway.METHODS:Human CABYR mRNA sequence was obtained from GenBank.The structure of cDNA sequence for the short hairpin RNA was BbsⅠ+sense+loop+ antisense+transcription terminator+KpnⅠ+Bam HⅠ.A CABYR silencing plasmid was constructed and transfected into the human embryo cell line 293T.Quantitative real-time polymerase chain reaction was used to analyze CABYR and NF-κB gene expression.RESULTS:The CABYR and NF-κB expressions were detected in 293T cells.The oligonucleotide(5'-GCT-CAGATGTTAGGTAAAG-3')efficiently silenced the expression of CABYR.The expression of NF-κB was not significantly affected by silencing CABYR(P=0.743).CONCLUSION:CABYR can be found in the human embryo cell line 293T.Cabyrmid 2 can efficiently silence its target,CABYR,indicating that CABYR is not related with the NF-κB signal transduction pathway.
基金Supported by The Breast Cancer Campaign and the Research Institute in Healthcare Sciences (Armesilla AL)The Wellcome Trust (Emerson M)
文摘Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs regulate these pathways by targeting specific proteins to cellular sub-domains where the levels of intracellular freecalcium are kept low by the calcium ejection properties of PMCAs. According to this model, PMCAs have been shown to interact functionally with the calcium-sensitive proteins neuronal nitric oxide synthase, calmodulindependent serine protein kinase, calcineurin and endothelial nitric oxidase synthase. Transgenic animals with altered expression of PMCAs are being used to evaluate the physiological significance of these interactions. To date, PMCA interactions with calcium-dependent partner proteins have been demonstrated to play a crucial role in the pathophysiology of the cardiovascular system via regulation of the nitric oxide and calcineurin/nuclear factor of activated T cells pathways. This new evidence suggests that PMCAs play a more sophisticated role than the mere ejection of calcium from the cells, by acting as modulators of signaling transduction pathways.
基金Joint Innovation Fundation of JIICM:Health Management of Chronic Kidney Disease Based on Integrated Traditional Chinese And Western Medicine(No.2021IR009)Natural Science Foundation-funded Project:the Mechanism of Modified Huangqi Chifeng Decoction Protect Damaged Podocyte via Cross-Talking of PI3K/AKT/mTOR and AMPK/mTOR/ULK1 Signaling Pathway Regulate Autophapy(No.81873300)+1 种基金the Central Publicinterest Scientific Institution Basal Research Fund of the China Academy of Chinese Medical Sciences:Comprehensive Evaluation of Clinical efficacy of Modified Huangqi Chifeng Decoction on IgA Nephropathy(No.ZZ11-023)the Beijing Municipal of Science and Technology Major Project:Evaluation of Clinical Efficacy of Modified Huangqi Chifeng Decoction in Treating Proteinuria in IgA Nephropathy Based on"Deficiency-Wind-Blood-Stasis-Toxicity"Mechanism in Chinese Medicine(No.Z191100006619063)。
文摘OBJECTIVE:To examine the nephroprotective mechanism of modified Huangqi Chifeng decoction(加味黄芪赤风汤,MHCD)in immunoglobulin A nephropathy(IgAN)rats.METHODS:To establish the IgAN rat model,the bovine serum albumin,lipopolysaccharide,and carbon tetrachloride 4 method was employed.The rats were then randomly assigned to the control,model,telmisartan,and high-,medium-,and low-dose MHCD groups,and were administered the respective treatments via intragastric administration for 8 weeks.The levels of 24-h urinary protein,serum creatinine(CRE),and blood urea nitrogen(BUN)were measured in each group.Pathological alterations were detected.IgA deposition was visualized through the use of immunofluorescence staining.The ultrastructure of the kidney was observed using a transmission electron microscope.The expression levels of interleukin-6(IL-6),monocyte chemoattractant protein-1(MCP-1),and transforming growth factor-β1(TGF-β1)were examined by immunohistochemistry and quantitative polymerase chain reaction.Levels of toll-like receptor 4(TLR4),myeloid differentiation factor 88(MyD88),and nuclear factor-kappa B(NF-κB)P65,were examined by immunohistochemistry,Western blotting,and quantitative polymerase chain reaction.RESULTS:The 24-h urine protein level in each group increased significantly at week 6,and worsen from then on.But this process can be reversed by treatments of telmisartan,and high-,medium-,and low-dose of MHCD,and these treatments did not affect renal function.Telmisartan,and high-,and medium-dose of MHCD reduced IgA deposition.Renal histopathology demonstrated the protective effect of high-,medium-,and low-dose of MHCD against kidney injury.The expression levels of MCP-1,IL-6,and TGF-β1 in kidney tissues were downregulated by low,medium and high doses of MHCD treatment.Additionally,treatment of low,medium and high doses of MHCD decreased the protein and mRNA levels of TLR4,MyD88,and NF-κB.CONCLUSIONS:MHCD exerted nephroprotective effects on IgAN rats,and MHCD regulated the expressions of key targets in TLR4/MyD88/NF-κB signaling pathway,thereby alleviating renal inflammation by inhibiting MCP-1,IL-6 expressions,and ameliorating renal fibrosis by inhibiting TGF-β1 expression.
基金Natural Science Foundation Project of Chongqing Municipality:a Metabolome-based Study on the Protective Mechanism of Yemazhui(Herba Eupatorii Lindleyani)Sesquiterpene Lactones Against Acute Lung Injury(No.cstc2021jcyj-msxmX0365)Science and Technology Research Program of Chongqing Municipal Education Commission:a Cytokine Storm-based Study of the Protective Effect of Yemazhui(Herba Eupatorii Lindleyani)Extract Intervention on COVID-19 Lung Injury(No.KJZD-K202215101)。
文摘OBJECTIVE:To investigate the impact of Yemazhui(Herba Eupatorii Lindleyani,HEL)against lipopolysaccharide(LPS)-induced acute lung injury(ALI)and explore its underlying mechanism in vivo.METHODS:The chemical constituents of HEL were analyzed by ultra-high performance liquid chromatographyquadrupole time-of-flight mass spectrometry method.Then,HEL was found to suppress LPS-induced ALI in vivo.Six-week-old male Sprague-Dawley rats were randomly divided into 6 groups:control,LPS,Dexamethasone(Dex),HEL low dose 6 g/kg(HEL-L),HEL medium dose 18 g/kg(HEL-M)and HEL high dose 54 g/kg(HEL-H)groups.The model rats were intratracheally injected with 3 mg/kg LPS to establish an ALI model.Leukocyte counts,lung wet/dry weight ratio,as well as myeloperoxidase(MPO)activity were determined followed by the detection with hematoxylin and eosin staining,enzyme linked immunosorbent assay,quantitative real time polymerase chain reaction,western blotting,immunohistochemistry,and immunofluorescence.Besides,to explore the effect of HEL on ALI-mediated intestinal flora,we performed 16s rRNA sequencing analysis of intestinal contents.RESULTS:HEL attenuated LPS-induced inflammation in lung tissue and intestinal flora disturbance.Mechanism study indicated that HEL suppressed the lung coefficient and wet/dry weight ratio of LPS-induced ALI in rats,inhibited leukocytes exudation and MPO activity,and improved the pathological injury of lung tissue.In addition,HEL reduced the expression of tumor necrosis factoralpha,interleukin-1beta(IL-1β)and interleukin-6(IL-6)in bronchoalveolar lavage fluid and serum,and inhibited nuclear displacement of nuclear factor kappa-B p65(NF-κBp65).And 18 g/kg HEL also reduced the expression levels of toll-like receptor 4(TLR4),myeloid differentiation factor 88,NF-κBp65,phosphorylated inhibitor kappa B alpha(phospho-IκBα),nod-like receptor family pyrin domain-containing 3 protein(NLRP3),IL-1β,and interleukin-18(IL-18)in lung tissue,and regulated intestinal flora disturbance.CONCLUSIONS:In summary,our findings revealed that HEL has a protective effect on LPS-induced ALI in rats,and its mechanism may be related to inhibiting TLR4/NF-κB/NLRP3 signaling pathway and improving intestinal flora disturbance.
基金supported by the Natural Science Foundation of Xinjiang Uygur Autonomous Region of China,No.2016D01C120(to JB)
文摘Acacetin(5,7-dihydroxy-4′-methoxyflavone), a potential neuroprotective agent, has an inhibitory effect on lipopolysaccharide-induced neuroinflammatory reactions. However, whether acacetin has an effect on inflammatory corpuscle 3(NLRP3) after cerebral ischemia-reperfusion injury has not been fully determined. This study used an improved suture method to establish a cerebral ischemia-reperfusion injury model in C57BL/6 mice. After ischemia with middle cerebral artery occlusion for 1 hour, reperfusion with intraperitoneal injection of 25 mg/kg of acacetin(acacetin group) or an equal volume of saline(0.1 mL/10 g, middle cerebral artery occlusion group) was used to investigate the effect of acacetin on cerebral ischemia-reperfusion injury. Infarct volume and neurological function scores were determined by 2,3,5-triphenyltetrazolium chloride staining and the Zea-Longa scoring method. Compared with the middle cerebral artery occlusion group, neurological function scores and cerebral infarction volumes were significantly reduced in the acacetin group. To understand the effect of acacetin on microglia-mediated inflammatory response after cerebral ischemia-reperfusion injury, immunohistochemistry for the microglia marker calcium adapter protein ionized calcium-binding adaptor molecule 1(Iba1) was examined in the hippocampus of ischemic brain tissue. In addition, tumor necrosis factor-α, interleukin-1β, and interleukin-6 expression in ischemic brain tissue of mice was quantified by enzyme-linked immunosorbent assay. Expression of Iba1, tumor necrosis factor-α, interleukin-1β and interleukin-6 was significantly lower in the acacetin group compared with the middle cerebral artery occlusion group. Western blot assay results showed that expression of Toll-like receptor 4, nuclear factor kappa B, NLRP3, procaspase-1, caspase-1, pro-interleukin-1β, and interleukin-1β were significantly lower in the acacetin group compared with the middle cerebral artery occlusion group. Our findings indicate that acacetin has a protective effect on cerebral ischemia-reperfusion injury, and its mechanism of action is associated with inhibition of microglia-mediated inflammation and the NLRP3 signaling pathway.
文摘骨结核是一种严重危害人体健康的骨科感染性疾病,其病灶组织破坏的最大特点是骨质的吸收及破坏,其中破骨细胞是骨吸收的主要细胞。破骨细胞是由造血干细胞分化而来的多核细胞,通常是由核因子κB受体活化因子配体(receptor activator of nuclear factor-κB ligand,RANKL)与核因子κB受体活化因子(receptor activator for nuclear factor-κB,RANK)调控产生。结核分枝杆菌可以通过RANKL信号通路激活破骨细胞生成转录因子,以增强破骨细胞对骨质的吸收。笔者通过综述RANKL信号通路的结构及破骨细胞的研究进展,以及它们在骨结核临床治疗中可能发挥的潜在作用,为该领域的研究提供新的思路。
文摘背景:基于核转录因子κB通路探究神经炎症的靶向治疗越来越值得探究,中药靶点多、范围广、机制丰富及不良反应少等优点在治疗各类疾病时都具有十分巨大的潜力。目的:基于核转录因子κB信号通路,对近年研究中出现的山奈酚、红花黄、汉黄芩苷及雷公藤甲素等中药单体治疗脊髓损伤后神经炎症的研究进展进行系统的阐述与归纳。方法:以“脊髓损伤,炎症,抗炎,中药单体,单体化合物,NF-κB信号通路,黄酮,糖苷,酚类,酯类,生物碱”为检索词在中国知网数据库中进行检索;以“Spinal cord injury,inflammation,anti-inflammatory,traditional Chinese medicine monomer,monomeric compound,NF-κB signaling pathway,flavonoids,glycosides,phenols,esters,alkaloids”为检索词在PubMed数据库中进行检索,最终共纳入67篇文献进行综述分析。结果与结论:①核转录因子κB信号通路在神经系统中的作用复杂多样,能够调控中性粒细胞、小胶质细胞、星形胶质细胞和巨噬细胞等,介导损伤后炎症的发生与发展;②中药单体如汉黄芩苷对核转录因子κB抑制蛋白的降解、红花黄素对核转录因子κB信号通路磷酸化过程的抑制、山奈酚对核转录因子κB信号通路p65核易位的抑制等作用可以降低炎症反应对机体造成的影响,从而促进神经功能恢复;③核转录因子κB信号通路在损伤早期能够促进炎症反应和免疫细胞迁移活化,在损伤中后期能够促进损伤部位的修复和纤维化的发生等,适当的激活核转录因子κB信号通路具有促进炎症因子的释放、提高细胞的抗氧化能力及促进免疫细胞的活化等能力,但过度激活的核转录因子κB信号通路则容易导致慢性炎症的发生和持续、细胞凋亡受到抑制等;④未来的研究可以进一步探索如何准确调控核转录因子κB信号通路的活化水平、如何实现对神经系统炎症和损伤的精准干预展开,也可围绕中药单体的制备及中药单体对信号通路的作用机制展开,以期为神经系统疾病的康复和功能恢复提供更有效的治疗策略。
基金Supported by the National Natural Science Foundation of China:Investigating the Mechanism of Total Saponins in Treating Gouty Arthritis Based on Toll-like Receptor/Myeloid Differentiation Factor 88/Nuclear Factor-Kappa B Signal Pathway and Nacht Leucine-Rich Repeat Protein 3-Inflammasome(No.81573670)Study on the Material Basis and Pathway of Taohong Siwu Decoction in Regulating the Release of Platelet Alpha Granules in Postpartum Blood Stasis(No.81473387)+2 种基金Study on the Regulatory Mechanism of Taohong Siwu Decoction on Experimental Cerebral Ischemia Angiogenesis Based on the Messenger Effect of Platelet Microparticles(No.81503291)Investigating the Material Basis and Molecular Mechanism of Taohong Siwu Decoction Against Vascular Dementia Based on Microdialysis Technology and NOD-Like Receptor Protein 3 Inflammasome Vascular Endothelial Cell Interaction(No.81903953)the Anhui Province Key Research and Development Program:Research on the Development and Preparation of Taohong Siwu Granules(No.1704a0802141)。
文摘OBJECTIVE:To investigate the effect of Taohong Siwu decoction(桃红四物汤,TSD)on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking.METHODS:Sixty healthy male Sprague-Dawley rats were randomly divided into 6 groups with 10 rats in each group:control group,model group,atorvastatin group(AT,2.0 mg/kg),and TSD groups(20,10,5 g/kg)after 7 d of acclimation.The model of atherosclerosis was successfully established except the control group by high fat diet(HFD)and vitamin D2.Biochemical analyzers were used to detect the levels of triglyceride(TG),total cholestero(TC),low density lipoprotein-cholesterol(LDLC)and high density lipid-cholesterol(HDL-C)in blood lipid.The levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and interleukin-1β(IL-1β)were determined by enzyme-linked immunosorbent assay.Sudan IV staining and Hematoxylin and eosin staining(HE staining)were performed to observe the pathological changes in aortic tissue.Molecular docking technology was used to predict the best matching between the main components of TSD and the target proteins.The expression of target proteins was further detected by quantitative real time polymerase chain reaction(q RTPCR)and Western blot analysis.RESULTS:The results showed that TSD restricted atherosclerosis development and decreased the inflammatory cytokines in plasma.Molecular docking results predicted that the main components of TSD showed a strong binding ability with toll-like receptor(TLR4),myeloid differentiation primary response protein 88(My D88),and nuclear factor kappa-B(NF-κB).The results of q RT-PCR and Western blot analysis showed that the m RNA and protein expressions of TLR4,My D88 and NF-κB p65 in the aorta were reduced in atorvastatin group and TSD group.CONCLUSIONS:TSD can ameliorate atherosclerosis in rats,and the underlying mechanism is supposed be related to the suppression of inflammatory response by regulating TLR4/My D88/NF-κB signal pathway.