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1.
International Eye Science ; (12): 53-56, 2022.
Article in Chinese | WPRIM | ID: wpr-906729

ABSTRACT

@#Microglial activation is one of the main pathogenic factors to cause retinal neuroinflammation. Recently, with the advancement of retinal imaging technologies, hyperreflective foci(HRF), as a novel biomarker in optical coherence tomography(OCT)imaging, have received more attention in retinal neuroinflammation. Current research demonstrated that HRF are the aggregates mainly derived from the activated microglia in retina or mononuclear phagocyte-macrophage from the blood. HRF were defined as discrete and well-circumscribed hyperreflective dot-shaped lesions with the maximum diameter between 20-50μm in retina and choroid imaged with OCT. Under pathological conditions, the number of HRF increases significantly. Under pathological condations, the number of HRF was obviously increased, which might be related to the severity of some retinal diseases. However, the research on the source and function of HRF is still in its infancy. This review is aimed to describe the basic characteristics of HRF and their roles in both retinal inflammatory diseases and neurodegenerative diseases of the central nervous system. HRF are expected to be a potential and novel biomarker of inflammation for early diagnosis and prognosis of neuroinflammation in both retinal and central nervous system diseases.

2.
Article in English | WPRIM | ID: wpr-928988

ABSTRACT

OBJECTIVES@#During pregnancy, pregnant women are prone to stress reactions due to external stimuli, affecting their own health and fetal development. At present, there is no good treatment for the stress reactions from pregnant women during pregnancy. This study aims to explore the effect of probiotics on abnormal behavior and hippocampal injury in pregnant stressed offspring.@*METHODS@#SD pregnant rats were divided into a control group, a stress group, and a probiotics group, with 6 rats in each group. The control group was untreated; the stress group was given restraint stress on the 15th-20th day of pregnancy; the probiotics group was given both bifidobacterium trisporus capsules and restraint stress on the 15th-20th day of pregnancy, and the offspring continued to be fed with probiotics until 60 days after birth (P60). The offspring rats completed behavioral tests such as the open field test, the elevated plus maze test, the new object recognition test, and the barnes maze test at 60-70 d postnatally. Nissl's staining was used to reflect the injury of hippocampal neurons; immunohistochemical staining was used to detect the expression of microglia marker ionized calcium binding adapter molecule 1 (IBA-1) which can reflect microglia activation; ELISA was used to detect the content of plasma TNF-α and IL-1β; Western blotting was used to detect the expression of Bax, Bcl-2, and caspase-3.@*RESULTS@#The retention time of offspring rats in the stress group in the central area of the open field was significantly less than that in the control group (P<0.01), and the retention time of offspring rats in the probiotic group in the central area of the open field was significantly more than that in the stress group (P<0.05). The offspring rats in the stress group stayed in the open arm for a shorter time than the control group (P<0.05) and entered the open arm less often than the control group (P<0.01); the offspring rats in the probiotic group stayed in the open arm for a longer time than the stress group and entered the open arm more often than the stress group (both P<0.05). The discrimination ratio for new to old objects in the offspring rats of the stress group was significantly lower than that of the control group (P<0.01), and the discrimination ratio for new to old objects in the offspring rats of the probiotic group was significantly higher than that of the stress group (P<0.05). The offspring rats in the stress group made significantly more mistakes than the control group (P<0.05), and the offspring rats in the probiotic group made significantly fewer mistakes than the stress group (P<0.05). Compared with the control group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly reduced in the offspring rats of the stress group (all P<0.001), the number of activated microglia in DG area of hippocampus was significantly increased (P<0.01), the contents of TNF-α and IL-1β in peripheral blood were significantly increased (P<0.05 or P<0.01), the protein expression level of Bcl-2 was significantly down-regulated, and the protein expression levels of Bax and caspase-3 were significantly up-regulated (all P<0.001). Compared with the stress group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly increased in the probiotic group offspring rats (P<0.001, P<0.01, P<0.05), the number of activated microglia in the DG area of hippocampus was significantly reduced (P<0.05), and the TNF-α and IL-1β levels in peripheral blood were significantly decreased (both P<0.05), the protein expression level of Bcl-2 was significantly up-regulated, and the protein expression levels of Bax and caspase-3 were significantly down-regulated (all P<0.001).@*CONCLUSIONS@#Probiotic intervention partially ameliorated anxiety and cognitive impairment in rats offspring of pregnancy stress, and the mechanism may be related to increasing the number of neurons, inhibiting the activation of hippocampal microglia, and reducing inflammation and apoptosis.


Subject(s)
Animals , Caspase 3/metabolism , Female , Hippocampus/physiopathology , Humans , Pregnancy , Probiotics/therapeutic use , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Stress, Psychological/therapy , Tumor Necrosis Factor-alpha/metabolism , bcl-2-Associated X Protein/metabolism
3.
Article in English | WPRIM | ID: wpr-928241

ABSTRACT

Objective To examine the neuroanatomical substrates underlying the effects of minocycline in alleviating lipopolysaccharide (LPS)-induced neuroinflammation. Methods Forty C57BL/6 male mice were randomly and equally divided into eight groups. Over three conse-cutive days, saline was administered to four groups of mice and minocycline to the other four groups. Immediately after the administration of saline or minocycline on the third day, two groups of mice were additionally injected with saline and the other two groups were injected with LPS. Six or 24 hours after the last injection, mice were sacrificed and the brains were removed. Immunohistochemical staining across the whole brain was performed to detect microglia activation via Iba1 and neuronal activation via c-Fos. Morphology of microglia and the number of c-Fo-positive neurons were analyzed by Image-Pro Premier 3D. One-way ANOVA and Fisher's least-significant differences were employed for statistical analyses. Results Minocycline alleviated LPS-induced neuroinflammation as evidenced by reduced activation of microglia in multiple brain regions, including the shell part of the nucleus accumbens (Acbs), paraventricular nucleus (PVN) of the hypothalamus, central nucleus of the amygdala (CeA), locus coeruleus (LC), and nucleus tractus solitarius (NTS). Minocycline significantly increased the number of c-Fo-positive neurons in NTS and area postrema (AP) after LPS treatment. Furthermore, in NTS-associated brain areas, including LC, lateral parabrachial nucleus (LPB), periaqueductal gray (PAG), dorsal raphe nucleus (DR), amygdala, PVN, and bed nucleus of the stria terminali (BNST), minocycline also significantly increased the number of c-Fo-positive neurons after LPS administration. Conclusion Minocycline alleviates LPS-induced neuroinflammation in multiple brain regions, possibly due to increased activation of neurons in the NTS-associated network.


Subject(s)
Animals , Female , Lipopolysaccharides/toxicity , Male , Mice , Mice, Inbred C57BL , Minocycline/pharmacology , Neuroinflammatory Diseases , Solitary Nucleus
4.
Article in Chinese | WPRIM | ID: wpr-928133

ABSTRACT

Neuropathic pain is one of the common complications of diabetes. Tetrahydropalmatine(THP) is a main active component of Corydalis Rhizoma with excellent anti-inflammatory and pain-alleviating properties. This study aims to investigate the therapeutic effect of THP on diabetic neuropathic pain(DNP) and the underlying mechanism. High-fat and high-sugar diet(4 weeks) and streptozotocin(STZ, 35 mg·kg~(-1), single intraperitoneal injection) were employed to induce type-2 DNP in rats. Moreover, lipopolysaccharide(LPS) was used to induce the activation of BV2 microglia in vitro to establish an inflammatory cellular model. Fasting blood glucose(FBG) was measured by a blood glucose meter. Mechanical withdrawal threshold(MWT) was assessed with von Frey filaments, and thermal withdrawal latency(TWL) with hot plate apparatus. The protein expression levels of OX42, inducible nitric oxide synthase(iNOS), CD206, p38, and p-p38 were determined by Western blot, the fluorescence expression levels of OX42 and p-p38 in the dorsal horn of the rat spinal cord by immunofluorescence, the mRNA content of p38 and OX42 in rat spinal cord tissue by qRT-PCR, and levels of nitric oxide(NO), interleukin-1β(IL-1β), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), and serum fasting insulin(FINS) by enzyme-linked immunosorbent assay(ELISA). RESULTS:: showed that the mo-del group demonstrated significant decrease in MWT and TWL, with pain symptoms. THP significantly improved the MWT and TWL of DNP rats, inhibited the activation of microglia and p38 MAPK signaling pathway in rat spinal cord, and ameliorated its inflammatory response. Meanwhile, THP promoted the change of LPS-induced BV2 microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, suppressed the activation of the p38 MAPK signaling pathway, decreased the expression levels of inflammatory factors NO, IL-1β, IL-6, and TNF-α, and increased the expression level of anti-inflammatory factor IL-10. The findings suggested that THP can significantly ameliorate the pain symptoms of DNP rats possibly by inhibiting the inflammatory response caused by M1 polarization of microglia via the p38 MAPK pathway.


Subject(s)
Animals , Berberine Alkaloids , Blood Glucose/metabolism , Diabetes Mellitus , Diabetic Neuropathies/genetics , Interleukin-10 , Interleukin-6/metabolism , Lipopolysaccharides/pharmacology , Microglia , Neuralgia/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction , Spinal Cord/metabolism , Streptozocin/therapeutic use , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
5.
Article in Chinese | WPRIM | ID: wpr-928090

ABSTRACT

This study investigated the mechanism of baicalin on lipopolysaccharide(LPS)/interferon γ(IFN-γ)-induced inflammatory microglia based on the triggering receptor expressed on myeloid cells 2(TREM2)/Toll-like receptor 4(TLR4)/nuclear factor kappaB(NF-κB) pathway. Specifically, LPS and IFN-γ were used to induce inflammation in mouse microglia BV2 cells. Then the normal group, model group, low-dose(5 μmol·L~(-1)) baicalin group, medium-dose(10 μmol·L~(-1)) baicalin group, high-dose(20 μmol·L~(-1)) baicalin group, and minocycline(10 μmol·L~(-1)) group were designed. Cell viability was detected by CCK-8 assay and cell morphology was observed under bright field. The expression of interleukin-1β(IL-1β), interleukin-4(IL-4), inducible nitric oxide synthase(iNOS), interleukin-6(IL-6), interleukin-10(IL-10), and arginase-1(Arg-1) mRNA was detected by real-time quantitative PCR, the protein expression of tumor necrosis factor-α(TNF-α), IL-1β, TREM2, TLR4, inhibitor kappaB-alpha(IκBα), p-IκBα, NF-κB p65 and p-NF-κB p65 by Western blot, and transfer of NF-κB p65 from cytoplasm to nucleus by cellular immunofluorescence. Compared with the normal group, most of the BV2 cells in the model group tended to demonstrate the pro-inflammatory M1 amoeba morphology, and the model group showed significant increase in the mRNA levels of IL-1β, IL-6, and iNOS, decrease in the mRNA levels of IL-4, IL-10, and Arg-1(P<0.01), rise of the protein expression of TNF-α, IL-1β, TLR4, p-IκBα, and p-NF-κB p65(P<0.01), reduction in TREM2 protein expression, and increase in the expression of NF-κB p65 in nucleus. Compared with the model group, baicalin groups and minocycline group showed the recovery of BV2 cell morphology, significant decrease in the mRNA levels of IL-1β, IL-6 and iNOS, increase in the mRNA levels of IL-4, IL-10, and Arg-1(P<0.01), reduction in the protein expression of TNF-α, IL-1β, TLR4, p-IκBα, and p-NF-κB p65(P<0.05), rise of TREM2 protein expression, and decrease in the expression of NF-κB p65 in nucleus. In summary, these results suggest that baicalin can regulate the imbalance between TREM2 and TLR4 of microglia and inhibit the activation of downstream NF-κB, thus promoting the polarization of microglia from pro-inflammatory phenotype to anti-inflammatory phenotype.


Subject(s)
Animals , Flavonoids , Inflammation/genetics , Interferon-gamma , Lipopolysaccharides/adverse effects , Mice , NF-kappa B/metabolism , Toll-Like Receptor 4/metabolism
6.
Article in Chinese | WPRIM | ID: wpr-927904

ABSTRACT

Objective: To establish an improved method of separating microglia from aged rats and to observe the biological characteristics of spinal microglia of aged rats. Methods: Young SD rats (2 months) were used as control group. Single cell suspension of rat microglia were prepared by trypsin, trypsin substitutes or mechanical net rubbing method. Then, by assessing the purity and survival rate of cells, and observing the morphological characteristics and analyzing the inflammatory functional characteristics, we optimized the isolation and purification method of microglia from aged rats (20 months old) , and observed the functional characteristics of spinal microglia in aged rats. Results: The survival rate of cells digested by pancreatic enzyme was low(young rats 83%, aged rats 60%). Although the survival rate of mechanical net rubbing method was higher than that of pancreatic enzyme digest methods (95%), the cell acquisition rate was lower(young rats(0.207±0.020)×106, aged rats(0.243±0.023)×106). Trypsin substitute dissociation combining density gradient centrifugation method was the best way to get abundant, active and higher survival microglia, and the purity reached more than 85%. We used this method to separate microglia from spinal cord of rats. Compared with the young rats, the spinal cord tissue of old rats was larger, the digestive fluid volume was higher, but the digestion time was shorter. Compared with the young rats, the aged rat spinal microglia had larger and rounder cell body, fewer and shorter protrusions, it tended to be activated morphologically, the level of proinflammatory cytokine IL-1β of microglia in aged rats was lower, and the level of antiinflammatory factor IL-10 was higher. Conclusion: The method of trypsin substitute dissociation combined with density gradient centrifugation was successfully established to isolate and purify microglia from spinal cord of rats, the spinal microglia of old rats showed anti-inflammatory phenotype.


Subject(s)
Animals , Cytokines , Microglia , Rats , Rats, Sprague-Dawley , Spinal Cord , Trypsin
7.
Biol. Res ; 552022.
Article in English | LILACS-Express | LILACS | ID: biblio-1383914

ABSTRACT

Abstract Background: In Alzheimer's disease (AD), the neuroinflammatory response mediated by the activation of senescent microglia is closely related to energy dysmetabolism. However, the mechanism underlying the interaction between the energy metabolism of aging microglia and neuroinflammation remains unclear. Methods: We used biochemical methods, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and western blot to determine the effects and mechanism of CD38 knockdown on energy metabolism and neuroinflammation in Aβ1-40 injured BV2 cells. Using AD model mice, we detected CD38 enzyme activity, energy metabolism factors (ATP, NAD +, and NAD +/NADH), and neuroinflammatory factors (IL-1β, IL-6, and TNF-α) following the addition of CD38 inhibitor. Using a combination of biochemical analysis and behavioral testing, we analyzed the effects of the CD38 inhibitor on energy metabolism disorder, the neuroinflammatory response, and the cognition of AD mice. Results: Following Aβ1-40 injury, SA-β-Gal positive cells and senescence-related proteins P16 and P21 increased in BV2 cells, while energy-related molecules (ATP, NAD +, and NAD +/NADH) and mitochondrial function (mitochondrial ROS and MMP) decreased. Further studies showed that CD38 knockdown could improve Aβ1-40-induced BV2 cells energy dysmetabolism and reduce the levels of IL-1β, IL-6, and TNF-α. In vivo results showed an increase in senile plaque deposition and microglial activation in the hippocampus and cortex of 34-week-old APP/PS1 mice. Following treatment with the CD38 inhibitor, senile plaque deposition decreased, the number of Iba1 +BV2 cells increased, the energy metabolism disorder was improved, the proinflammatory cytokines were reduced, and the spatial learning ability was improved. Conclusions: Our results confirm that senescent microglia appeared in the brain of 34-week-old APP/PS1 mice, and that Aβ1-40 can induce senescence of BV2 cells. The expression of CD38 increases in senescent BV2 cells, resulting in energy metabolism disorder. Therefore, reducing CD38 expression can effectively improve energy metabolism disorder and reduce proinflammatory cytokines. Following intervention with the CD38 inhibitor in APP/PS1 mice, the energy metabolism disorder was improved in the hippocampus and cortex, the level of proinflammatory cytokines was reduced, and cognitive impairment was improved.

8.
Arq. bras. oftalmol ; 84(1): 67-73, Jan.-Feb. 2021. graf
Article in English | LILACS | ID: biblio-1153097

ABSTRACT

ABSTRACT Purpose: Diabetic retinopathy is currently considered a chronic inflammatory disease involving NOD-like receptor family pyrin domain containing 3 inflammasome activation and retinal microglial pyroptosis. In this study, we aimed to investigate whether NOD-like receptor family pyrin domain containing 3 inflammasome signaling induces pyroptotic death of retinal microglia under high-glucose conditions. Methods: Retinal microglia were stimulated by high glucose levels for 24 h. Cell viability, lactate dehydrogenase release, and caspase-1 activity were detected in vitro. The expression of pro-inflammatory cytokine (interleukin-1β, activated microglia marker ionized calcium-binding adapter molecule-1), NOD-like receptor family pyrin domain containing 3, cleaved caspase-1, and cleaved gasdermin D were examined. Subsequently, retinal microglia were pretreated with the inhibitors of NOD-like receptor family pyrin domain containing 3 inflammasome signaling prior to stimulation with high glucose, and their molecular and functional changes were evaluated. Results: High-glucose (25, 50, or 100 mM) stimulation decreased cell viability, but enhanced lactate dehydrogenase release and caspase-1 activity in a dose-dependent manner. Moreover, high glucose upregulated the protein expression of interleukin-1β, ionized calcium-binding adapter molecule-1, NOD-like receptor family pyrin domain containing 3, cleaved caspase-1, and cleaved gasdermin D. However, pretreatment with the inhibitors of NOD-like receptor family pyrin domain containing 3 inflammasome signaling inhibited high glucose (25 mM)-induced cytotoxicity, NOD-like receptor family pyrin domain containing 3 inflammasome activation, and pyroptosis of retinal microglia. Conclusions: NOD-like receptor family pyrin domain containing 3 inflammasome signaling may modulate retinal microglia-related inflammation and pyroptosis under high-glucose conditions.


RESUMO Objetivo: Atualmente, a retinopatia diabética é considerada uma doença inflamatória crônica envolvendo a ativação de inflamassomas NLRP3 e piroptose da micróglia da retina. Neste estudo, objetivamos investigar se a sinalização de inflamassomas NLRP3 induz a morte da micróglia da retina sob condições de alta glicose. Métodos: A micróglia da retina foi estimulada por altos níveis de glicose durante 24 horas. A viabilidade celular, a liberação de LDH e a atividade da caspase1 foram analisadas in vitro. Avaliou-se a expressão de citocina pró-inflamatória (IL1β), de marcador de micróglia ativado (Iba1), de NLRP3, de caspase1 clivada e de GSDMD clivada. Subsequentemente, a micróglia da retina foi pré-tratada com inibidores da sinalização de inflamassomas NLRP3 antes da estimulação com altos níveis de glicose e suas alterações moleculares e funcionais foram avaliadas. Resultados: A estimulação com altos níveis de glicose (25 mM, 50 mM ou 100 mM) diminuiu a viabilidade celular, mas aumentou a liberação de LDH e a atividade da caspase1 de forma dependente da dose. Além disso, os altos níveis de glicose aumentaram a expressão das proteínas IL1β, Iba1, NLRP3, caspase1 clivada e GSDMD clivada. No entanto, o pré-tratamento com inibidores da sinalização de inflamassomas NLRP3 e a posterior estimulação com altos níveis de glicose (25 mM) induziu citotoxicidade, a ativação de inflamassomas NLRP3 e a piroptose da micróglia da retina. Conclusão: A sinalização de inflamassomas NLRP3 pode modular a inflamação e a piroptose da micróglia da retina na presença de altos níveis de glicose.


Subject(s)
Humans , Inflammasomes , Pyroptosis , Microglia , Interleukin-1beta , NLR Family, Pyrin Domain-Containing 3 Protein , Glucose
9.
Acta Pharmaceutica Sinica ; (12): 383-390, 2021.
Article in Chinese | WPRIM | ID: wpr-873786

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive impairment. To date, however, no disease-modifying strategies to prevent or cure AD exist. Synapses are involved in the connection of neurons and present as the key component for the memory and other neural activities. Synapse loss is a critical hallmark of AD pathology. In brain, glia cells, including microglia and astrocytes, are a group of highly specific cell types other than neurons. Microglia and astrocytes play a key role in maintaining the healthy neural circuit and regulating synaptic plasticity. Under development and physiological conditions, glial cells contribute to construct and maintain mature central neural networks via synaptic pruning. However, during AD pathogenesis, glial cells engulf synapses excessively, which leads to synapse loss, neuronal dysfunction, and cognitive impairment. Here, we review recent advances in our understanding of the underlying mechanisms for glia-mediated synaptic pruning in AD, and provide a novel strategy for the development of AD drugs.

10.
Article in Chinese | WPRIM | ID: wpr-907363

ABSTRACT

Early brain injury (EBI) is a series of pathophysiological changes occurring within 72 h after subarachnoid hemorrhage (SAH) and before cerebral vasospasm, which is a key factor affecting the outcome of SAH. The possible pathological mechanisms include cell metabolism, oxidative stress and immune inflammation, in which inflammatory response plays an important role. As the important immune cells in the central nervous system, microglia undergo M1/M2 polarization after brain injury. On the one hand, microglia secrete proinflammatory cytokines through Toll-like receptor 4 (TLR4), calcium sensing receptor (CaSR) and triggering receptor expressed on myoid cells 1 (TREM-1) mediated signaling pathways, which are involved in neuronal apoptosis, blood-brain barrier damage and brain edema after SAH. On the other hand, microglia play the anti-inflammatory and protective effects through the expression of neuroglobin and heme oxygenase 1. This article reviews the M1/M2 polarization process of microglia in EBI after SAH and its dual mechanisms of action.

11.
Article in Chinese | WPRIM | ID: wpr-907350

ABSTRACT

As an important imaging marker of cerebral small vessel disease, white matter hyperintensity is closely associated with the clinical manifestations such as cognitive impairment, gait abnormalities, and urinary incontinence. Current studies have shown that the destruction of blood-brain barrier and inflammation response are the important pathophysiological mechanisms of white matter hyperintensity. As the most common immune cell in the inflammatory response of the central nervous system, microglia activation is the key to the occurrence and development of white matter hyperintensity. This article reviews the pathophysiological mechanisms of microglia involved in brain white matter hyperintensity.

12.
Article in Chinese | WPRIM | ID: wpr-906231

ABSTRACT

Objective:To observe the effect of modified Shuyuwan in amyloid precursor protein/ presenilin 1 (APP/PS1) dementia mice on cognitive and memory impairment and to explore its mechanism. Method:The 40 APP/PS1 mice were divided into model group (given Physiological saline), low and high-dose modified Shuyuwan (14,64 g·kg<sup>-1</sup>)group, and donepezil group (1 mg·kg<sup>-1</sup>) and 10 wild mice were set as the blank control group (given Physiological saline). All of the mice were administered intragastrically for 35 days. The memory and space exploration ability of mice was detected by Morris water maze, the morphology of mouse hippocampal neurons were observed by Nissl staining. The deposition of <italic>β </italic>amyloid 1-42(A<italic>β</italic><sub>1-42</sub>) in mouse hippocampus was detected by immunohistochemistry, and the expression of ionized calcium-binding adapter molecule 1(Iba1), a marker of hippocampal microglia (MG) and Nitric oxide synthase(iNOS), a marker of actived MG, were detected by immunofluorescence. The protein expression of NLR family pyrin domain containing 3(Nlrp3), Apoptosis-associated speck-like protein containing a Caspase-recruitment domain (ASC), cysteine protease-1(Caspase-1)and interleukin-1 beta (IL-1<italic>β</italic>) were detected by Western blot, and the expression of IL-1<italic>β</italic>, tumor necrosis factor-<italic>α</italic>(TNF-<italic>α</italic>)and interleukin-18 (IL-18) mRNA were detected by Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR). Result:Compared with the blank control group, the memory and space exploration ability of the model group were significantly reduced (<italic>P</italic><0.05), the number of hippocampal neurons decreased, the deposition of A<italic>β</italic><sub>1-42</sub> increased, the markers of actived MG Iba1,iNOS increased, the protein expression of Nlrp3, ASC, Caspase-1, IL-1<italic>β</italic> increased significantly (<italic>P</italic><0.05), and the mRNA expression of IL-1<italic>β</italic>, IL-18, and TNF-<italic>α</italic> increased significantly (<italic>P</italic><0.05). Compared with model group, the Chinese medicine group can improve the APP/PS1 mice's space exploration ability and memory ability (<italic>P</italic><0.05), increase the number of hippocampal neurons, reduce A<italic>β</italic><sub>1-42</sub> deposition, reduce the activation of MG, and reduce the protein expression of Nlrp3, ASC, Caspase-1 and IL-1<italic>β</italic> (<italic>P</italic><0.05), and reduced the expression of IL-1<italic>β</italic> mRNA (<italic>P</italic><0.05). Conclusion:Modified Shuyuwan can reduce the expression of IL-1<italic>β</italic> and other inflammatory factors in the hippocampus of APP/PS1 mice by inhibiting the Nlrp3/ASC/Caspase-1 pathway, and relieve nerve inflammation and pathological injury of AD.

13.
Article in Chinese | WPRIM | ID: wpr-906206

ABSTRACT

Objective:To investigate the effect of rhein on aquaporin 4 (AQP4) and brain edema after cerebral ischemia and the role of microglia-mediated inflammation in this process. Method:The modified thread embolization method was selected to establish the cerebral ischemia model of the right middle cerebral artery embolism (MCAO) in rats. The rats were divided into sham operation group, model group, minocycline group, and high, medium and low-dose rhein groups (3.46,1.73,0.865 mg·kg<sup>-1</sup>). The neurobehavioral function was measured by a modified neurobehavioral score. Wet and dry weight methods were used to measure the changes of water content in brain tissue of rats with cerebral ischemic injury. Western blot was used to detect the expressions of interferon-<italic>γ</italic> (IFN-<italic>γ</italic>) and interleukin-2 (IL-2) in the peripheral ischemic area of rats in each group. Immunofluorescence double labeling method was used to detect the expressions and localization of microglia fine markers Iba-1 and AQP4. Result:Compared with the sham operation group, neurological function score and water content on the side of brain tissue injury of the model group were significantly increased (<italic>P</italic><0.05). Compared with the model group, the neurological function score and the water content of the brain tissue of each drug group were reduced (<italic>P</italic><0.05, <italic>P</italic><0.01). Compared with sham operation group, the protein expressions of IFN-<italic>γ</italic> and IL-2 in the model group increased significantly (<italic>P</italic><0.05). Compared with the model group, the protein expressions of IFN-<italic>γ</italic> and IL-2 in the peripheral area of cerebral ischemia of each drug group were significantly improved (<italic>P</italic><0.05, <italic>P</italic><0.01). Immunofluorescence double staining results showed that compared with the sham operation group, the model group showed significant increase in the fluorescence expression of AQP4 protein on activated microglia, while each drug group could reduce the fluorescence expression of AQP4 protein on activated microglia, different levels of activated microglia markers Iba-1 and AQP4 were co-localized in the peripheral area of cerebral ischemia in each group. Conclusion:Rhein could reduce the degree of brain edema caused by cerebral ischemic injury, and its mechanism may be related to the inhibition of microglia-mediated neuroinflammation and the down-regulation of AQP4 expression.

14.
Article in Chinese | WPRIM | ID: wpr-906046

ABSTRACT

Objective:To investigate the effect of Xiaoyaosan on depressive behavioral phenotype in mice with vascular dementia (VaD) mice and its possible mechanism. Method:Sixty three-month-old male C57/BL6 mice were divided into the normal control group, model group, positive control group, as well as low-, medium-, and high-dose Xiaoyaosan groups. Mice in all groups except for the normal control group underwent bilateral carotid artery stenosis. Two weeks later, they were subjected to chronic restraint stress, 6 h per day, for inducing VaD complicated with depression. Mice in the low-, medium-, and high-dose Xiaoyaosan groups were treatment with intragastric administration of Xiaoyaosan decoction (5, 10, 20 g·kg<sup>-1</sup>), the ones in the positive control group with fluoxetine (10 mg·kg<sup>-1</sup>), and those in the normal control group and model group with an equal volume of normal saline for four weeks, during which the restraint stress was maintained. The depressive behavioral phenotype of mice was observed in sugar water preference test and tail suspension test. The fluorescence expression of myelin basic protein (MBP) in ventral hippocampus (vHIP) was detected by fluorescence immunoassay. The ultrastructure of myelin sheath in vHIP was observed by transmission electron microscopy. The protein expression levels of MBP, myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG), triggering receptor expressed on myeloid cells-2 (TREM2), inducible nitric oxide synthase (iNOS), arginase 1 (Arg1), interleukin-I<italic>β</italic> (IL-1<italic>β</italic>), tumor necrosis factor-<italic>α</italic> (TNF-<italic>α</italic>), interleukin-4 (IL-4), and interleukin-10 (IL-10) were assayed by Western blot. Result:As revealed by behavioral test, compared with the normal control group, the model group exhibited prolonged immobility time and decreased percentage of sugar water preference (<italic>P</italic><0.01). Compared with the model group, Xiaoyaosan significantly shortened the immobility time of mice (<italic>P</italic><0.05) and increased the percentage of sugar water preference (<italic>P</italic><0.01). Western blot results showed that the protein expression levels of MBP, MOG, and MAG in vHIP of the model group were remarkably decreased as compared with those of the normal control group (<italic>P</italic><0.01). The protein expression levels of MBP, MOG, and MAG in vHIP of the low-dose Xiaoyaosan group were increased in contrast to those in the model group (<italic>P</italic><0.05, <italic>P</italic><0.01), while the protein expression of iNOS was decreased (<italic>P</italic><0.01). The protein expression levels of MBP, MOG, MAG, TREM2, Arg1, IL-4, and IL-10 in the medium- and high-dose Xiaoyaosan groups were up-regulated (<italic>P</italic><0.05, <italic>P</italic><0.01), whereas those of iNOS, IL-1<italic>β</italic>, and TNF-<italic>α</italic> were down-regulated (<italic>P</italic><0.01). The immunofluorescence findings demonstrated that the mean fluorescence intensity of MBP in the model group declined in comparison with that in the normal control group (<italic>P</italic><0.01), while the mean fluorescence intensities of MBP in the low-, medium-, and high-dose Xiaoyaosan groups were enhanced to different degrees (<italic>P</italic><0.01). It was observed under the transmission electron microscope that the myelin structure of the model group was loosened and the dense layer was separated and irregularly arranged. Xiaoyaosan improved the structural integrity of myelin sheath and the looseness of lamellar structure. Conclusion:Xiaoyaosan ameliorates the depressive behavioral phenotype of VaD mice, which may be related to the up-regulation of TREM2, the induction of M2 polarization of microglia cells, the enhancement of their anti-inflammatory and phagocytic abilities, and the promotion of damaged myelin sheath regeneration.

15.
Article in Chinese | WPRIM | ID: wpr-906018

ABSTRACT

Objective:To observe the activation of microglia in hippocampus of depressed and anxious mice induced by maternal separation with acute restraint stress and the expression of interleukin-1<italic>β</italic>(IL-1<italic>β</italic>),interleukin-6(IL-6),tumor necrosis factor-<italic>α</italic>(TNF-<italic>α</italic>), investigating the mechanism of Wenyang Jieyu prescription in treating anxiety and depression. Method:Eighty four male C57BL offspring were randomly divided into control group, acute restraint stress group and model group on postnatal day 0(PD0). Maternal separation combined with acute restraint stress was used to prepare anxious and depressed model mice, dividing the model mice into model group, Wenyang, Jieyu, Wenyang Jieyu and fluoxetine group according to random number table method. During the period of PD21-PD90, the control, acute restraint stress and model mice were fed with normal diet, with the other groups fed with corresponding medicine mixed diet. The Wenyang, Jieyu and Wenyang Jieyu groups were given 5.85, 12.03 and 16.71 g·kg<sup>-1</sup>·d<sup>-1</sup> respectively. The fluoxetine group was given 2.60 mg·kg<sup>-1</sup>·d<sup>-1</sup>. Open field, zero maze test and social interaction tests were used to evaluate the anxiety and depression of model mice. The expression of Iba-1 in hippocampal microglia was detected by immunohistochemistry(IHC). The mRNA expression of IL-1<italic>β</italic>, IL-6, TNF-<italic>α</italic>, Iba-1 and glucocorticoid receptor(GR)were detected by Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR). Result:Compared with the control group, total movement distance and time spent in central zone in 5 min of the model mice significantly decreased(<italic>P</italic><0.01), time spent in opened arm and total movement distance decreased significantly(<italic>P</italic><0.05,<italic>P</italic><0.01), investigation time during testing and training increased significantly(<italic>P</italic><0.01). The expression of Iba-1 protein and mRNA,IL-1<italic>β</italic>,IL-6,TNF-<italic>α</italic> mRNA significantly increased(<italic>P</italic><0.01), the expression levels of GR mRNA significantly decreased(<italic>P</italic><0.01). The result of IHC staining showed that microglia were over activated. Compared with the model group, total movement distance and time spent in central zone in 5 min of mice in the Wenyang Jieyu and fluoxetine group significantly increased(<italic>P</italic><0.05,<italic>P</italic><0.01).Time spent in opened arm significantly increased(<italic>P</italic><0.01). Investigation time during testing and training significantly decreased(<italic>P</italic><0.05,<italic>P</italic><0.01). The expression of Iba-1 protein and mRNA,IL-1<italic>β</italic>,IL-6,TNF-<italic>α</italic> mRNA significantly decreased(<italic>P</italic><0.05,<italic>P</italic><0.01). The expression of GR mRNA increased significantly(<italic>P</italic><0.05,<italic>P</italic><0.01). IHC staining showed the microglia recovered. Time spent in opened arm of mice in the Wenyang group and Jieyu group significantly increased (<italic>P</italic><0.01), time spent investigating during testing decreased significantly (<italic>P</italic><0.05), the expression levels of Iba-1 protein and mRNA,IL-6 mRNA significantly decreased (<italic>P</italic><0.05,<italic>P</italic><0.01). The expression of GR mRNA of mice in the Wenyang group significantly increased (<italic>P</italic><0.05), the expression of TNF-<italic>α </italic>mRNA significantly decreased (<italic>P</italic><0.05). Total movement distance of mice in the Jieyu group increased significantly (<italic>P</italic><0.01), time spent investigating during training decreased significantly (<italic>P</italic><0.05),the expression level of IL-1<italic>β </italic>mRNA significantly decreased (<italic>P</italic><0.05). IHC staining showed that microglia recovered partly in both groups. Conclusion:The comprehensive curative effect and pharmacological action of Wenyang Jieyu prescription were better than Wenyang prescription and Jieyu prescription. Wenyang Jieyu prescription can treat anxiety and depression in maternal separation and acute restraint stress mice, its possible mechanism may be related to the decreased activation of microglia, down-regulation of IL-1<italic>β</italic>,IL-6,TNF-<italic>α</italic> expression and up-regulation of GR expression.

16.
Article in Chinese | WPRIM | ID: wpr-905957

ABSTRACT

Objective:To observe the activation of microglia and the expression of inflammatory factors in hippocampus of mice with depression-like behavior after mother-infant separation (MS) combined with lipopolysaccharide (LPS) stress, and to explore the possible anti-depression mechanisms of Wenyang (WY), Jieyu (JY), and Wenyang Jieyu (WYJY) prescriptions from the perspective of warming Yang and relieving depression. Method:Seventy offspring mice were randomly divided into a normal group (<italic>n</italic>=10), a LPS stress group (<italic>n</italic>=10), and a modeling group (<italic>n</italic>=50). After undergoing 8 h·d<sup>-1 </sup>mother-infant separation during postnatal day 5 (PD<sub>5</sub>)–PD<sub>14</sub>, mice in the modeling group were further divided into the MS + LPS group, WY group, JY group, WYJY group, and fluoxetine (FLU) group, with 10 in each group. The birth date of the offspring mice was recorded as PD<sub>0</sub>. The mice in the normal, LPS, and MS + LPS groups were fed a normal diet during PD<sub>21</sub>–PD<sub>90</sub>, while those in the other groups were treated with the mixtures of corresponding drugs and feed, followed by seven-day intraperitoneal injection of LPS since PD<sub>91</sub> for inducing depression. The depression-like behavior of mice in each group was detected in the open-field, O-maze, and social interaction tests. The protein expression of microglia-specific ionized calcium-binding adaptor molecule 1 (Iba-1) in the hippocampus was assayed by immunohistochemistry, and the mRNA expression of interleukin-1<italic>β </italic>(IL-1<italic>β</italic>), interleukin-6 (IL-6), tumor necrosis factor-<italic>α </italic>(TNF-<italic>α</italic>), Iba-1, and glucocorticoid receptor (GR) by real-time fluorescence quantitative PCR (Real-time PCR). Result:Compared with the normal group, the LPS group exhibited significantly reduced residence time at the central area within 5 min (<italic>P</italic><0.01) and shortened total exercise distance (<italic>P</italic><0.01). In the MS + LPS group, the open-arm activity time and the total activity distance decreased significantly (<italic>P</italic><0.01, <italic>P</italic><0.05), whereas the training, discrimination and exploration time increased significantly (<italic>P</italic><0.01). The expression of Iba-1 in hippocampal CA1 region of mice in the LPS and MS + LPS groups was remarkably elevated (<italic>P</italic><0.01). Compared with the LPS group, the MS + LPS group displayed significantly prolonged distance of 5-min exercise (<italic>P</italic><0.05), increased training, discrimination and exploration time (<italic>P</italic><0.05, <italic>P</italic><0.01), and up-regulated Iba-1 expression in hippocampal CA1 area (<italic>P</italic><0.01). As revealed by comparison with the MS + LPS group, both the total 5-min exercise distance (<italic>P</italic><0.01) and the training and discrimination time (<italic>P</italic><0.01, <italic>P</italic><0.05) of mice in each administration group was significantly shortened. The discrimination and exploration time of mice in the JY, WYJY, and FLU groups was significantly reduced (<italic>P</italic><0.01), and the expression of Iba-1 in hippocampal CA1 region of mice in each administration group was significantly down-regulated (<italic>P</italic><0.01). Conclusion:The warming Yang and relieving depression method helps to inhibit the occurrence and development of depression due to its efficacy in activating microglia in hippocampus of depression mice and lowering the expression of IL-1<italic>β</italic>, IL-6, and TNF-<italic>α</italic>.

17.
Article in Chinese | WPRIM | ID: wpr-921772

ABSTRACT

When ischemia or hemorrhagic stroke occurs, astrocytes are activated by a variety of endogenous regulatory factors to become reactive astrocytes. Subsequently, reactive astrocytes proliferate, differentiate, and migrate around the lesion to form glial scar with the participation of microglia, neuron-glial antigen 2(NG2) glial cells, and extracellular matrix. The role of glial scars at different stages of stroke injury is different. At the middle and late stages of the injury, the secreted chondroitin sulfate proteoglycan and chondroitin sulfate are the main blockers of axon regeneration and nerve function recovery. Targeted regulation of glial scars is an important pathway for neurological rehabilitation after stroke. Chinese medicine has been verified to be effective in stroke rehabilitation in clinical practice, possibly because it has the functions of promoting blood resupply, anti-inflammation, anti-oxidative stress, inhibiting cell proliferation and differentiation, and benign intervention in glial scars. This study reviewed the pathological process and signaling mechanisms of glial scarring after stroke, as well as the intervention of traditional Chinese medicine upon glial scar, aiming to provide theoretical reference and research evidence for developing Chinese medicine against stroke in view of targeting glial scarring.


Subject(s)
Astrocytes , Axons/pathology , Cicatrix/pathology , Gliosis/pathology , Humans , Medicine, Chinese Traditional , Nerve Regeneration , Stroke/drug therapy
18.
Article in Chinese | WPRIM | ID: wpr-921539

ABSTRACT

Alzheimer's disease(AD)is a chronic neurodegenerative disease whose cause remains unclear.The β-amyloid plaques in the brain are one of the major pathological features of AD.However,the drugs targeting extracellular β-amyloid plaques have failed to cure the disease.Innate immunity and neuroinflammation play a role in the pathogenesis and progression of AD.As the macrophages existing in the central nervous system,microglia are related with extracellular β-amyloid deposition,intracellular neurofibrillary tangle formation,and neuron injury.Accumulating evidence demonstrates that the activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3(NLRP3)inflammasome in microglia plays a role in AD,suggesting new therapeutic target for AD in this signaling pathway.This article reviewed the studies about the activation and regulation of NLRP3 inflammasome in the pathogenesis and progression of AD as well as the development of AD therapies targeting this pathway,aiming to provide reference for further studies in this field.


Subject(s)
Alzheimer Disease , Humans , Inflammasomes , Microglia , NLR Family, Pyrin Domain-Containing 3 Protein , Neurodegenerative Diseases , Nucleotides , Pyrin Domain
19.
Cancer Research and Clinic ; (6): 713-716, 2021.
Article in Chinese | WPRIM | ID: wpr-912954

ABSTRACT

Glioma is a common tumor in the central nervous system. Because the natural immunosuppression of tumor microenvironment is conducive to tumor growth, transformation and migration, the traditional treatment has little effect and is difficult to make a breakthrough. Glioma-associated microglia and macrophage (GAM), an important part of brain tumor microenvironment, plays a more and more key role in tumor progression and regulation of anti-tumor immune response. This article reviews the latest progress of the source, recruitment, polarization and the role in development of gliomas as well as potential therapeutic targets of gliomas.

20.
Article in Chinese | WPRIM | ID: wpr-912010

ABSTRACT

Objective:To explore the function of epidermal growth factor 8 in the polarization of microglia after ischemic brain injury and its mechanism.Methods:Forty C57BL/6 mice were randomly divided into a sham operation group, an ischemia group, a recombinant mouse milk fat globule epidermal growth factor 8 (rmMFG-E8) group and an rmMFG-E8 + colivelin TFA group, each of 10. The middle cerebral artery occlusion and reperfusion model (tMCAO) was established in all except the sham operation group. Right after the modelling the mice in the rmMFG-E8 group were immediately injected with 2μL of 0.4μg/μL of rmMFG-E8 into the ventricle contralateral to the cerebral infarction. The rmMFG-E8+ Colivelin TFA group was injected with the same dose of rmMFG-E8 plus 2μL of 5pmol/μL colivelin TFA. On the 1st, 3rd, 5th and 7th day after the modelling, neurological functioning was documented using behavioral tests. The volume proportion of the cerebral infarction was observed after tissue staining on the 7th day after the operation. The gene expression levels of M1 polarization marker-induced nitric oxide synthase (iNOS), M2 polarization marker arginase-1 (Arg1) and mouse chitinase-like molecule 3 (YM1) in the microglia were detected using real-time fluorescence quantitative polymerase chain reactions. The protein expression levels of MFG-E8, phosphorylated signal transduction and transcription factor 3 (p-STAT3) and cytokine signal transduction inhibitor-3 (SOCS3) were determined using western blotting.Results:The behavior tests revealed significant differences between the sham operation group and the other groups on all four days. Compared with the sham operation group, the average expression of MFG-E8 gene and its protein, Arg1 and Ym1, and the SOCS3/GAPDH protein ratio had decreased significantly in the ischemic group, while the average expression of iNOS and the p-STAT3/STAT3 protein ratio had increased significantly. On the 7th day after the modelling, compared with the ischemic group, the infarct volume was significantly smaller in the rmMFG-E8 group. The average expression of iNOS and the average p-STAT3/STAT3 ratio in the rmMFG-E8+ colivelin TFA group had increased significantly compared with the rmMFG-E8 group, while the average expression of Arg1 and Ym1, and the SOCS3/GAPDH ratio were significantly lower.Conclusion:MFG-E8 promotes the polarization of M2-type microglia after cerebral ischemia through STAT3 signaling, promoting the recovery of neurological functioning.

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