Improved Promotion of M2 Microglial Polarization by Zuogui Jiangtang Jieyu Formulation in Diabetes-Related Depression

Abstract Background Zuogui Jiangtang Jieyu formulation (ZGJTJY) is a Chinese polyherbal prescription for diabetes-related depression (DD). The mechanism underlying hippocampal M1/M2 polarization in DD and the ZGJTJY treatment effects remain unclear. This study aimed to investigate M1/M2 microglial polarization in the hippocampus of DD rats and HAPI (highly aggressively proliferating immortalized) cells simulating the DD state, as well as to examine the ZGJTJY intervention effects, both in vivo and in vitro. Methods We subjected Sprague Dawley rats to a high-fat diet, streptozotocin, and unpredictable chronic mild stress; subsequently, we orally administered ZGJTJY. HAPI cells were induced using high glucose and corticosterone; subsequently, ZGJTJY-containing serum was added to examine changes in M1/M2 microglial polarization. Moreover, metformin combined with fluoxetine (DMGB/F) was used as a positive drug for evaluating the ZGJTJY intervention. Laser confocal scanning was used to examine the microglial morphology. Further, real-time PCR was used to determine M1 markers (MHCII, iNOS, MCP-1, CD11b), M2 markers (Arg1, Mrc1, Ym1), pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and anti-inflammatory cytokines (IL-4, IL-10). Additionally, an enzyme-linked immunosorbent assay was used to examine inflammatory cytokines. Results There was significant activation of M1 polarization in the hippocampus of DD rats and HAPI cells induced using high glucose and corticosterone. Compared with DMGB/F, ZGJTJY inhibited and promoted M1 and M2 polarization, respectively; moreover, it decreased the M1-to-M2 polarization ratio both in vivo and in vitro. Conclusions The study indicated that hippocampal M1 polarization is crucially involved in DD pathogenesis; moreover, there is a need for further research on the neuroprotective effect of Chinese medicine associated with M2-polarized microglia.

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NQO1 Alleviates Renal Fibrosis by Inhibiting TLR4/NF-κB and TGF-β/Smad Signaling Pathway in Diabetic Nephropathy

10.21203/rs.3.rs-754216/v1 ◽

2021 ◽

Author(s):

Duojun Qiu ◽

Shan Song ◽

Yawei Bian ◽

Chen Yuan ◽

wei zhang ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Protein Expression ◽

Inflammatory Cytokines ◽

High Glucose ◽

Renal Tubular ◽

Tgf Β1 ◽

Cytokines Secretion ◽

Pro Inflammatory Cytokines

Abstract Background: Diabetic nephropathy is one of the main complications of diabetes, inflammation and fibrosis play an important role in its progress. NAD (P) H: quinone oxidoreductase 1 (NQO1) protects cells from oxidative stress and toxic quinone damage. In present study, we aimed to investigate the protective effects and underlying mechanisms of NQO1 on diabetes-induced renal inflammation and fibrosis. Methods: In vivo, adeno-associated virus serotype 9 was used to infect the kidneys of type 2 diabetes model db/db mice to overexpress NQO1. In vitro, human renal tubular epithelial cells (HK-2) transfected with NQO1 pcDNA were cultured in high glucose. The gene and protein expression were assessed by quantitative real-time PCR, western blot, immunofluorescence, and immunohistochemical staining. Mitochondrial reactive oxygen species was detected by MitoSox red. Result: Our study revealed that the expression of NQO1 was markedly down-regulated, Toll-like receptor 4 (TLR4) and TGF-β1 upregulated in vivo and in vitro under diabetic conditions. Overexpression of NQO1 suppressed pro-inflammatory cytokines secretion (IL-6, TNF-α, MCP-1), extracellular matrix (ECM) accumulation (collagen Ⅳ, Fibronectin) and epithelial-mesenchymal transition (EMT) (α-SMA, E-cadherin) in db/db mice kidney and high glucose cultured human renal tubular cells (HK-2). Furthermore, NQO1 overexpression ameliorated high glucose-induced TLR4/NF-κB and TGF-β/Smad pathway activation. Mechanistic studies demonstrated that TLR4 inhibitor (TAK-242) suppressed TLR4/NF-κB signaling pathway, pro-inflammatory cytokines secretion, EMT and ECM-related protein expression in HG-exposed HK-2 cells. In addition, we found that antioxidants NAC and tempol increased the expression of NQO1, decreased the expression of TLR4, TGF-β1, Nox1, Nox4 and ROS production in HK-2 cells cultured with high glucose. Conclusions: These above data suggest that NQO1 alleviates diabetes-induced renal inflammation and fibrosis by regulating TLR4/NF-κB and TGF-β/Smad signaling pathways.

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TREM2, Driving the Microglial Polarization, Has a TLR4 Sensitivity Profile After Subarachnoid Hemorrhage

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.693342 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yangchun Hu ◽

Chao Li ◽

Xiaojian Wang ◽

Weiwei Chen ◽

Yu Qian ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Neuroprotective Effect ◽

Neurological Dysfunction ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Microglial Polarization ◽

The Relationship

Increasing evidence suggests that triggering receptor expressed on myeloid cells 2 (TREM2) is implicated in the pathophysiology of neuroinflammation. The aim here was to investigate the neuroprotective role of TREM2 and its regulatory mechanism after subarachnoid hemorrhage (SAH). TREM2 siRNA was administered to measure the detrimental role of TREM2 in mediating microglial polarization in vivo and in vitro after experimental SAH. The relationship between Toll-like receptor 4 (TLR4) signaling and TREM2 was further explored. The soluble TREM2 from the cerebrospinal fluid (CSF) of patients with SAH was detected. The results showed that TREM2 mainly located in the microglia and presented a markedly delayed elevation after SAH. TREM2 knockdown triggered increased pro-inflammatory productions, aggravated microglial activities, and further exacerbated neurological dysfunction after SAH. Significantly, TLR4 knockout increased the expression of TREM2, accompanied by ameliorated neuroinflammation and improved neurological function. Corresponding to different clinical Hunt–Hess grades, obviously enhanced accumulation of soluble TREM2 was detected in the CSF of patients with SAH. TREM2 played a pivotal role in mediating microglial polarization after SAH, and the neuroprotective effect of TREM2 might be potentially suppressed by the hyperactive TLR4 in the early phase of SAH. Pharmacological targeting of TREM2 may be a promising strategy for SAH therapy.

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SHED-Derived Exosomes Regulate Microglial Polarization in the Treatment of Traumatic Brain Injury in Rats via miR-330-5p

10.21203/rs.3.rs-65521/v1 ◽

2020 ◽

Author(s):

Ye Li ◽

Xinxin Wang ◽

Xiaoyu Cao ◽

Na Li ◽

Sun Meng ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Structural Damage ◽

Inhibitory Effect ◽

Deciduous Teeth ◽

Luciferase Reporter ◽

Enzyme Linked Immunosorbent Assay ◽

M2 Polarization ◽

M1 Polarization

Abstract Background: Traumatic brain injury (TBI) causes structural damage and impairs motor and cognitive function of the brain. Our previous study suggested that exosomes (EXs) secreted by stem cells from human exfoliated deciduous teeth (SHED) extenuated motor damage in TBI rats by regulating microglia. The molecular mechanism of SHED-EXs was investigated in the present study. Methods: The miRNA array was performed to determine the differential miRNA expression in SHED-EXs treating microglia. The key miRNA was selected. Flow cytometry, immunofluorescence, enzyme linked immunosorbent assay (ELISA) and Griess assay were performed to detect the function of key miRNA. Real-time PCR, Western blotting and dual luciferase reporter assay were used to confirm the relationship between key miRNA and the target gene. Chromatin immunoprecipitation (ChIP) was performed to determine the downstream pathway of EXs-miRNA. Traumatic brain injury rat model was established and local injection of EXs-miRNA was performed to evaluate the effect.Results: SHED-EXs delivery of miR-330-5p was the key in the regulation of microglia polarization by inhibiting M1 polarization and promoting M2 polarization. Mechanistically, miR-330-5p had an inhibitory effect on Ehmt2, and miR-330-5p/Ehmt2 promoted the transcription of CXCL14 through H3K9me2. In vivo data showed that SHED-EXs/miR-330-5p reduced neuro-inflammation and repaired neurological function of TBI rats. Conclusions: SHED-EXs/miR-330-5p improved the motor function of rats after TBI by inhibiting M1 polarization and promoting M2 polarization of microglia through Ehmt2/H3K9me2/CXCL14 pathway.

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L-Theanine Reduced the Development of Knee Osteoarthritis in Rats via Its Anti-Inflammation and Anti-Matrix Degradation Actions: In Vivo and In Vitro Study

Nutrients ◽

10.3390/nu12071988 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1988 ◽

Cited By ~ 1

Author(s):

Hui Bai ◽

Zhiheng Zhang ◽

Yue Li ◽

Xiaopeng Song ◽

Tianwen Ma ◽

...

Keyword(s):

Nitric Oxide ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Quantitative Polymerase Chain Reaction ◽

Hydrolytic Enzyme ◽

Enzyme Linked Immunosorbent Assay ◽

Matrix Degradation ◽

In Vivo Animal Model

The etiology of osteoarthritis (OA) is multifactorial, with no effective disease-modifying-drugs. L-theanine has been reported to inhibit inflammatory responses in some diseases and this study aimed to investigate the effect of L-theanine on Interleukin-1(IL-1)β-stimulated chondrocytes, and in an injury-induced OA rat model. Primary chondrocytes were stimulated by IL-1β (10 ng/mL) for 24 h and then co-cultured with L-theanine for 24 h. The effects of L-theanine on IL-1β-stimulated expression of pro-inflammatory cytokines and hydrolytic enzyme were analyzed using Western blotting, quantitative polymerase chain reaction (q-PCR) and enzyme-linked immunosorbent assay (ELISA) kits. An immunofluorescence assay was used to detect nuclear factor kappa B (NF-κB) phosphorylation. OA was induced by anterior cruciate ligament transection (ACLT) surgery in rats and celecoxib was used as a positive control. OA severity was measured using the Osteoarthritis Research Society International (OARSI) grading system to describe histological changes. The results showed that L-theanine decreased the expression of pro-inflammatory mediators, including cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE-2), inducible nitric oxide synthase (iNOS), and nitric oxide (NO), both in vivo and in vitro. L-theanine treatment inhibited IL-1β-induced upregulation of matrix metalloproteinases (MMP)-3 and MMP-13, as well as inhibited NF-κB p65 activation. In vivo animal model showed that L-theanine administration (200 mg/kg) significantly alleviated OA lesions and decreased OARSI score. Our data indicated that L-theanine decreased inflammatory cytokines and protected extracellular matrix degradation through inhibition of the NF-κB pathway, and L-theanine may be considered a promising therapeutic strategy in OA prevention.

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Cordycepin Improved Neuronal Synaptic Plasticity Through CREB-Induced NGF Up-Regulation Driven By Microglial M2 Polarization: A Symphony Communication Between Microglia and Neurons in AD

10.21203/rs.3.rs-184003/v1 ◽

2021 ◽

Author(s):

Linchi Jiao ◽

Mingyan Liu ◽

Xin Zhong ◽

Weifan Yao ◽

Guowei Ma ◽

...

Keyword(s):

Synaptic Plasticity ◽

Animal Behavior ◽

Cell Biology ◽

Neuronal Apoptosis ◽

Microglial Activation ◽

Neuroprotective Effect ◽

M2 Polarization ◽

Improved Learning

Abstract Background: The purpose of this study was to explore the molecular mechanism of the neuroprotective effect of Cordycepin (CCS) on improving the neuro-immune microenvironment of AD neurons by mediating microglial M2 polarization. Methods: We investigated microglial M2 polarization from M1, neuronal senescence, and synaptic plasticity by biological techniques such as animal behavior, cell biology, morphology, and bioinformatics. Results: CCS improved learning and memory impairment in 9-month-old APP/PS1 mice. CCS induced the microglial M2 polarization, up-regulated the expression and secretion level of NGF, and inhibited neuronal apoptosis, senescence, and synaptic damage caused by abnormal microglial activation in vivo and in vitro. CREB was activated by the M2 polarization and mediated the NGF expression and secretion after CCS treatment. CREB bound with the Sg3 promoter region of NGF (-1018~-1011), which increased NGF expression and secretion. CREB-induced NGF upregulation driven by microglial M2 polarization to improve the neuronal synaptic plasticity inhibits neuronal apoptosis and senescence. As a novel participant in the intercellular communication between MG and neurons, NGF contributed to the neuroprotective efficacy of CCS treatment. Conclusions: CCS improved the neuronal synaptic plasticity and senescence by promoting microglial M2 activation driven by CERB-induced NGF upregulation and conducted the symphony communication of MG-Neuron in AD.

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Astrocytes Stimulate Microglial Proliferation and M2 Polarization In Vitro through Crosstalk between Astrocytes and Microglia

International Journal of Molecular Sciences ◽

10.3390/ijms22168800 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8800

Author(s):

Sumin Kim ◽

Youngsook Son

Keyword(s):

Immune Functions ◽

Mixed Glial Culture ◽

Gm Csf ◽

Microglial Polarization ◽

Brain Functions ◽

M2 Polarization ◽

M2 Microglia ◽

Microglial Proliferation

Microglia are resident immune cells of the central nervous system that act as brain-specific macrophages and are also known to regulate the innate immune functions of astrocytes through secretory molecules. This communication plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia could crosstalk to induce microglial polarization and proliferation, which can be further regulated under a microenvironment mimicking that of brain stroke. Microglia in a mixed glial culture showed increased survival and proliferation and were altered to M2 microglia; CD11b−GFAP+ astrocytes resulted in an approximately tenfold increase in microglial cell proliferation after the reconstitution of astrocytes. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced them to become CCR7+ M1 microglia, which have a phenotype that could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and substance P. In addition, the astrocytes in the microglial co-culture showed an A2 phenotype; they could be activated to A1 astrocytes by TNF-α and IFN-γ under the stroke-mimicking condition. Altogether, astrocytes in the mixed glial culture stimulated the proliferation of the microglia and M2 polarization, possibly through the acquisition of the A2 phenotype; both could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimicking environment. This study demonstrated that microglia and astrocytes could be polarized to M2 microglia and A2 astrocytes, respectively, through crosstalk in vitro and provides a system with which to explore how microglia and astrocytes may behave in the inflammatory disease milieu after in vivo transplantation.

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Anti-Depressive Effectiveness of Baicalin In Vitro and In Vivo

Molecules ◽

10.3390/molecules24020326 ◽

2019 ◽

Vol 24 (2) ◽

pp. 326 ◽

Cited By ~ 13

Author(s):

Li Liu ◽

Yu Dong ◽

Xin Shan ◽

Lin Li ◽

Baomei Xia ◽

...

Keyword(s):

Cell Culture ◽

Pc12 Cells ◽

Culture Medium ◽

Enzyme Linked Immunosorbent Assay ◽

Mild Stress ◽

Cell Culture Medium ◽

Tnf Α ◽

Immobility Time

Baicalin (BA), a major polyphenol compound isolated from the extracts of Scutellaria radix, has been previously reported to ameliorate depressive-like behaviors in mice with chronic unpredictable mild stress (CUMS). However, its underlying antidepressant mechanisms remain unclear. This study was designed to confirm the antidepressant-like effects of BA on CUMS induced behavioral abnormalities in mice, and sought to explore the pharmacological mechanisms in vivo and in vitro. The CUMS procedure was carried out to induce depression in mice. Afterwards, the tail suspension test (TST), forced swim test (FST), and open field test (OFT) were performed within 24 h, then sucrose preference test (SPT) was conducted. Additionally, PC12 cells were pretreated with BA for 2 h, then further stimulated with corticosterone for 24 h. The levels of Interleukin-1β (IL-1β), IL-6 and Tumor Necrosis Factor-α (TNF-α) in serum, hippocampus homogenate and cell culture medium were determined using the enzyme-linked immunosorbent assay (ELISA) method. The protein expressions of inhibition of high mobility group box 1 protein (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathways in hippocampus and PC12 cells were detected. Our results showed that CUMS-treated mice presented notable depressive-like symptoms, such as decreased sucrose consumption, increased FST and TST immobility time. While BA (25, 50 mg/kg) significantly attenuated these changes. Besides, BA treatment considerably inhibited inflammatory cytokinesl (IL-1β, IL-6, TNF-α) levels in serum, hippocampus homogenate and cell culture medium. Western blot analysis indicated that BA inhibited the expressions of HMGB1, TLR4, and p-NF-κBp65 both in vivo and in vitro. In conclusion, the present study confirmed that BA possessed efficient antidepressant effects on depression, which was possibly related to the inhibition of HMGB1/TLR4/NF-κB pathways.

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MiR-203-3p inhibits the oxidative stress, inflammatory responses and apoptosis of mice podocytes induced by high glucose through regulating Sema3A expression

Open Life Sciences ◽

10.1515/biol-2020-0088 ◽

2020 ◽

Vol 15 (1) ◽

pp. 939-950

Author(s):

Jingfu Chen ◽

Qing Xu ◽

Wei Zhang ◽

YuLan Zhen ◽

Fei Cheng ◽

...

Keyword(s):

Oxidative Stress ◽

Inflammatory Cytokines ◽

High Glucose ◽

Renal Injury ◽

Inflammatory Responses ◽

Cell Model ◽

The Body ◽

Enzyme Linked Immunosorbent Assay ◽

Podocyte Injury

AbstractDiabetic nephropathy (DN) is the most serious long-term microvascular complication of diabetes, which mainly causes podocyte injury. Many studies have shown that microRNAs play a vital role in the development of DN. Studies have shown that miR-203-3p is involved in mesangial cell proliferation and apoptosis of DN mice. Therefore, we speculated that miR-203-3p might be related to the development of DN, but our study does not provide any evidence. In animal experiments, diabetic mice (db/db) were transfected with iR-203-3p overexpression lentiviral vectors (LV-miR-203-3p) and their control (LV-miR-con), with normal mice (db/m) being used as the control. High glucose (HG)-induced podocytes were used to construct a DN cell model in vitro. The expression levels of miR-203-3p, Semaphorin 3A (Sema3A) and inflammatory cytokines were detected by quantitative real-time polymerase chain reaction. Also, serum creatinine and blood urea nitrogen levels were used to evaluate the degree of renal injury in DN mice. Sema3A and apoptosis-related protein levels were assessed by the western blot analysis. Enzyme-linked immunosorbent assay was used to determine the different oxidative stress-related indicators and inflammatory cytokines. Flow cytometry and caspase-3 activity detection were used to analyze the degree of podocyte apoptosis. Our results suggested that the expression of miR-203-3p was lower in DN mice and in HG-induced podocytes. Overexpression of miR-203-3p reduced the body weight, blood glucose and renal injury of DN mice in vivo, as well as relieve the oxidative stress, inflammatory response and apoptosis of HG-induced podocytes in vitro. Functionally, Sema3A was a target of miR-203-3p, and Sema3A overexpression reversed the inhibitory effect of miR-203-3p on HG-induced podocyte injury. Our findings revealed that miR-203-3p alleviated the podocyte injury induced by HG via regulating Sema3A expression, suggesting that miR-203-3p might be a new therapeutic target to improve the progression of DN.

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LncRNA HOXA-AS2 regulates microglial polarization via recruitment of PRC2 and epigenetic modification of PGC-1α expression

Journal of Neuroinflammation ◽

10.1186/s12974-021-02267-z ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Xiaodong Yang ◽

Yi Zhang ◽

Yimeng Chen ◽

Xiaoqin He ◽

Yiwei Qian ◽

...

Keyword(s):

Mononuclear Cells ◽

Epigenetic Modification ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peripheral Blood Mononuclear ◽

Microglial Polarization ◽

M2 Polarization ◽

Anti Inflammatory

Abstract Background Microglia-mediated neuroinflammation plays an important role in Parkinson’s disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype. Hence, promoting microglia toward the anti-inflammatory M2 phenotype is a potential therapeutic approach for PD. Long noncoding RNAs (lncRNAs) are crucial in the progression of neurodegenerative diseases, but little is known about their role in microglial polarization in PD. Methods In our study, we profiled the expression of lncRNAs in the peripheral blood mononuclear cells (PBMCs) of PD patients using a microarray. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers both in vitro and in vivo. RIP and ChIP assays were analyzed for the underlying mechanism of lncRNA regulating microglial polarization. Results We found that HOXA-AS2 was upregulated in the PBMCs of PD patients and negatively associated with peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α) expression. Moreover, HOXA-AS2 knockdown significantly repressed microglial M1 polarization and promoted M2 polarization by regulating PGC-1α expression. Mechanistic investigations demonstrated that HOXA-AS2 could directly interact with polycomb repressive complex 2 (PRC2) and modulate the histone methylation of the promoter of PGC-1α. Conclusions Our findings identify the upregulated lncRNA HOXA-AS2 promotes neuroinflammation by regulating microglial polarization through interacts with the PRC2 complex and epigenetically silencing PGC-1α. HOXA-AS2 may be a potential therapeutic target for microglia-mediated neuroinflammation in patients with PD.

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In vitro and in vivo anti-inflammatory properties of Mayan propolis

European Journal of Inflammation ◽

10.1177/2058739220935280 ◽

2020 ◽

Vol 18 ◽

pp. 205873922093528

Author(s):

Jorge Xool-Tamayo ◽

Ivan Chan-Zapata ◽

Víctor Ermilo Arana-Argaez ◽

Fabiola Villa-de la Torre ◽

Julio César Torres-Romero ◽

...

Keyword(s):

Inflammatory Cytokines ◽

High Performance ◽

Enzyme Linked Immunosorbent Assay ◽

Thiazolyl Blue Tetrazolium Bromide ◽

Tnf Α ◽

Anti Inflammatory ◽

Main Components ◽

Macrophage Viability

Introduction Propolis has been used traditionally for different human diseases and even recently as dental biomaterials because of its antibacterial, antimycotic, and anti-inflammatory properties. However, a proper correlation between in vitro and in vivo anti-inflammatory properties has not been clearly established. Methods The composition of propolis was determined by high-performance liquid chromatography–ultraviolet mass spectrometry (HPLC-UV-MS). Viability of ethanolic propolis solution was evaluated by thiazolyl blue tetrazolium bromide (MTT) assay on murine macrophages. The anti-inflammatory properties were assessed both in vitro through the enzyme-linked immunosorbent assay (ELISA) quantification of various cytokines and in vivo by induced edemas. Results Chemical analysis showed pinocembrin, pinobanksin-3-O-acetate, and pinobanksin-3-O-propionate as the main components of propolis. Macrophage viability was high (106%) when propolis was used up to 50 µg/mL. ELISA studies showed a reduction in the expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) up to 145 pg/mL, 350 pg/mL, and 210 pg/mL, respectively, while the anti-inflammatory cytokines (IL-10 and IL-4) were increased up to 833 pg/mL and 446 pg/mL. Finally, edema was reduced on paw and ear mice by 9% and 22%, respectively. Conclusion Mayan propolis has strong in vitro anti-inflammatory properties without compromising macrophage viability, resulting in a low-to-mild in vivo anti-inflammatory response.

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